tag:blogger.com,1999:blog-10135521210366605242024-03-18T15:37:55.676-07:00The Quest for Height: Grow Taller | Increase Height | Bone SizeGrowing Taller: How Mesenchymal Stem Cells, Microfractures, Hydrostatic Pressure, and Periosteum makes increasing height possibleTyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.comBlogger692125tag:blogger.com,1999:blog-1013552121036660524.post-44972859686169447702013-12-20T12:59:00.031-08:002023-04-30T19:01:39.114-07:00Case(s) of adult bone length growthIt has been shown that <a href="http://www.heightquest.com/2011/10/why-dont-people-with-osteoarhritis-grow.html">there is endochondral ossification involved in both osteoarthritis and that occurs in normal aging</a>. Why doesn't this articular cartilage ossification result in height increase? Maybe enhancing this process of the articular cartilage can result in height increase of course you'd have to find a way preserve the articular cartilage from fully ossifying to maintain joint integrity.<br />
<br />
The following studies serve as a bit of a proof of concept for adult bone length increase by showing that the two most distal of the three finger bones can increase in length with age and that the skull bone can increase in length.<br />
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Here are some selections from a statement by Roy Wuthier, a retired scientist in regards to non-growth plate methods of bone growth:<br />
<br />
"<b>Not all bone growth occurs via growth plate-dependent mechanisms.</b> The growth of phalanx bone apparently is not totally dependent on growth plate elongation. As you realize, appositional growth can be mediated via osteoblasts that reside under the periosteal membrane. Thus in phalanx bones, both types of bone growth must contribute to their expansion during overall skeletal growth."<-so perhaps on the proximal end of the phalanx bone there may be a periosteal membrane despite being separated by articular cartilage.<br />
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"During typical long bone growth (elongation), you will note that the ends of the long bones (where the growth plates reside) have a larger cross-sectional area than occurs at the mid-shaft. The cells that sculpt the shape of the long bones are the osteoclasts which have the ability to remove bone. In fact in a genetic disease where osteoclast formation is suppressed, the shape of the long bones is almost "post-like" with no reduction in mid-shaft cross-sectional area."<-Perhaps the larger cross-sectional area of the epiphysis formed by growth plate growth facilitates osteoclast absorption. Thus, osteoclasts may be able to remove bone that is generated by endochondral ossification at a fast enough rate such that there is no net bone length increase. And, in ends of the bones not formed by growth plates don't have as large a cross-sectional area favoring absorption thus apposition at the ends of the bones is greater than osteoclast resorption.<br />
<br />
A way to test this is with osteoclast inhibitors however articular cartilage endochondral ossification is slow and osteoclasts are needed for many functions. You could elevate HGH levels which increases both bone formation and resorption thus allowing you to safely lower osteoclast levels. HGH would also increase the rate of the growth so it could occur in a reasonable time frame. And then see if articular cartilage endochondral ossification could make you taller.<br />
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<b>Metacarpophalangeal length changes in humans during adulthood: A longitudinal study</b><br />
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Metacarpophalangeal refers to hand bones essentially.<br />
<br />
"Total lengths of the 19 diaphyseal hand bones were measured from standardized radiographs of healthy American whites as young adults (ca. 21 years) and again at ca. 55 years of age. <b>The four hand-bone rows exhibit distinctive length changes: Distal and middle phalanges continue to increase significantly in length{the distal phalange may have periosteum at the distal end of the bone so it may be able to grow by appositional growth but that is not true of of the middle phalange}</b>, proximal phalanges constitute a transition zone of little change, and metacarpals uniformly decrease in length[there are three bones in a non thumb finger. The end bone is the distal bone and the one closest to the the end is the proximal phalange. The metacarpals are part of the hand.]. Clear-cut sex differences are noteworthy: Males change more (lose more in some bone rows, gain more in others) than females. <b><u>Progressive elongation was greatest in the distal phalanges where apposition around the distal aspect (“tufting”) is not constrained by a joint or epiphysis</u>.</b> Loss of bone length in the metacarpals by subchondral resorption is consistent with documented reductions in activity levels and grip strength with age, as well as diminished joint spaces which alter loading of the joints."<br />
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The increase in bone length was about 0.34 mm per decade.<br />
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"To test for [the possibility that the bone length gain was due to residual gain due to growth plate growth], we partitioned the sample into those cases whose younger-adult age at examination was less than 25 years and those with a radiograph after 25 years of age. Using a two-way factorial analysis of variance, grouping by age grade and sex, none of the 19 tests achieved statistical significance. "<br />
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"<b>In the distal and middle phalanges most of the increase was accounted for by progressive apposition at the distal, epiphysis-free ends of the bones</b>"<br />
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If you look at the phalanx x-rays you can see that distal ends of the bones do not have a growth plate.<br />
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<a href="http://4.bp.blogspot.com/-WC4qImc85bE/UKAbw2PR4eI/AAAAAAAAAj4/wCsDCThJe0c/s1600/hand+growth+plates.gif" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="320" src="https://4.bp.blogspot.com/-WC4qImc85bE/UKAbw2PR4eI/AAAAAAAAAj4/wCsDCThJe0c/s320/hand+growth+plates.gif" width="228" /></a></div>
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Only the proximal(closest to the body) side has growth plates. Maybe bone growth can be renewed if you remove the epiphysis somehow. LSJL via fluid based shear strain may degrade some of the epiphysis allowing for new height growth.<br />
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"the distal phalanges, which exhibit appreciable increase, are unique in not being constrained distally by a joint or epiphysis"<br />
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"<b>When cartilage thickness exceeds the critical dimensions that limit nutrition by diffusion, the cartilage cells hypertrophy and degenerate, the spaces become vascularized, and osteoblasts develop to initiate endochondral bone formation in the midst of the articular cartilage</b>."<div><br /></div><div><b>Age Changes in the External Dimensions of Adult Bone<br /></b><div><br /></div><div>"Humeri from a large, ossuary-derived sample are used to demonstrate that considerable size variability is introduced to transverse skeletal measurements when young adults and older adults are pooled. Humeri from young adults (epiphyseal lines still visible, N = 25) are smaller in transverse</div><div>dimensions than those of older adults (N = 300). Among left humeri, only shaft diameters demonstrate statistically significant differences. The right humeri, however, show statistically significant differences for six of the eight measurements. The increased size of the older adult humeri reflects the fact that appositional growth continues throughout adulthood. The more pronounced differences seen on the right side probably reflect developing dominance asymmetry.</div><div><br /></div><div>Recognition of this source of intrasample variability will influence the choice of skeletal measurements used for population comparisons and/or indicators of robusticity."</div><div><br /></div><div><div>"<b>Differences in right lengths are not statistically significant, but they are great enough to arouse</b></div><div><b>curiosity</b>. Left side lengths show virtual identity. Indeed, total length among young adults is 0.5 mm greater than that among older adults."</div></div><div><br /></div><div>"subperiosteal surface apposition continues lifelong or at least through the tenth decade"</div><div><br /></div><div>"<b>The increases in total length and physiological length may also be tied to the continuing appositional process. Appositional increase at the articular surfaces has been cited as a possible explanation for the slight increase in total body height seen up to ages 25-30</b>."<-I think the increase in this study is too large to be due to appositional growth.</div><div><br /></div><div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/a/AVvXsEikKDK8ERbJlz6dKf0hCPE0v1yllzX36iztCQR20Fmj0mrxubH-4xHvV3szAqLOl-OPLOcdEZLaP8t_r6swLQsS7PHNUmJ4Ofjvyn_-b2IjFY6ZQqj05AvokvXvFwRGeRQogxOmbdgyIZxhNSY_YjJSiOvFgFg_faAvWAoFLHJ9gdGs-CKFAx8O3Q6p" style="margin-left: 1em; margin-right: 1em;"><img alt="" data-original-height="912" data-original-width="1076" height="240" src="https://blogger.googleusercontent.com/img/a/AVvXsEikKDK8ERbJlz6dKf0hCPE0v1yllzX36iztCQR20Fmj0mrxubH-4xHvV3szAqLOl-OPLOcdEZLaP8t_r6swLQsS7PHNUmJ4Ofjvyn_-b2IjFY6ZQqj05AvokvXvFwRGeRQogxOmbdgyIZxhNSY_YjJSiOvFgFg_faAvWAoFLHJ9gdGs-CKFAx8O3Q6p" width="283" /></a></div><div class="separator" style="clear: both; text-align: left;">The increase in right humeral length is huge. Much more than can be accounted for by appositional growth. Since left did not increase it furthers the likelihood of a mechanical loading driven mechanism.</div><div><br /></div>"<b>persistent physical activity stimulates bone growth in length.</b> Among subjects who had, for occupational reasons, vigorously exercised the dominant limb (i.e., tennis players) that limb was found to be longer than the nondominant limb. Assuming that the Kleinburg people were, indeed, right handed, one can conclude that response to activity has stimulated a differential increase in length and breadth on the dominant side."</div><div><br /></div><div>This study echoes that bilateral asymmetry is contributed to by mechanical loading:</div><div><b><br /></b></div><div><b>Bilateral asymmetry of the humerus during growth and development</b></div><b><br /></b><div>"<span style="background-color: white; color: #212121; font-family: BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif; font-size: 16px;">A large skeletal sample of nonadults from English archaeological sites was examined using standard metric techniques to assess when right-sided asymmetry first appears in the human skeleton. Results of this work indicate a change in directional asymmetry during growth and development, with infants and young children exhibiting no significant asymmetry and older children and adolescents demonstrating right-sidedness. This trend is consistent with what has been observed in previous studies of upper limb asymmetry in skeletal material and behaviorally in living children, adding further strength to the premise that <b>biomechanical forces strongly influence bilateral asymmetry in the upper limb bones</b>. Variability in the magnitude of asymmetry between different features of the humerus was also noted. This characteristic can be explained by differing degrees of genetic canalization, with length and articular dimensions being more strongly canalized than diaphyseal properties."</span></div><div><span style="background-color: white; color: #212121; font-family: BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif; font-size: 16px;"><br /></span></div>"This could include a process, such as a left-right difference in blood oxygen level, which would potentially lead to unequal bone growth"<br /><b>The aging craniofacial complex: a longitudinal cephalometric study from late adolescence to late adulthood<br /></b><div><br /></div>"This was a recall study with 39 subjects (19 male, 20 female). Their lateral cephalograms taken during late adolescence (T1; mean age, about 17 years), midadulthood (T2; mean age, about 47 years), and late adulthood (T3; mean age, about 57 years) were evaluated. To test for significant differences between times, sexes, and the sex and time interaction, repeated measures analysis of variance was used. For the comparisons of time (T1 vs T2, T2 vs T3), the nominal alpha level was set at 0.01.<br /><br />Skeletal changes were significant only from late adolescence to midadulthood; soft-tissue changes were significant from late adolescence to midadulthood, and mid- to late adulthood. Changes in skeletal tissues consisted of increases in sella-nasion length, midfacial length, and lower anterior facial height. Sex differences were apparent in the mandible. The women had downward and backward mandibular rotation; the men, on the other hand, had more forward rotation of the mandible and increased chin prominence. Mandibular growth was greater in the men. Changes in the soft tissues were the most remarkable and included significant thinning and elongation of the upper lip. Significant changes in the nose took place, including drooping of the nasal tip and columella, the latter leading to more acute nasolabial angles."<br /><br />"The early examinations took place when the subjects were between 17 and 19 years of age. The later examinations occurred from 65 to 83 years, with an age range of 25 to 83 years at the final records"</div><div><br /></div><div><b>"this investigation provided further evidence for the continuation of changes in the craniofacial complex with age, and it did not corroborate the
hypothesis that growth stops soon after puberty"</b></div><div><b><br /></b></div><div><b>"</b>Statistically significant changes occurred from late
adolescence to midadulthood and from mid- to late
adulthood. <b>Changes in the skeletal tissues consisted of
increases in sella-nasion length, midfacial length, and
lower anterior facial height"</b></div><div><br /></div><div>"<b>From late adolescence
through late adulthood, skeletal changes included on
average a 2-mm increase in maxillary length, about a
3-mm increase in mandibular length, and about a
3.5-mm increase in lower anterior facial height."</b></div><div><b><br /></b></div><div><b>"</b>increase in anterior cranial
base length in their adult growth study"</div><div><br /></div><div>"<b>Small
increases were noted in the men from mid- to late
adulthood, and these changes were not statistically
significant. Similar findings of increases in mandibular length after adolescence were noted in previous
studies."</b></div><div><b><br /></b></div><div>The papers being <b>Facial and dental changes in
adulthood., Changes in the craniofacial complex
from adolescence to adulthood: a cephalometric study</b>, and . <b>Recent knowledge concerning craniofacial aging</b></div><div><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhh2LNC5BI507VcaRcsczoV6X6SvFtZHmgMa6_HLaN2fraBV9gMZVORacYL6dfinlEdgW-wQ45zwv4zDuAf-HmBqZUXVDDfoYV2fgUMyofsikf77xXAMtlohf5PztTl84JOFb_mGdLW0LG95v7t_bXI6yCwX4upXNosJEYEXs_rVQEbyKtRXewW97XB/s1519/cranofacial%20growth%20with%20aging.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="930" data-original-width="1519" height="196" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhh2LNC5BI507VcaRcsczoV6X6SvFtZHmgMa6_HLaN2fraBV9gMZVORacYL6dfinlEdgW-wQ45zwv4zDuAf-HmBqZUXVDDfoYV2fgUMyofsikf77xXAMtlohf5PztTl84JOFb_mGdLW0LG95v7t_bXI6yCwX4upXNosJEYEXs_rVQEbyKtRXewW97XB/s320/cranofacial%20growth%20with%20aging.png" width="320" /></a></div><div class="separator" style="clear: both; text-align: left;">You can see that T2 and T3 is well past skeletal maturity</div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiKBD0Di_EynjXNVqjkhYS5cyvKRKlsef9X5ENGxbYlQTwDb1XU0aQSaGYkakBllDOFwtRb1GYgcXhBHW5Bd3VooeOndAi5PCv0pWqu5Ajmcntey6QtwUTYWeW-K9ATD97XZprtbim45Z4hAuHLI-65ytSodxpfgpce_2FA9OxdwHmsh9UgGFhmvStJ/s800/age%20in%20years.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="211" data-original-width="800" height="84" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiKBD0Di_EynjXNVqjkhYS5cyvKRKlsef9X5ENGxbYlQTwDb1XU0aQSaGYkakBllDOFwtRb1GYgcXhBHW5Bd3VooeOndAi5PCv0pWqu5Ajmcntey6QtwUTYWeW-K9ATD97XZprtbim45Z4hAuHLI-65ytSodxpfgpce_2FA9OxdwHmsh9UgGFhmvStJ/s320/age%20in%20years.png" width="320" /></a></div><br /><div class="separator" style="clear: both; text-align: left;"><br /></div><br /><div><br /><div><b>Dynamic loading stimulates mandibular condyle remodeling</b></div><div><b><br /></b></div><div>"We and others have reported that low-magnitude high-frequency dynamic loading has an osteogenic effect on alveolar bone. Since chondrocytes and osteoblasts originate from the same progenitor cells, we reasoned that dynamic loading may stimulate a similar response in chondrocytes. A stimulating effect could be beneficial for patients with damaged condylar cartilage or mandibular deficiency.<br />Studies were conducted on growing Sprague-Dawley rats divided into three groups: control, static load, and dynamic load. <b>The dynamic load group received a dynamic load on the lower right molars 5 minutes per day with a 0.3 g acceleration and peak strain of 30 με registered by accelerometer and strain gauge</b>. The static load group received an equivalent magnitude of static force (30 με). The control group did not receive any treatment. Samples were collected at days 0, 28, and 56 for reverse transcriptase polymerase chain reaction analysis, microcomputed tomography, and histology and fluorescent microscopy analysis.<br /> Our experiments showed that dynamic loading had a striking effect on condylar cartilage, increasing the proliferation and differentiation of mesenchymal cells into chondrocytes, and promoting chondrocyte maturation. This effect was <b><u>accompanied by increased endochondral bone formation resulting in lengthening of the condylar process.</u></b><br />Low-magnitude, high-frequency dynamic loading can have a positive effect on condylar cartilage and endochondral bone formation in vivo. This effect has the potential to be used as a treatment for regenerating condylar cartilage and to enhance the effect of orthopedic appliances on mandibular growth."<br /><div><span style="color: #505050; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif;"><b>A longitudinal study of arch size and form in untreated adults</b></span></div><div><span style="color: #505050; font-family: NexusSerif, Georgia, Times New Roman, Times, STIXGeneral, Cambria Math, Lucida Sans Unicode, Microsoft Sans Serif, Segoe UI Symbol, Arial Unicode MS, serif;"><b><br /></b></span></div><div><span style="font-family: inherit;"><span style="color: #505050;"><b>"</b></span><span style="color: #2e2e2e;"><b>Adulthood—the lengthy phase following attainment of biologic maturity—often is perceived as a period of “no change” or one of slow deterioration. Recent skeletodental studies discount this stereotype.</b> Changes in arch size and shape were studied here in a longitudinal series of 60 adults with intact dentitions. Full-mouth study models were taken at about 20 years of age and again at about 55 years. Some variables—particularly those between arches (incisor overbite and overjet, molar relationship) and mandibular intercanine width—remained age-invariant. In contrast, all other measures of arch width and length changed significantly (</span><em style="box-sizing: border-box; color: #2e2e2e; margin: 0px; padding: 0px; scroll-behavior: auto;">P</em><span style="color: #2e2e2e;"><0.01):<b> Arch widths increased over time, especially in the distal segments, whereas arch lengths decreased. These changes significantly altered arch shape toward shorter-broader arches. The data suggest that changes during adulthood occur most rapidly during the second and third decades of life, but do not stop thereafter.</b> Possible mechanisms driving these changes in tooth position are discussed."</span></span></div><div><span style="font-family: inherit;"><span style="color: #2e2e2e;"><br /></span></span></div><div><span style="font-family: inherit;"><span style="color: #2e2e2e;">"</span></span>Dental casts were taken on 60 older adults"</div><div><br /></div><div>Figure 2 shows arch width and length.</div><div><div><div class="Banner" id="banner" style="box-sizing: border-box; color: #2e2e2e; font-family: NexusSans, Arial, Helvetica, "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", STIXGeneral, "Cambria Math", "Arial Unicode MS", sans-serif; margin: 0px 0px 8px; padding: 0px; scroll-behavior: auto;"><div class="wrapper truncated" style="box-sizing: border-box; margin: 0px; padding: 0px; scroll-behavior: auto;"><div class="AuthorGroups text-xs" style="box-sizing: border-box; line-height: 1.57; margin: 0px; padding: 0px; scroll-behavior: auto;"><div class="author-group" id="author-group" style="box-sizing: border-box; margin: 0px; padding: 0px; scroll-behavior: auto;"></div></div></div></div>
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<b>Continuing bone growth throughout life: A general phenomenon</b><br />
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"Cross-sectional data on 2799 subjects from five different populations and longitudinal data on 113 older adults indicate continuing adult bone growth in the second metacarpal. Similar <b>6-decade increases in the size of the cranium confirm continuing bone growth</b> as a general phenomenon not necesarily related to weightbearing or flexion stress and representing an increase of approximately 10% in skeletal volume concomitant with the major age-associated decrease in skeletal mass."<br />
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"there is a small but completely systematic three-decade gain in metacarpal width at mid-shaft in both sexes and all five populations sampled"<br />
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The scientists reported an increase in skull length.<br /><br />
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<b><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5322859/">Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis.</a></b></div>
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<a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998000/">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3998000/</a></div>
"Modeling-based bone formation contributes to the periosteal expansion, just as remodeling-based resorption is responsible for the medullary expansion seen at the long bones with aging."<-Can we translate this into height?<br />
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<div>
"Odanacatib inhibits bone resorption by inhibiting cathepsin K activity, whereas modeling-based bone formation is stimulated at periosteal surfaces. Inhibition of sclerostin stimulates bone formation and histomorphometric analysis demonstrated that bone formation is predominantly modeling based."</div>
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<br /></div>
<div>
"<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">Strain alone can induce a significant increase in bone morphogenetic protein 2 (BMP2) mRNA levels in human BM-MSPCs without any addition of osteogenic supplements"</span></div>
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<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><br /></span></div>
<div>
<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">"<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">Excessive strain causes regional microdamage, which leads to targeted remodeling removing the damaged bone and a larger volume of the surrounding undamaged bone, this temporary volume deficit increases the strain in neighboring bone and the potential establishment of a vicious cycle between damage and repair"</span></span></div>
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<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><br /></span></span></div>
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<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">"<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">Bone modeling has been demonstrated in aging humans. Modeling-based bone formation contributes to the periosteal expansion, just as remodeling-based resorption is responsible for the medullary expansion seen at long bones and ribs with aging"</span></span></span></div>
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<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><br /></span></span></span></div>
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<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">"<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">Osteocytes are terminally differentiated osteoblasts which become embedded in newly formed bone matrix and produce sclerostin. Sclerostin binds to lipoprotein-related peptide (LRP) 5/6 and thereby inhibits LRP5/6 from binding to the frizzled receptor and activating the Wnt pathway"</span></span></span></span></div>
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<b><a href="http://www.turkishneurosurgery.org.tr/pdf/pdf_JTN_922.pdf">Extreme elongation of the transverse processes of the fifth lumbar vertebra: an unusual variant.</a></b><br />
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"The fifth lumbar vertebra has massive transverse processes that are continuous with the pedicle and encroach the body of the vertebra. These processes are mainly meant for the attachment of the iliolumbar ligament. With increasing age, the iliolumbar ligament can undergo secondary degenerative changes such as calcification, hyalinization, and myxoid degeneration. [We discovered an] extremely elongated transverse processes of the fifth lumbar vertebra in a 45-year-old woman who underwent surgery for an intervertebral disc herniation. T<b>his unusual variant may be caused by calcification of the iliolumbar ligament rather than a congenital anomaly</b>."</div>
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Causing calcification of ligaments isn't really reproducible but it's still bone length increase in a 45 year old.</div>
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If you look figure 1A and 1B you can see that the increase in transverse process is insane with the elongated transverse process being about 3 times longer than the other bones.</div>
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"[There was] a calcified nodular lesion in the left pelvic cavity, suggesting the presence of a calcified uterine myoma[mesenchymal tumor]."</div>
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"the trabecular bone of the transverse processes have normal shape and length, and the compact bone is elongated."</div>
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"[There was] a large, extruded intervertebral disc on the right side, compressing the dural sac."</div>
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"the direction of elongation of the transverse process corresponded to the position of the iliolumbar ligament." Thus providing evidence that the iliolumbar ligament was calcified.</div>
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"The iliolumbar ligament is attached to the tip and the anteroinferior aspect of the transverse processes of the fifth lumbar vertebra"<-So the ligament may have been used as a scaffold to grow the bone longer. Maybe a ligament can be inserted into a long bone so you can grow taller forever.</div>
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"the iliolumbar ligament does not exist at birth, but develops gradually in the first decade and attains full differentiation only in the second decade."<br />
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<b>Mechanical strain leads to condylar growth in adult rats.</b><br />
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"Mechanical strain produced by forward mandibular positioning was found to enhance mandibular condylar growth in experimental animals and in patients. [We] identify the changes in number and rate of the proliferating mesenchymal cells in mandibular condyles of adult rats and to correlate these changes to the expression of SOX9 and type II collagen under mechanical strain. <b>Seventy-eight 120-day-old female Sprague-Dawley rats{rats generally stop growing at six months} were randomly allotted to six groups, nine animals in each experimental group according to different time points</b>. Cell kinetic studies for expression of PCNA were used to identify number and rate of proliferating mesenchymal cells. Immunostaining of SOX9 and in situ hybridization of Col2a1 gene were carried out. Results showed a significant increase in number of replicating mesenchymal cells and proliferation rate. <b>The expression of SOX9 was enhanced and Col2a1 gene transcript was then activated. The proliferative layer became thicker on experimental day 21. The thickness of chondroblast layer and chondrocyte layer showed significant increase from experimental day 14 to day 30</b>.<b> Mechanical strain produced by mandibular advancement in adult rats promotes the proliferation of mesenchymal cells. Under control of transcription factor SOX9, these mesenchymal cells are then committed to enter the chondrogenic route leading to condylar growth.</b>"</div>
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Producing proliferating of MSCs which then differentiate into chondrocytes via SOX9 is exactly what we're trying to accomplish with LSJL.<br />
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"<b>mandibular advancement reactivates endochondral ossification in the posterior condyle and ultimately results in new bone formation in the condyle</b>"</div>
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"In the adult patients treated with Herbst appliance this would be the result of a reactivation of cells of prechondroblast zone, thus representing an area of active condylar growth"</div>
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"continuous bite jumping devices induce morphological adaptation in the mandible especially the length of condylar head in adult rats"</div>
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"During mandibular growth, the condyle undergoes endochondral ossification and the condylar cartilage acts as a template for bone growth. However, in the adults, the remnant condylar cartilage serves more 'articular' function than 'growth' function. From growing to adults, the thickness of cartilage becomes thinner. It has been reported that t<b>he adult rat's condyle is covered by a thin layer of cartilage, which is composed of 2-3 layers of chondrocytes </b>and there is no obvious hypertrophic layer in the cartilage since a weak staining of Type X collagen, the marker of endochondral ossification, was obscured. This result implies that adult rat condyle stops growth or becomes inactive of endochondral ossification. Bone growth in the condyle is closely related to cartilage formation in the growing rats"</div>
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"The fibrous zone of the condylar cartilage of adult rats is composed of several layers of flattened cells . The cells in the proliferative layer, which was densely packed, located beneath the fibrous layer . Underneath the proliferative layer, the cells became chondrospecific and flattened gradually. The extracellular matrix was positively stained with type II collagen and thus this layer was termed as "type II collagen positive layer" in the present stud which may represent the level of expression of type II collagen. The current study showed that the thickness of cartilage in posterior condyle was apparently affected by the bite-jumping device. Analysis showed the thickness of each layer of cartilage in controls was unchanged during the observation period. In the experimental group, there were significant changes observed in all the layers. The thickness of fibrous layer showed significant increase from day 14 of mandibular advancement and was maintained from day 30 to day 60 Mandibular advancement resulted in an increase in the thickness of the proliferative layer on day 21 which was then followed by a decrease to the level found in the matched controls. The thickness of type II collagen positive layer showed a significant increase from experimental day 14. The highest level was presented on experimental day 21 followed by a lower level on day 30. The level of expression of type II collagen expressed on day 60 returned to the level expressed in the controls."</div>
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"The population [of MSCs] in that of mandibular advancement groups was significantly increased on day 21" No differences were observed in the control group.</div>
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"In the control groups, only a few SOX9 positive cells existed in the proliferative layer. On experimental day 3, SOX9 positive cells were remarkably increased in the proliferative layer of experimental animals. On experimental day 21, the SOX9 positive cells were increased in both proliferative layer and chondroblast layer but no positive staining can be detected in the hypertrophic chondrocyte"</div>
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"mandibular advancement in adult rats resulted in increase in condylar growth as measured by a significant increase in: the number and rate of replicating mesenchymal cells; the expression of transcription factor SOX9, the factor that regulates mesenchymal cell differentiation into chondroblasts; the thickness of cartilage layers and finally increase in the amount of osteocytes that led to increase in the production of new bone in the adult condyles "</div>
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a forward biting jump appliance is only similar to LSJL if the joint loading done by LSJL is similar to the pull by that of the lateral pterygoid muscle.<br />
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"[The] significant increase in SOX9 expression level coincided with the rate of proliferation of mesenchymal cells"</div>
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It should be noted that the population of MSCs began to decline after thirty days. That may be related to an adaptative response and indicates that there may need to be a deconditioning period with LSJL after 30 days.</div>
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" Each group consisted of nine rats with bite-jumping appliances and four untreated controls"</div>
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On this page is an example of a <a href="http://insigniaortho.com/index/aoalab-products-herbst">bite jumping appliance</a>(It's the Herbst) mentioned earlier.</div>
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Here's the picture of experimental jaw versus control:</div>
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<a href="http://3.bp.blogspot.com/-NbtC7UlslBo/UNDXADzYseI/AAAAAAAAAqI/MY0GCmIJ0Dc/s1600/mandibularadvancement+control+v+experimental.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="320" src="https://3.bp.blogspot.com/-NbtC7UlslBo/UNDXADzYseI/AAAAAAAAAqI/MY0GCmIJ0Dc/s320/mandibularadvancement+control+v+experimental.jpg" width="215" /></a></div>
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I'm planning on looking for ectopic signs of cartilage formation later as that is what we're trying to induce with LSJL. However there is some blue staining(which means it's positive for cartilage) on A but it is very faint. Note though that the entire shape of B(experimental) is different than A(control) so there must be some mechanism to achieve that.<br />
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"Alcian blue-PAS staining showing the overview of rat's TMJ condyle at age of 141-day (experimental day 21). The thickness of cartilage in the posterior condyle is remarkably increased by mandibular advancement (B) than that of control (A). Two measurement frames are illustrated on (B), one for the measurement of thickness of layers (1104×811µm, black) and the other frame for the cell counting (547×402µm, red)."<br />
Here's the ectopic chondrogenesis highlighted with GIMP(blue line):<br />
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<a href="http://2.bp.blogspot.com/-082db9ldG0I/UNNMSsB-wUI/AAAAAAAAAqk/JZq2KLn51-c/s1600/ectopiccartilageformation.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="320" src="https://2.bp.blogspot.com/-082db9ldG0I/UNNMSsB-wUI/AAAAAAAAAqk/JZq2KLn51-c/s320/ectopiccartilageformation.jpg" width="215" /></a></div>
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Here's the Col2a1 expression areas:<br />
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<a href="http://2.bp.blogspot.com/-aXgJLIksQos/UNNMonK_rVI/AAAAAAAAAqs/B94egUY5IkA/s1600/Sox9expression.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="236" src="https://2.bp.blogspot.com/-aXgJLIksQos/UNNMonK_rVI/AAAAAAAAAqs/B94egUY5IkA/s320/Sox9expression.jpg" width="320" /></a></div>
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"In situ hybridization showing the localization of type II collagen (Col2a1) mRNA (marked with arrow) in the condylar cartilage of control (A) and experimental animal (C.D) on experimental day 21. (D) is higher magnification of (C). In situ hybridization with sense probe shows no hybridization signal in the cartilage (B)." So there was no active COL2A1 mRNA production in B which is the control.</div>
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<a href="http://3.bp.blogspot.com/-E4FLCmSuYJw/UNNN2xgLQoI/AAAAAAAAArE/b0TVydbdyyY/s1600/Sox9expression.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="236" src="https://3.bp.blogspot.com/-E4FLCmSuYJw/UNNN2xgLQoI/AAAAAAAAArE/b0TVydbdyyY/s320/Sox9expression.jpg" width="320" /></a></div>
Arrows point to two possible areas where the bone ends both are distant from the Col2a1 staining indicating that the new growth plate formation is within the bone thus providing evidence for proof of concept for LSJL to form new growth plates within bone.<br />
<br />Here's another paper with the same author:</div><div><br /></div><div><b><a href="https://meridian.allenpress.com/angle-orthodontist/article/74/1/86/131930/The-Effect-of-Continuous-Bite-Jumping-in-Adult">The effect of continuous bite-jumping in adult rats: a morphological study</a></b></div><div><b><br /></b></div>"The aim of this study was to determine the mandibular morphology before, during, and after bite-jumping in nongrowing species. Fifty-two adult female Sprague-Dawley rats were divided into four experimental groups and four control groups. The experimental groups were fitted with fixed bite-jumping devices that protruded the mandible. The animals were sacrificed on days 3, 14, 30, and 60. Right halves of the mandible were harvested and freed of soft tissue. Digital pictures were obtained in a standardized manner. Selected linear and angular measurements were made. There were no morphological differences between the controls and experimental group on days 3 and 14<b>. The length of condylar process increased significantly on day 30 and remained so on day 60 in the experimental group.</b> The angulation of the condylar process was significantly affected because of increased apposition of bone in the middle and especially the posterior parts of the condyle. Thus, bite-jumping of the mandible in adult rats affects the size and angulation of the condylar process because of differential apposition of bone on the condylar head."</div><div><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="https://th.bing.com/th/id/OIP.BvcI8X0Iu5BE2FUQrEVpHQHaFj?w=226&h=180&c=7&r=0&o=5&pid=1.7" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="180" data-original-width="226" height="180" src="https://th.bing.com/th/id/OIP.BvcI8X0Iu5BE2FUQrEVpHQHaFj?w=226&h=180&c=7&r=0&o=5&pid=1.7" width="226" /></a></div><div class="separator" style="clear: both; text-align: left;"><br /></div>Above is the condylar process.</div><div><br /></div><div>"<span style="background-color: white; color: #1a1a1a; font-family: "Source Sans Pro"; font-size: 16px;"> sagittal deviation using the postural hyperpropulsor on male rats from the age of 48 to 180 days, which resulted in greater length of mandible than that of control. Experiments of continuous bite-jumping in young rats resulted in enhanced mandibular growth and remodeling of the glenoid fossa"</span></div><div><span style="color: #1a1a1a; font-family: Source Sans Pro;"><br /></span></div><div><span style="color: #1a1a1a; font-family: Source Sans Pro;">"</span><span style="background-color: white; color: #1a1a1a; font-family: "Source Sans Pro"; font-size: 16px;">Fifty-two <b>120-day-old nongrowing</b></span><span style="background-color: white; font-family: "Source Sans Pro"; font-size: 16px;"><span style="color: #0952ab;"><b> </b></span></span><span style="background-color: white; color: #1a1a1a; font-family: "Source Sans Pro"; font-size: 16px;"><b>female Sprague-Dawley rats</b> were included in this study."</span></div><div><span style="color: #1a1a1a; font-family: Source Sans Pro;"><br /></span></div><div><span style="color: #1a1a1a; font-family: Source Sans Pro;">"</span><span style="background-color: white; color: #1a1a1a; font-family: "Source Sans Pro"; font-size: 16px;">mandibular advancement could also stimulate the adaptive growth of the condyle in adult rats. This finding does not support previous experimental results where it was reported that adult monkeys lost the ability for condylar remodeling.</span><span style="background-color: white; color: #1a1a1a; font-family: "Source Sans Pro"; font-size: 16px;"> The possible reason may be that the stage of dentition could not reflect the exact chronological age of experimental monkeys."</span></div><div><span style="color: #1a1a1a; font-family: Source Sans Pro;"><br /></span></div><div><span style="color: #1a1a1a; font-family: Source Sans Pro;">"</span><span style="background-color: white; color: #1a1a1a; font-family: "Source Sans Pro"; font-size: 16px;">Because there was no increase in the length of the mandibular base, the remodeling of the condyle ultimately resulted in the increase in mandibular length "</span></div><div><span style="color: #1a1a1a; font-family: Source Sans Pro;"><br /></span></div><div><span style="color: #1a1a1a; font-family: Source Sans Pro;">Let's look at one of the studies that shows that monkeys lost the ability to grow in mandible length with age:</span></div><div><span style="color: #1a1a1a; font-family: Source Sans Pro;"><br /></span></div><div><a href="https://meridian.allenpress.com/angle-orthodontist/article/54/2/154/56685/Effect-of-Age-on-the-Adaptive-Response-of-the"><b>Effect of Age on the Adaptive Response of the Adult Temporomandibular Joint: A study of induced protrusion in Macaca mulatto</b><span style="background-color: white; color: #1a1a1a; font-family: "Source Sans Pro"; font-size: 0.75rem;"> </span></a></div><div><br /></div><div><-in this study the authors speculate it is perhaps a deficit in neuromuscular function that made the monkeys unable to move the jaw forward enough to stimulate growth and not due to capacity(I am not able to copy and paste the study).<br /><div><br /><div> <b><a href="http://ejo.oxfordjournals.org/content/26/4/353.long">Forward mandibular positioning enhances condylar adaptation in adult rats.</a></b></div><div>
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"The aim of this investigation was to assess quantitatively the adaptive changes in the condyles of adult rats to forward mandibular positioning. The level of types II and X collagen expressed in the condyles of adult rats was compared with that formed in response to forward mandibular positioning and the levels of expression were correlated to the amount of bone formed in response to mandibular advancement. Seventy-eight 120-day-old female Sprague-Dawley rats were included in this study. The rats were randomly allocated to six groups. Each group consisted of nine rats with bite-jumping devices and four untreated controls. The animals in each group were sacrificed on days 3, 7, 14, 21, 30, and 60. Immunostaining was used for the detection of types II and X collagen, while Alcian blue-PAS was used to observe the extracellular matrix and new bone formation. <b>New cartilage was formed in the posterior condyle.</b> The highest level of expression of types II and X collagen were present on day 21, the amount of increase was 247.99 and 540.08 per cent, respectively. <b>The highest level of new bone formation was measured at day 30 of advancement when the amount of increase in new bone formation was 318.91 per cent</b>. Forward mandibular positioning causes changes in the biophysical environment of the temporomandibular joint (TMJ) of adult rats that leads to condylar adaptation."<br />
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The rats were advanced 4 mm in continuous advancement. I don't know exactly what this means.</div>
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The study won't let me copy and paste. When I get a chance, I might print the paper out and scan the images in. Click on the link and look at figure 2 for new cartilage growth. Note in figure 2a that the region of new cartilage formation pointed to by the arrow is disconnected from the rest the cartilage. Also note that there is red staining in scattered quantities throughout the entirety of the epiphysis with the exception of that attached to the bone attached to the new red zone. <br />
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Note that in figure 1 there is staining for Type II Collagen deep within the epiphysis in the control group. <br />
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In figure 3a there is staining for Type II collagen throughout the entire bone. If you look at figure five bone formed downward furthering the possibility that you can increase bone length via the articular cartilage.<br />
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If you look at figure 5 you can see the new bone formation.<br />
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If you look at figure 6, it took until about day 21 to start seeing results and results decreased at day 60 so there could be an adaptive mechanism.<br />
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It would be interesting to note if intermittent mandibular forward positioning could result in the same objective.<br />
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<b><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2724385/">Condylar growth after non-surgical advancement in adult subject: a case report.</a></b></div>
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"case of altered condylar morphology in adult male with temporomandibular disorders was reported in 30-year-old male patient. Erosion and flattening of the left mandibular condyle were observed by panoramic x-ray. The patient was treated with splint therapy that determined mandibular advancement. Eight months after the therapy, reduction in joint pain and a greater opening of the mouth was observed, although crepitation sounds during mastication were still noticeable."</div>
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"<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">The mandibular condyle is an ovoidal bony structure that articulates with the temporal bone by means of a biconcave disk."</span></div>
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<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><br /></span></div>
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<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">"Both articular surfaces are covered by a connective fibrous tissue (condylar cartilage). On the articular surface of the condyle, the collagen fibres are parallel to the condylar surface, and are in continuity with the fibrous layer of the periosteum.</span></div>
<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"></span><br />
<div id="__p8" style="-webkit-text-stroke-width: 0px; background-color: transparent; color: black; font-family: &quot; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; margin-bottom: 11.04px; margin-left: 0px; margin-right: 0px; margin-top: 11.04px; margin: 11.04px 0px; orphans: 2; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">
<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">The condylar cartilage covers very dense undifferentiated mesenchyme, within which are multipotential cells, forming either cartilage or bone, depending upon the environmental circumstances"<-the presence of this mesenchyme may not be present in other regions.</span></div>
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<div style="-webkit-text-stroke-width: 0px; background-color: transparent; color: black; font-family: &quot; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; margin-bottom: 11.04px; margin-left: 0px; margin-right: 0px; margin-top: 11.04px; margin: 11.04px 0px; orphans: 2; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">
<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">"Mandibular condylar cartilage is characterised histologically as fibrocartilage containing a layer of pre-chondroblastic mesenchymal stem cells which can undergo rapid differentiation into chondrocytes.</span></div>
<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">
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<br />
<div id="__p31" style="-webkit-text-stroke-width: 0px; background-color: transparent; color: black; font-family: &quot; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; margin-bottom: 11.04px; margin-left: 0px; margin-right: 0px; margin-top: 11.04px; margin: 11.04px 0px; orphans: 2; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">
<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">Other forms of mature articular cartilage do not have such progenitor cells and only poorly responsive chondrocytes "<-this is a problem. Though I do not think this is entirely true.</span></div>
<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">
</span>
<div style="-webkit-text-stroke-width: 0px; background-color: transparent; color: black; font-family: &quot; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; margin-bottom: 11.04px; margin-left: 0px; margin-right: 0px; margin-top: 11.04px; margin: 11.04px 0px; orphans: 2; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">
<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">"<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">subcondylar trabecular bone formation is apparently not affected by age"<-The study mentioned is </span></span></div><b>Induced growth of the mandibular condyle in the rat<br /></b><br />"Advancement of the calcification front in the cartilage, which is a measure of the growth of the cartilage, can be determined by the administration of two dose bone‐markers at specific intervals. It appears that growth still takes place in animals of 12–18 months. This growth is possible by the persistence of chondrogenic cells. <b>The overall growth of the central part of the condyle amounts to about 2 mm over the period from 2 to 18 months.<br /></b><br /><b>Raising of the bite in the rat has an obvious influence on the temporomandibular joint, and on the condyle in particular</b>. Within a few days an increase of growth‐rate of cartilage can be demonstrated. This extra growth is temporary, and the intensity and duration of the response is determined by the age of the animal. This adaptation is related to the presence of chondrogenic cells in the cartilaginous layer in the condyle."<div><br /></div><div>"From the results it can be seen that an increase of the vertical dimension leads to a
temporary period of extra growth of the condyle. Not only is the chondrogenic zone
activated but the cartilaginous zone also reacts with heightening of its layer by production of cartilaginous substance<br /><div style="-webkit-text-stroke-width: 0px; background-color: transparent; color: black; font-family: &quot; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; margin-bottom: 11.04px; margin-left: 0px; margin-right: 0px; margin-top: 11.04px; margin: 11.04px 0px; orphans: 2; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><div class="loa-wrapper loa-authors hidden-xs" style="background-color: white; box-sizing: border-box; color: #1c1d1e; font-family: "Open Sans", sans-serif; font-size: 14px; margin: 15px 0px;"><div class="accordion" id="sb-1" style="box-sizing: border-box;"></div></div></span></span></div>
<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">
</span><br />
<div>
<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><b>Effects of mechanical loads on surface morphology of the condylar cartilage of the mandible in rats.,</b> "Hard-diet condyles had a rougher, more porous articular surface while soft/hard-diet condyles were intermediate between nonporous and slightly roughened condyles. None of the condyles showed ridges or elevations on the articular surface. Sex, age and time of the diets did not significantly affect these results."</span></span></div>
<div>
<b><span style="font-size: x-large;"></span></b><br />
<b></b><i></i><u></u><sub></sub><sup></sup><strike></strike><br />
<b>Cell and matrix response of temporomandibular cartilage to mechanical loading.</b></div>
<div>
<b><br /></b></div>
"The generation of transgenic mice expressing green fluorescent proteins (GFPs) has greatly aided our understanding of the development of connective tissues such as bone and cartilage. Perturbation of a biological system such as the temporomandibular joint (TMJ) within its adaptive remodeling capacity is particularly useful in analyzing cellular lineage progression. The objectives of this study were to determine: (i) if GFP reporters expressed in the TMJ indicate the different stages of cell maturation in fibrocartilage and (ii) how mechanical loading affects cellular response in different regions of the cartilage.<br />
Four-week-old transgenic mice harboring combinations of fluorescent reporters (Dkk3-eGFP, Col1a1(3.6 kb)-GFPcyan, Col1a1(3.6 kb)-GFPtpz, Col2a1-GFPcyan, and Col10a1-RFPcherry) were used to analyze the expression pattern of transgenes in the mandibular condylar cartilage (MCC). To study the effect of TMJ loading,<b> animals were subjected to forced mouth opening with custom springs exerting 50 g force for 1 h/day for 5 days.</b> Dynamic mineralization and cellular proliferation (EdU-labeling) were assessed in loaded vs control mice.<br />
Dkk3 expression was seen in the superficial zone of the MCC, followed by Col1 in the cartilage zone, Col2 in the prehypertrophic zone, and Col10 in the hypertrophic zone at and below the tidemark. TMJ loading increased expression of the GFP reporters and EdU-labeling of cells in the cartilage, resulting in a thickness increase of all layers of the cartilage. In addition, mineral apposition increased resulting in Col10 expression by unmineralized cells above the tidemark.<br />
<b>The TMJ responded to static loading by forming thicker cartilage through adaptive remodeling</b>."<br />
<div>
<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-variant: normal; letter-spacing: normal; text-align: left; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-variant: normal; letter-spacing: normal; text-align: left; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><span face=""arial" , "helvetica" , "clean" , sans-serif" style="background-color: transparent; color: black; display: inline; float: none; font-size: 13.53px; font-variant: normal; letter-spacing: normal; text-align: left; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><b></b></span></span></span></div>
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<b></b><i></i><u></u><sub></sub><sup></sup><strike></strike><b></b><b></b><i></i><u></u><sub></sub><sup></sup><strike></strike><b></b><i></i><u></u><sub></sub><sup></sup><strike></strike><b></b><i></i><u></u><sub></sub><sup></sup><strike></strike><b></b><i></i><u></u><sub></sub><sup></sup><strike></strike><b></b><i></i><u></u><sub></sub><sup></sup><strike></strike><b></b><i></i><u></u><sub></sub><sup></sup><strike></strike><b></b><b></b><b></b><i></i><u></u><sub></sub><sup></sup><strike></strike><b></b><i></i><u></u><sub></sub><sup></sup><strike><br /></strike></div>
<div>
"<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">Unlike most hyaline articular cartilages in the appendicular joints, the MCC is classified as fibrocartilage "</span></div>
<div>
<br />
"new mineralized cartilage apposition within the 24-hour period"</div>
<div>
<br /></div>
<div>
If you look at figure 3 you can see signs of increased endochondral ossification.</div>
<div>
<br /></div>
<div>
"<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">The TB signal extended into in the mineralized cartilage zone and protruded further into the subchondral bone in the loaded group."</span></div>
<div>
<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"><br /></span></div>
<div>
<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">"<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">loading enhances the accumulation of mineralized cartilage resulting in a greater separation of the unmineralized cartilage from the subchondral bone."<-this seems to indicate that maybe endochondral ossification did not occur. And only cartilage mineralization.</span></span></div>
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<br />
<b>Biomechanical behavior of the temporomandibular joint disc.</b><br />
<div>
"The temporomandibular joint (TMJ) disc consists mainly of collagen fibers and proteoglycans constrained in the interstices of the collagen fiber mesh. This construction results in a viscoelastic response of the disc to loading and enables the disc to play an important role as a stress absorber during function. The viscoelastic properties depend on the direction (tension, compression, and shear) and the type of the applied loading (static and dynamic). The compressive elastic modulus of the disc is smaller than its tensile one because the elasticity of the disc is more dependent on the collagen fibers than on the proteoglycans. <b>When dynamic loading occurs, the disc is likely to behave less stiffly than under static loading because of the difference of fluid flow through and out of the disc during loading. I</b>n addition, the mechanical properties change as a result of various intrinsic and extrinsic factors in life such as aging, trauma, and pathology. Information about the viscoelastic behavior of the disc is required for its function to be understood and, for instance, for a suitable TMJ replacement device to be constructed. In this review, the biomechanical behavior of the disc in response to different loading conditions is discussed"</div>
<div>
<br /></div>
<div>
"The articular surfaces of the TMJ are highly incongruent. Due to this incongruence, the contact areas of the opposing articular surfaces are very small. When joint loading occurs, this may lead to large peak loads, which may cause damage to the cartilage layers on the articular surfaces. The presence of a fibro-cartilaginous disc in the joint is believed to prevent these peak loads since it is capable of deforming and adapting its shape to that of the articular surfaces. These deformations ensure that loads are absorbed and spread over larger contact areas. In addition, the shape of the disc and the area and location of its contact areas with the articular surfaces change continuously during jaw movement to adapt to the changing geometry of the articular surfaces of the mandible and temporal bone."</div>
<div>
<br /></div>
<div>
" while translation of the condyle in the forward direction to obtain a protrusive or open jaw position leads to a concentration of the deformation in the lateral part of the disc."</div>
<div>
<br /></div>
<div>
"When the disc is compressed or stretched in one direction, not only will it deform in that direction (primary strain), but it will also become thicker or thinner, respectively, in a direction perpendicular to it (secondary strain). "</div>
<div>
<br /></div>
<div>
"the small permeability of the collagen network impedes interstitial fluid flow through this network. Therefore, the loads acting on a cartilaginous structure as the disc are initially transmitted by a pressurization of the incompressible fluid without much deformation of the collagen network. Nonetheless, fluid flow through the collagen network leads to a gradual transfer of the load from the fluid to the collagen fibers. When further loaded, the collagen network deforms, and water is squeezed out of the disc while the orientation of the collagen fibers is re-arranged "</div>
<div>
<br /></div>
<div>
"The movement of fluid out of the disc and the re-arrangement of the collagen fibers are reversible when the disc is not deformed beyond the physiologic strain range. Even application of significant long-term stresses beyond the physiologic strain range introduces but minor changes in fiber waviness and alignment within the disc. This enables the disc to adapt its shape continuously to fit in the space between the opposing articular surfaces and to distribute loads suitably in the TMJ. Collagen gives the disc much of its tensile stiffness and strength. "</div>
<div>
<br /></div>
<div>
"mechanical stress affects the GAG synthesis in the disc, especially that of chondroitin sulfate, dermatan sulfate, and hyaluronic acid. Static loading decreases the proteoglycan synthesis in cartilaginous structures, whereas dynamic loading is positively related to this synthesis and is considered as an important factor for maintenance of the homeostasis of the joint cartilage "<-maybe because dynamic loading drives fluid flow and allows more nutrients to get in?</div>
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<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;"></span></div>
<b></b><i></i><u></u><sub></sub><sup></sup><strike></strike><b></b><i></i><u></u><sub></sub><sup></sup><strike></strike><br />
Here's a study on how progenitor cells in the cartilage may play a role in this process:<br />
<br />
<b><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613756/">Progenitor Cells of the Mandibular <span class="highlight" style="color: black; font-size: 18.2px; line-height: 22.75px; margin: 0px;">Condylar</span> Cartilage.</a></b><br />
<b></b><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613756/">https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4613756/</a><br />
<div>
"The secondary cartilage of the mandibular condyle is unique as it undergoes endochondral ossification during growth and robustly remodels in response to changes in its mechanical loading environment. This cartilage is derived from mesenchymal progenitor cells that express markers of early osteoblast differentiation, namely alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2). Interestingly, these progenitor cells then differentiate into cartilage with appropriate mechanical loading. these cells can be labeled by osteoblast progenitor cell markers, including the 3.6 fragment of the rat collagen type 1. However, the role these mesenchymal progenitor cells play in adult mandibular condylar cartilage maintenance and adaptation, as well as the existence of a more potent progenitor cell population within the mandibular condylar cartilage, remain in question. Further characterization of these cells is necessary to determine their potency and regenerative capacity to elucidate their potential for regenerative therapy."</div>
<div>
<br /></div>
<div>
"<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">After the cessation of growth, the mandibular condylar cartilage becomes phenotypically similar to other articular cartilages by entering into a post-mitotic state"</span></div>
<div>
<br /></div>
<div>
<b>"</b><span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">there still appears to be a progenitor cell population capable of reactivating in response to changes in mechanical loading"<-where these progintor cells are present in other articular cartilage is the question.</span><br />
<br />
Progenitor cells in other articular cartilage types:<br />
<br />
<b><a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413931/">Origin and function of cartilage stem/progenitor cells in osteoarthritis.</a></b></div>
<div>
<b><i><u><span style="color: #000120;"><br /></span></u></i></b></div>
<div>
"Articular cartilage is a physiologically non-self-renewing avascular tissue with a singular cell type, the chondrocyte, which functions as the load-bearing surface of the arthrodial joint. Injury to cartilage often progresses spatiotemporally from the articular surface to the subchondral bone, leading to development of degenerative joint diseases such as osteoarthritis (OA). Although lacking intrinsic reparative ability, <b>articular cartilage has been shown to contain a population of stem cells or progenitor cells</b>, similar to those found in many other adult tissues, that are thought to be involved in the maintenance of tissue homeostasis. These so-called cartilage-derived stem/progenitor cells (CSPCs) have been observed in human, equine and bovine articular cartilage, and have been identified, isolated and characterized on the basis of expression of stem-cell-related surface markers, clonogenicity and multilineage differentiation ability. However, the origin and functions of CSPCs are incompletely understood. We review here the current status of CSPC research and discuss the possible origin of these cells, what role they might have in cartilage repair, and their therapeutic potential in OA."</div>
<div>
<br /></div>
<div>
"<span style="background-color: transparent; color: black; display: inline; float: none; font-family: "times new roman" , "stixgeneral" , serif; font-size: 16px; font-style: normal; font-variant: normal; font-weight: 400; letter-spacing: normal; text-align: left; text-decoration: none; text-indent: 0px; text-transform: none; white-space: normal; word-spacing: 0px;">mild enzymatic insult to the cartilage ECM promoted CPCs migration in cultured articular cartilage explants."</span><br />
<br />
<b>Superficial cells are self‐renewing chondrocyte progenitors, which form the articular cartilage in juvenile mice</b></div>
<div>
<b><br /></b></div>
"Articular cartilage has little regenerative capacity. Recently, genetic lineage tracing experiments have revealed chondrocyte progenitors at the articular surface. We further characterized these progenitors by using in vivo genetic approaches. Histone H2B–green fluorescent protein retention revealed that superficial cells divide more slowly than underlying articular chondrocytes. Clonal genetic tracing combined with immunohistochemistry revealed that superficial cells renew their number by symmetric division, express mesenchymal stem cell markers, and generate chondrocytes via both asymmetric and symmetric differentiation. Quantitative analysis of cellular kinetics, in combination with phosphotungstic acid–enhanced micro–computed tomography, showed that superficial cells generate chondrocytes and contribute to the growth and reshaping of articular cartilage. Furthermore, we found that cartilage renewal occurs as the progeny of superficial cells fully replace fetal chondrocytes during early postnatal life. Thus, <b>superficial cells are self‐renewing progenitors that are capable of maintaining their own population and fulfilling criteria of unipotent adult stem cells</b>. Furthermore, the progeny of these cells reconstitute adult articular cartilage de novo , entirely substituting fetal chondrocytes."<br />
<div>
<br /></div>
<div>
<-We need to know how effective these stem cells are at self renewing as adults for adult height increase via articular cartilage.<br />
<br />
"whereas deep articular
chondrocytes in adult mice are derived from cells that
were initially at the cartilage surface in newborn mice,
which is consistent with appositional growth, beneath the
surface cartilage, growth is also interstitial"<br />
<br />
"superficial cells are slow-dividing
progenitors of middle and deep zone chondrocytes"</div>
<div>
<br />
<b>Regional shape change in adult facial bone curvature with age. </b><br />
<br />
"Three-dimensional semilandmarks representing the curvature of the orbits, zygomatic arches, nasal aperture, and maxillary alveolar process were collected from a cross-sectional cranial sample of mixed sex and ancestry (male and female; African- and European-American), partitioned into three age groups (young adult = 18-39; middle-aged = 40-59 years; and elderly = 60+ years). Each facial region's semilandmarks were aligned into a common coordinate system via generalized Procrustes superimposition. Regional variation in shape was then explored via a battery of multivariate statistical techniques. Age-related shape differences were detected in the orbits, zygomatic arches, and maxillary alveolar process."<br />
<br />
"adult craniofacial curvature shape is not static throughout human life. Instead, age-related spatial modifications occur in various regions of the craniofacial skeleton."<br />
<br />
"Increases in craniofacial dimensions such as facial height, mandibular length, bizygomatic and bigonial breadth, and head circumference, length, and breadth have been detected with advancing age"<br />
<br />
<b>Natural craniofacial changes in the third decade of life: a longitudinal study.</b><br />
<br />
"Natural head position lateral cephalometric films and dental casts of 30 people (14 women and 16 men) were evaluated. The mean age at the beginning of the observation period was 22.35 years for the women and 22.19 years for the men, and the observation period was approximately 10 years. Cephalometric films were superimposed by the structural method, and the measurements of the dental casts were made with a digital caliper. All tracings were digitized, and changes in the 65 cephalometric and 10 dental cast measurements were evaluated statistically. In this early adult period, small changes were found in the craniofacial and craniocervical parameters; the changes were more significant in the women. The most significant changes were found in the vertical dimension.<b> The total anterior face height increased in both genders, while the lower anterior face height increased significantly in the female group.</b> Soft tissue measurements reflected the vertical skeletal changes. The retrusion of the upper lip was significant in the women, and the upper lip thickness decreased in both genders. In the dentoalveolar region, the main movement was eruption of the teeth. The overbite amount increased significantly only in the female group. All dental arch measurements decreased in both sexes. The decrease in the mandibular arch length discrepancy was significant in the men."</div><div><br /></div><a href="http://medlib.yu.ac.kr/eur_j_oph/ijom/IJOMI/ijomi_15_252.pdf#:~:text=To%20place%20adult%20growth%20in%20its%20proper%20con-,of%20service%2C%20growth-related%20changes%20will%20begin%20to%20occur."><b>Adult Growth, Aging, and the Single-Tooth Implant.</b><br />
</a></div></div></div><div><b><br /></b></div><div>"Single-tooth implants are an increasingly popular method for replacing single teeth. While the effects of growth on implants in children have been well documented, the changes that occur in adults have not been studied with respect to single-tooth implants. It has been assumed that adults are stable and do not change; however, <b>research in the last few years has indicated that adults do change with aging, and adult growth does occur. The changes in adults occur over decades rather than rapidly, as seen in children.</b> Aging changes are readily apparent in the soft tissues of the face and create dramatic changes. Changes in the jaws and teeth occur as a result of continued, slow growth, in contrast to the aging effects seen in soft tissues. <b>Growth changes occur in the arches</b> and result in adaptive changes in the teeth over time, both vertically and horizontally, and in alignment. These dental changes may result in a lack of occlusion vertically or malposition of adjacent natural teeth relative to the implant crown. Clinicians may be well advised to observe and report these changes and warn patients that changes can occur over the service life of the implant-supported crown. These changes may require maintenance adjustments or possible remaking of the implant crown as a result of adult growth, wear, or the esthetic changes of aging."</div><div><br /></div><div><b>"the myth
of “adults don’t grow” was put to rest. Although the
effects of adult growth are very slow and measured
in terms of decades, changes do occur"</b></div><div><b><br /></b></div><div><b>"</b>Between 15 and 25 years, males increase their
standing height by 15%, their maxillary depth by
20%, and their mandibular depth by 26%, while
positioning their mandible forward by 30% and
changing their maxillomandibular relationship by
33%"</div><div><br /></div><div>"Underlying the soft tissue changes, <b>skeletal changes
also occur in adults</b>. The skeletal changes
appear more like the growth seen during adolescence"</div><div><br /></div><div>"Since nearly all of the facial sutures
close in early adulthood, the skeletal growth during
adulthood must take place as a result of remodeling. Facial height increases both anteriorly and
posteriorly, with a greater increase in the lower than
in the upper face, resulting in a significant change in
the area of the dentition. This increase in
facial height totals nearly 3 mm between 17 and 80
years, with the increase continuing into the
eighties"</div><div><br /></div><div>"While the average maxillary change is
small (1 mm) over a 60-year period, some individuals demonstrate as much as a 5-mm change.
Changes in <b>mandibular position and length</b> also
occur with increasing age. The symphysis[a fibrocartilagenous fusion between two bones] moves downward and forward throughout all age
spans, with males growing more than females."</div><div><br /></div><div>The mandibular ramus continues to grow.</div></div></div>Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com22tag:blogger.com,1999:blog-1013552121036660524.post-49661646248633030722013-10-31T10:54:00.002-07:002013-10-31T10:54:30.013-07:00Merger with Natural Height Growth dot ComI will now be making all new posts over at <a href="http://www.naturalheightgrowth.com/">Natural Height Growth</a>. I will still be maintaining this blog but mainly with technical/scientific stuff. All new posts regarding LSJL results, the LSJL method, height increase supplements, and definitive advancements in height increase methodology will be at the NHG website. But tangential, technical things will be on this website.<br />
<br />
Also, the search feature on this site can search both Natural Height Growth and Heightquest.Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com3tag:blogger.com,1999:blog-1013552121036660524.post-40826159756863847612013-07-08T16:05:00.003-07:002022-08-20T19:57:02.124-07:00Resveratrol - A Potential Height Increase Supplement<b> </b>Surprisingly Resveratrol is available for sale: <a href="http://www.amazon.com/gp/product/B0029O0RUS/ref=as_li_ss_tl?ie=UTF8&camp=1789&creative=390957&creativeASIN=B0029O0RUS&linkCode=as2&tag=thequ01-20">1000 MG Resveratrol Extreme Juice Capsules Resveratrol Juice capsules TM 3 Months 180 pills HIGHLY POTENT Pure Resveratrol pills. 3 MONTH GUARANTEE. TWICE AS POTENT AS many RESVERATROL, Resveratrol Juice Extreme</a><img alt="" border="0" height="1" src="http://ir-na.amazon-adsystem.com/e/ir?t=thequ01-20&l=as2&o=1&a=B0029O0RUS" style="border: none; margin: 0px;" width="1" />.<br />
Resveratrol may boost <a href="http://www.heightquest.com/2011/10/catch-up-growth-gene-expression-and-lsjl.html">SIRT1 which is implicated in catchup growth</a>. This is accroding to <b>Resveratrol boosts cognitive function by targeting SIRT1</b>. Metformin may boost SIRT1 also according to <b>Metformin Is a Direct SIRT1-Activating Compound: Computational Modeling and Experimental Validation.</b><div class="inline-authors" style="background-color: white; box-sizing: inherit; color: #5b616b; font-family: BlinkMacSystemFont, -apple-system, "Segoe UI", Roboto, Oxygen, Ubuntu, Cantarell, "Fira Sans", "Droid Sans", "Helvetica Neue", sans-serif; font-size: 16px; line-height: 1.5; margin-bottom: 1.2rem; scroll-behavior: auto;"></div>Resveratrol has a similar structure to estrogen and may prevent binding of estrogen to various cells that would decrease growth. Therefore, resveratrol may increase height if taken during development at the right dose. <br />
<br />
<a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0067859"><b> Resveratrol Treatment Delays Growth Plate Fusion and Improves Bone Growth in Female Rabbits </b></a><br />
<br />
"Trans-resveratrol (RES), naturally produced by many plants, has a structure similar to synthetic estrogen diethylstilbestrol. Pre-pubertal ovary-intact New Zealand white rabbits received daily oral administration of either vehicle (control) or RES (200 mg/kg) until growth plate fusion occurred{We don't know if this will have the same effect on men}. Bone growth and growth plate size were longitudinally monitored by X-ray imaging, while at the endpoint, bone length was assessed by a digital caliper. In addition, pubertal ovariectomized (OVX) rabbits were treated with vehicle, RES or estradiol cypionate (positive control) for 7 or 10 weeks and fetal rat metatarsal bones were cultured in vitro with RES (0.03 µM–50 µM) and followed for up to 19 days. In ovary-intact rabbits, sixteen-week treatment with RES increased tibiae and vertebrae bone growth and subsequently improved final length. In OVX rabbits, <b>RES delayed fusion of the distal tibia, distal femur and proximal tibia epiphyses and femur length and vertebral bone growth increased when compared with controls.</b> <b>RES-treated OVX rabbits had a wider distal femur growth plate, enlarged resting zone, increased number/size of hypertrophic chondrocytes, increased height of the hypertrophic zone, and suppressed chondrocyte expression of VEGF and laminin. In cultured fetal rat metatarsal bones, RES stimulated growth at 0.3 µM while at higher concentrations (10 μM and 50 μM) growth was inhibited. RES has the potential to improve longitudinal bone growth. The effect was associated with a delay of growth plate fusion resulting in increased final length. These effects were accompanied by a profound suppression of VEGF and laminin expression suggesting that impairment of growth plate vascularization might be an underlying mechanism.</b>"<br />
<br />
Note that only the smallest dosage of Resveratrol had an anabolic effect on growth which is consistent with the view that estrogen has an equilibrium level for growth. These rabbits were pre-puberty so estrogen levels should've been lower than puberty. Since estrogen levels increase during puberty doses should increase during puberty as estrogen would be higher than equilibrium level. It's hard to ascertain what that is for humans though.<br />
<br />
"Trans-resveratrol (3, 5, 4′-trihydroxystilbene), is a polyphenol naturally produced by a variety of plants such as peanuts, berries, skin of red grapes in response to stress, injuries and infections."<-Does anyone have anecdotal accounts of tall people or groups that ate lots of peanuts, berries, or red grapes? Or drink red wine?<br />
<br />
"in weanling rats demonstrating that 6 days of treatment with very low doses of RES (1–100 μg/day) had no significant effect on radial bone growth"<br />
<br />
The Rabbits were twelve weeks old.<br />
<br />
"tibia length 111.6±0.6 mm in the RES group vs. 109.5±0.6 mm in control" over 8 weeks. That's approximately a 5% increase in growth rate. Vertebral height was increased as well.<br />
<br />
"<b>RES-treatment delayed the time of growth plate fusion in all studied growth plates</b>."<this could be due to Resveratrol's effects on sirt1 and catch up growth<br />
<br />
"After 10 weeks, 33% of the animals in the RES group had unfused distal femur growth plates while only 10% of control animals had"<br />
<br />
Surprisingly, RES decreased the number of proliferative chondrocytes per area in growth plates versus control but this is consistent with the view that Resveratrol delays growth plate senescence.<br />
<br />
"chondrocyte expression of VEGF to be clearly suppressed in RES-treated rabbits as compared to controls (265±54 vs. 626±50 VEGF positive cells/mm2) while in the E2 group VEGF expression was similar as in controls (632±153 vs. 626±50 positive cells/mm2). Also the expression of laminin was decreased in the RES-treated group as compared to controls (17.7±0.6 vs. 27.4±1.04 positive cells/mm2;). In contrast, laminin expression was elevated in E2 treated animals (44.4±0.8 vs. 27.4±1.04 positive cells/mm2 in control)"<br />
<br />
"RES significantly improves bone growth by delaying the process of epiphyseal fusion in female animals. Animals treated with RES had wider growth plates with enlarged resting zone, fewer proliferative chondrocytes, increased number and size of hypertrophic chondrocytes and markedly suppressed VEGF and laminin expression."Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com62tag:blogger.com,1999:blog-1013552121036660524.post-76687226884171272242013-07-05T10:51:00.002-07:002022-08-20T20:16:36.493-07:00Zone of RanvierIn the studies of <a href="http://www.heightquest.com/2012/10/bony-bridge-and-growth-arrest.html">physeal briding</a>, the zone of ranvier's unobstruction was critical for normal longitudinal bone growth without angular deformities. The zone of ranvier is also placed on the longitudinal side of the bone so may be key to LSJL. As the zone of ranvier is on the longitudinal side, it can be more easily accessed than something that's within the bone itself. Studying how much the zone of ranvier is maintained post diaphyseal/epiphyseal fusion may be key to forming new growth plates. If the zone of ranvier is maintained to any degree post fusion than it may be possible to restore growth.<br />
<br />
Here's an image of the zone of ranvier:<br />
<img class="irc_mut" height="480" id="irc_mi" src="http://cal.vet.upenn.edu/projects/saortho/chapter_02/02F12.jpg" style="margin-top: 67px;" width="331" /> From <a href="http://cal.vet.upenn.edu/projects/saortho/chapter_02/02mast.htm">Normal Bone Formation</a>.<br />
<br />
"The growth plate may be divided anatomically into three components: a cartilaginous component, itself divided into various histologic zones; a bony component, metaphysis; and a fibrous component surrounding the periphery of the plate comprising the groove of Ranvier and the perichondrial ring of LaCroix."<br />
<br />
"The epiphyseal artery supplies the epiphysis, or the secondary center of ossification, which itself is not part of the growth plate. Small branches arise at right angles to the main epiphyseal artery in the epiphysis and pass through small cartilage canals in the reserve zone to terminate at the top of the cell columns in the proliferative zone. Each small branch from the epiphyseal artery arborizes in rakelike fashion to supply the top portion of from four to ten cell columns. The proliferative zone, therefore, is well supplied with blood. None of the branches from the epiphyseal arteries penetrate the cartilage portion of the growth plate beyond the uppermost part of the proliferative zone; that is, no vessels pass through the proliferative zone to supply the hypertrophic zone."<br />
<br />
"The reserve zone lies immediately adjacent to the secondary bony epiphysis. Various terms have been applied to this zone, including resting zone, zone of small-size cartilage cells, and germinal zone. However, these cells are not resting, are not small in comparison with the cells in the proliferative zone, and they are not germinal cells. They appear to store lipid and other materials and perhaps are held in reserve for later nutritional requirements. If that is true, the term reserve zone may be appropriate. The cells in this zone are spherical, exist singly or in pairs, are relatively few when compared with the number of cells in other zones, and are separated from each other by more extracellular matrix than are cells in any other zone. The cells in the reserve zone are approximately the same size as the cells in the proliferative zone. The cytoplasm exhibits a positive staining reaction for glycogen. These cells contain abundant endoplasmic reticulum, a clear indication that they are actively synthesizing protein. They contain more lipid bodies and vacuoles than do cells in other zones but contain less glucose-6-phosphate dehydrogenase, lactic dehydrogenase, malic dehydrogenase, and phosphoglucoisomerase. The zone also contains the lowest amount of alkaline and acid phosphatase, total and inorganic phosphate, calcium, chloride, potassium, and magnesium. The matrix in the reserve zone contains less lipid, glycosaminoglycan, protein polysaccharide, moisture, and ash than the matrix in any other zone. It exhibits less incorporation of radiosulfur (35S) than any other zone and also shows less Iysozyme activity than the other zones. It contains the highest content of hydroxyproline of any zone in the plate. Collagen fibrils in the matrix exhibit random distribution and orientation. Matrix vesicles are also seen in the matrix, but they are fewer than in other zones. The matrix shows a positive histochemical reaction for the presence of a neutral mucopolysaccharide or an aggregated proteoglycan."<br />
<br />
Another image of the Zone of Ranvier and LaCroix:<br />
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh3TUXYk7ZrEdCjQxr1v613Vd7nnBbO63A5V1aYBd3UOwNupgACi3gYGNsHbp5qKxUrHo6AGD4D6SIWgbvZSNQU6-2EoHQ2yzbGNT0t5tWK7SkSsyRH0xtlp4uJ-sNY_fGvhvqVW7I0sPTaojXcRgDKMU5Ry1gBVzdW-zDRDHaikLIqb40aspkTx2t5/s474/zone%20of%20ranvier%20ring%20of%20la%20croix.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em; text-align: center;"><img border="0" data-original-height="355" data-original-width="474" height="240" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh3TUXYk7ZrEdCjQxr1v613Vd7nnBbO63A5V1aYBd3UOwNupgACi3gYGNsHbp5qKxUrHo6AGD4D6SIWgbvZSNQU6-2EoHQ2yzbGNT0t5tWK7SkSsyRH0xtlp4uJ-sNY_fGvhvqVW7I0sPTaojXcRgDKMU5Ry1gBVzdW-zDRDHaikLIqb40aspkTx2t5/s320/zone%20of%20ranvier%20ring%20of%20la%20croix.jpg" width="320" /></a><br /><br />
"The perichondrial ring is a dense fibrous band that encircles the growth plate at the bone-cartilage junction and in which collagen fibers run vertically, obliquely, and circumferentially. It is continuous at one end with the group of fibroblasts and collagen fibers in the ossification groove and at the other end with the periosteum and subperiosteal bone of the metaphysis. In rodents, rabbits, and dogs, the innermost layer of the perichondrial ring consists of bone that may or may not be attached to the subperiosteal bone of the metaphysis. This cylindrical sheath of bone may not be present in all species at all ages in all growth plates. For instance, it is not present in the proximal femur in the human at any age. " Whether or not bone is present in the perichondrial ring, there is no doubt that the ring provides mechanical support for the otherwise weak bone-cartilage junction of the growth plate" <br />
<br />
<b>If we can somehow prove that the zone of Ranvier is retained post fusion then that would be a huge breakthrough for forming new growth plates.</b><br />
<br />
<b><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750766/">Identification of a stem cell niche in the zone of Ranvier within the knee joint.</a></b><br />
<div>
<br /></div>
<div>
"A superficial lesion of the articular cartilage does not spontaneously self-repair and has been suggested to be partly due to lack of progenitor cells within the joint that can reach the site of injury. To study whether progenitor cells are present within the joint, 3-month-old New Zealand white rabbits were exposed to bromodeoxyuridine (BrdU) for 12 consecutive days and were then sacrificed 4, 6, 10, 14, 28 and 56 days after the first BrdU administration. Presence of BrdU and localization of progenitor markers were detected. <b>After 10 days of BrdU exposure, BrdU-positive cells, i.e. proliferating cells, were abundantly detected in the epiphyseal plate, the perichondrial groove of Ranvier, and in all zones of the articular cartilage{so the rabbits were skeltally immature}</b>. After a wash-out period, BrdU-positive cells were still present, i.e. those considered to be progenitor cells, in these regions of the knee except for the proliferative zone of the epiphyseal plate. <b>Cells in the perichondrial groove of Ranvier were further positive for several markers associated with progenitor cells and stem cell niches, including Stro-1, Jagged1, and <a href="http://www.naturalheightgrowth.com/2013/10/31/bmpr1a-may-key-form-new-growth-plates/">BMPr1a</a></b>. A small population of progenitor cells is present in the perichondrial groove of Ranvier as well as within the articular cartilage in the knee. The perichondrial groove of Ranvier demonstrates the properties of a stem cell niche."</div>
<div>
<br /></div>
<div>
"The growth plate is surrounded by an encircling fibrochondrosseous structure. This anatomical structure consists of the zone of Ranvier and the ring of LaCroix. The area [harbors] prechondrocytes responsible for the circumferential growth of cartilage."</div>
<div>
<br /></div>
<div>
"perichondrial cells from the ring of LaCroix, which is a fibrous band that surrounds the groove of Ranvier and is continuous with the periosteum of the metaphysis, serve as a reservoir for precartilaginous cells in the germinal layer of the epiphyseal growth plate"</div>
<div>
<br /></div>
<div>
"A larger number of BrdU-positive cells in the epiphyseal plate[were] near the perichondrial groove of Ranvier than in the central area of the epiphyseal plate. [Cells may migrate] from the perichondrial groove of Ranvier into the epiphysis."<-Based on how much the Zone of Ranvier is retained this can be used to form new growth plates.</div>
<div>
<br /></div>
<div>
<div>
<b><a href="http://endo.endojournals.org/content/150/8/3627.long">Regulation of rapid signal transducer and activator of transcription-5 phosphorylation in the resting cells of the growth plate and in the liver by growth hormone and feeding.</a></b></div>
</div>
<div>
<br /></div>
<div>
"The Janus kinase (Jak)-signal transducer and activator of transcription (STAT)-5 pathway is activated by GH, so we developed a method to visualize nuclear Stat5b and phosphorylated Stat5 in single cells in response to a pulse of GH. Hep2 cells did not show a Stat5 phosphorylation (pY-Stat5) response to GH except in cells transfected to express GH receptors. ATDC5 cells express GH receptors and showed GH-induced pY-Stat5 responses, which varied with their state of chondrocyte differentiation. In vivo, Stat5b(+ve) nuclei were seen in the resting and prehypertrophic chondrocytes of the growth plate. <b>After a single ip pulse of human GH or mouse GH, but not prolactin, pY-Stat5 responses were visible in cells in the resting zone and groove of Ranvier, 10-45 min later{Maybe LSJL mimics these pulses}</b>. Prehypertrophic chondrocytes showed no pY-Stat5 response to GH. GH target cells were also identified in other tissues, and a marked variability in spatiotemporal pY-Stat5 responses was evident. Endogenous hepatic pY-Stat5 was detected in mice with intact GH secretion but only during a GH pulse. Fasting and chronic exposure to GH attenuated the pY-Stat5 response to an acute GH injection. <b>pY-Stat5 responses to GH vary in time and space, are sensitive to nutritional status, and may be inhibited by prior GH exposure{GH needs to be cycled}</b>. GH [regulates] the fate of immature chondrocytes."</div>
<div>
<br /></div>
<div>
"Although Stat1, -3, -5a, and -5b can all be activated by GH, Stat5b is the major target for growth promotion because it is uniquely responsive to the temporal pattern of plasma GH"</div>
<div>
<br /></div>
<div>
<img alt="Figure" src="http://press.endocrine.org/na101/home/literatum/publisher/endo/journals/content/endo/2009/endo.2009.150.issue-8/en.2008-0985/production/images/medium/zee0080948650002.jpeg" /></div>
<div>
Groove of Ranvier identified in A.</div>
<div>
<br /></div>
<div>
<div>
<b>Development of the distal femoral epiphysis: a microscopic morphological investigation of the zone of Ranvier.</b></div>
</div>
<div>
<br /></div>
<div>
"The distal femoral epiphysis, physis, and contiguous metaphysis were examined radiographically, morphologically, and histologically in 97 human specimens ranging in age from 9 prenatal weeks to 16 postnatal years. The earliest development of the femoral anlage was characterized by patterns of appositional and interstitial chondrogenesis throughout its entire structure. Once central endochondral ossification began, chondrogenic interstitial and appositional growth became regionally restricted to the femoral epiphyses. Interstitial chondrogenesis became limited to the germinal region of the developing physis, and <b>appositional chondrogenesis was restricted to the region of loosely packed cells of the perichondrial ossification zone of Ranvier</b>. Appositional chondrogenesis within the perichondrium appears to make its greatest contribution to transverse expansion of the distal femoral epiphysis during the first 5 months of gestation. After the sixth month of gestation, the perichondrial appositional growth contribution appears to decline steadily."</div>
<div>
<br /></div>
<div>
Appositional growth by deposition underneath the periosteum and interstitial growth are two methods suggested by the study for growth of the physis in width(it doesn't say what the mechanism of interstitial growth is).<br />
<br />
Eventually the zone of ranvier is not apparent. The bone collar incorporates into the metaphyseal bone. There is a region of loosely packed cells that does seem to persist.</div>
<div>
<br /></div>
<div>
According to <b>The expression of the nuclear oncogenes c-myc and c-jun in the groove of Ranvier of the rabbit growth plate.</b>, cells in the Groove of Ranvier are positive for c-Myc and c-Jun.</div>
<div>
<br /></div>
<div>
<div>
<b>Role of the ossification groove of Ranvier in normal and pathologic bone growth: a review.</b></div>
</div>
<div>
<br /></div>
<div>
"cells in the groove [of Ranvier] and adjacent periosteum contain type II collagen messenger RNA (mRNA) characteristic of cartilage"</div>
<div>
<br /></div>
<div>
"The normal interstitial growth of the reserve cell zone or the germinal layer of the growth plate leads to migration of cells toward the periphery, where some cells give rise to new cell columns inside the groove. Other cells have their structure changed and enter the inner cell layer of the well-vascularized tissue in the ossiffication groove. These cells lose their surrounding ground substance entering the groove but retain their ability to synthesize type II collagen mRNA. With continued growth of the bone, the cells are left behind and give rise to osteoblasts and bone."<br />
<br />
<b> The periphysis and its effect on the metaphysis: I. Definition and normal radiographic pattern</b><br />
<br />
"The zone of Ranvier and the ring of LaCroix, together with the membranous bone bark they produce, are termed the periphysis in order to emphasize their normal effect (the metaphyseal collar) on the metaphysis of the infant and young child. In the first 7 years of life, the normal collar at the wrist is 1-3 mm wide. The step-off between the metaphyseal collar and the curvilinear metaphysis, at the margin of the periphysis, should not be mistaken for abuse fracture. The periphyseal bone bark may be radiologically visible at the edge of the physis at the distal ulna in 9% of infants and should not be mistaken for fracture or rickets."<b> </b><br />
<br />
"The periphysis surrounds the growth plate (physis) of tubular bones and also the most recently formed several millimeters of metaphysis in infants. It is a fibrochondroosseous structure that (a) appears to maintain the transverse diameter of the physis and at the same time (b) allows gradual transverse growth of the same physis. That portion of the periphysis adjacent to the physis has been described under the names zone or groove of Ranvier, that portion adjacent to the metaphysis, as the<br />
ring of LaCroix.<br />
Histologically, the Ranvier and LaCroix zones are a single structure; both lay down a continuous thin layer of bone, termed bone bark, centrally at the periphery of the physis and metaphysis. This bone bark is produced by membranous, rather than enchondral, bone formation. In the first several years of life that portion of the metaphysis surrounded by the periphysis has a flat, longitudinally directed periphery on radiographs, rather than a smooth curved contour characteristic of the margins of other portions of the metaphysis. The result is the short metaphyseal collar"<br />
<br />
"The periphysis [restrains] longitudinal widening of the physis."<br />
<br />
<a href="https://gupea.ub.gu.se/bitstream/2077/20289/1/gupea_2077_20289_1.pdf"><b>Cartilage Tissue Engineering; the search for chondrogenic progenitor cells and associated signalling pathways </b></a><br />
<br />
"Stem cells [are] not only in the articular cartilage but also in the groove of Ranvier located in the periphery of the epiphyseal growth plate.<br />
The groove of Ranvier exhibited properties as a stem cell niche structure. Further biopsies<br />
from human normal articular cartilage, as well as regenerated and repaired cartilage after ACI<br />
were studied. The human normal articular cartilage demonstrated expression of the stem cell<br />
associated markers STRO-1 and Bcrp1 in cells in the superficial zone, and activity of the<br />
fundamental Wnt (Wingless-related proteins) and Notch signalling pathways. The distribution<br />
showed a distinct zonal pattern in the normal cartilage. In biopsies from regenerated cartilage<br />
with almost normal histological architecture, the markers and pathways studied demonstrated a<br />
distinct zonal pattern similar to that in normal cartilage."<br />
<br />
"in articular cartilage there are subpopulations of cells with mesenchymal stem cell properties"<br />
<br />
"From the lateral plate mesoderm, undifferentiated mesenchymal cells begin to migrate to areas destined to become bone, followed by tight packing of the cells, known as mesenchymal condensation. The cartilage anlagen for the future skeletal elements have now formed. Cellular condensation is associated with increased cell to cell contact and increased cell to matrix interaction. Molecules taking part in the intercellular communication are e.g. neural cell adhesion molecule (N-CAM), Ncadherin, tenascin, versican, fibronectin and gap junctions (connexin 42 and 43),"<br />
<br />
"The first sign of joint formation is the appearance of an interzone. The interzone cells gives rise to the articular layer of the future long bones while the chondrocytes developing from the mesenchymal condensation are assumed to be a part of epiphyseal growth plate and to take part in endochondral ossification, these cells are called transient chondrocytes. It has been unclear whether the interzone cells derive from transdifferentiation of local prechondrocytes into interzone cells or if there is migration of mesenchymal cells into the joint site, or a combination"<br />
<br />
"It[perichondrial groove of Raniver] is a circumferential anatomical structure in the periphery of the epiphyseal growth plate and consists of the zone of Ranvier and the ring of LaCroix. It is a well defined structure in the growing skeleton. <b>In the adult it is assumed to be integrated with the periosteum however, this has not been well explored in the adult human being</b>."<br />
<br />
"Markers associated with and suggested to define possible stem cells or progenitor cells in mesenchymal tissue and also, in some cases, in adult cartilage are CD105(Endoglin), CD166 (Alcam) and FGFR3 (Fibroblast Growth Factor receptor 3)"<br />
<br />
ID1 and ID3 are involved in the proliferation of adult articular chondrocytes.<br />
<br />
"A significant decrease in DNA synthesis was noticed when antisense nucleotides against Id1 and Id3 were added, both in normal chondrocytes and chondrosarcoma cells."<br />
<br />
"Progenitor cells exist in the perichondrial groove of Ranvier and in the articular cartilage of rabbits (IV)"<br />
<br />
"The markers associated with stem cells/progenitor cells and stem cell niches: Stro-1, Notch1, Patched, Jagged1, <u>BMPr1a</u>, 1-Integrin and N-cadherin"<br />
<br />
"Progenitor cells exist in the knee of sexually mature rabbits and are mainly located to the perichondrial groove of Ranvier. Progenitor cells have also been detected in small numbers dispersed throughout the articular cartilage."<br />
<br />
"The groove of Ranvier in the joint is a potential stem cell niche"</div><div><span style="background-color: white; color: #1c1d1e; font-family: "Open Sans", icomoon, sans-serif; font-size: 1.375rem;"><br /></span></div><b>Possible Contribution of Wnt-Responsive Chondroprogenitors to the Postnatal Murine Growth Plate</b><br /><div class="pb-dropzone" data-pb-dropzone="publicaitonContent-versions" style="background-color: white; box-sizing: border-box; color: #1c1d1e; font-family: "Open Sans", icomoon, sans-serif; font-size: 14px; scroll-behavior: auto !important;"></div><div class="loa-wrapper loa-authors hidden-xs desktop-authors" style="background-color: white; box-sizing: border-box; color: #1c1d1e; font-family: "Open Sans", icomoon, sans-serif; font-size: 14px; margin: 0.9375rem 0px; scroll-behavior: auto !important;"><div class="accordion" id="sb-1" style="box-sizing: border-box; scroll-behavior: auto !important;"><div class="comma__list" style="box-sizing: border-box; scroll-behavior: auto !important;"></div></div></div>"Active cell proliferation and turnover in the growth plate is essential for embryonic and postnatal bone growth. We performed a lineage tracing of Wnt/β-catenin signaling responsive cells (Wnt-responsive cells) using Axin2CreERT2;Rosa26ZsGreen mice and <b>found a novel cell population that resides in the outermost layer of the growth plate facing the Ranvier's groove (RG; the perichondrium adjacent to growth plate). These Wnt-responsive cells rapidly expanded and contributed to formation of the outer growth plate from the neonatal to the growing stage but stopped expanding at the young adult stage when bone longitudinal growth ceases.{since these cells are WNT responsive things that stimulate WNT would stimulate longitudinal bone growth}.</b> In addition, <b>a second Wnt-responsive sporadic cell population was localized within the resting zone of the central part of the growth plate during the postnatal growth phase. While it induced ectopic chondrogenesis in the RG, ablation of β-catenin in the Wnt-responsive cells strongly inhibited expansion of their descendants toward the growth plate.</b> These findings indicate that the Wnt-responsive cell population in the outermost layer of the growth plate is a unique cell source of chondroprogenitors involving lateral growth of the growth plate and suggest that Wnt/β-catenin signaling regulates function of skeletal progenitors in a site- and stage-specific manner."<div><br /></div>"Matrix production and accumulation are also important for interstitial growth."<br /><br />"During long bone growth, chondroprogenitors for the growth plate may reside in several locations. Cell labeling studies using tritiated thymidine or bromodeoxyuridine have suggested that the long-term labeled cells (slow-cycling cells), one of the characteristics of stem cells, are present in the perichondrium adjacent to the growth plate and the border between epiphyseal bone and the growth plate during postnatal growth in rodents and rabbits.The former region is called Ranvier's groove (RG) or the groove of Ranvier and the latter is the resting (reservoir) zone of growth plate. Previous histological and functional studies have addressed that <b>these two regions likely provide new cells to the growth plate.</b>"<br /><div><br /></div>"Wnt proteins, likely mediated by β-catenin signaling, maintain embryonic stem cell phenotype in culture."<div><br /></div>"During the growth plate development, Wnt/β-catenin signaling is indispensable. Inactivation of β-catenin signaling strongly affects cartilage development and induces morphological and functional abnormality of the growth plate, suggesting that Wnt/β-catenin signaling may participate in regulation of chondroprogenitors in the growth plate. We hypothesized that chondroprogenitors may be Wnt-regulated cells and can be visualized as Wnt/β-catenin signaling–responsive cells (Wnt-responsive cells)."<div><br /></div>"This study demonstrates that a small number of specific cells in the outermost layer of the growth plate near the RG contribute to the appositional growth of the growth plate from the early postnatal to the growing stage in mice."<div><br /></div>"decreases in number and proliferation activity of the resting chondrocytes are closely linked to reduction in bone growth with age and pathological growth arrest, indicating that the resting zone contains chondroprogenitors"Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com3tag:blogger.com,1999:blog-1013552121036660524.post-14483163478093360212013-06-24T14:42:00.002-07:002013-06-24T14:42:33.396-07:00Inhibiting growth plate ossification without inhibiting growthUsually, when the ossification stage of endochondral bone growth is inhibited so is growth like when MMP13 is inhibited for example. However, in the chicken growth plate, ossification can be inhibited without affecting longitudinal bone growth. If we apply this to humans, we can have <b>eternally open growth plates</b>.<br />
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We do know there are instances in humans where ossification is inhibited but tall stature is achieved by means such as <a href="http://www.heightquest.com/2010/09/aromatase-inhibitors-may-not-increase.html">aromatase deficiency</a>. It's possible that the people with aromatase deficiency could have quincidentally had tall stature or they could have had other mutations in addition to aromatase defiency that makes estrogen less essential to longitudinal bone growth. Perhaps, these mutations are related to making growth plates more like the chicken growth plate.<br />
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<b>Pinealectomy in a broiler chicken model impairs endochondral ossification and induces rapid cancellous bone loss </b><br />
<br />
"Adolescent idiopathic scoliosis (AIS) in humans is a lateral curvature of the spine often associated with osteopenia. It has recently been accepted that the development of AIS is closely associated with spinal overgrowth{a more controlled means of inducing spinal overgrowth with a similar pathology to scoliosis may be a possible height increase technique}. Pinealectomy (PNX) in a chicken model consistently induces scoliosis with anatomic features similar to human AIS.<br />A histomorphometric study was performed to analyze longitudinal bone growth and cancellous bone remodeling before the development of scoliosis. Static and dynamic parameters in cancellous bone and chondro-osseous junction of the 7th thoracic vertebral body at 9 days after hatching were compared between PNX chickens and control chickens with no surgery.<br />PNX resulted in a rapid and marked loss of cancellous bone volume (7.9±0.9% vs. 14.2±1.8%) and profoundly disrupted trabecular structure with increases in dynamic formative parameters, such as mineralizing surface, mineralization apposition rate, and adjusted appositional rate. In the chondro-osseous junction, activated osteoclasts phagocytized degenerating chondrocytes, leaving a minimal amount of cartilage matrix and activated osteoblasts, losing their scaffolding for bone formation, and directly covering the hypertrophic zone cells. The osteoid surface and thickness in the chondro-osseous junction were significantly increased in PNX chickens (43.1±14.2% vs. 11.6±5.7% and 4.1±0.2μm vs. 2.9±0.4 μm). <b>In the subjacent cartilage regions being protected from further resorption, abundant labeled cartilage remained with higher cellularity</b>.<br />
<b>Fast-growing birds have a unique paradigm of rapid bone elongation with minimal metaphyseal bone production.</b> <b>A bone-forming surface exists at the front of cartilage ossification in the growth plate; therefore, papillae of hypertrophic chondrocytes become included between the trabeculae of metaphyseal bone and the overall thickness of the growth plate increases considerably in addition to distal expansion</b>. Our results indicate that the unique mechanism for rapid bone elongation in chicken is more pronounced after PNX." <br />
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"Supplementation with melatonin, the hormone produced by the pineal gland, in PNX chickens produces less severe spinal deformities"<-but does melatonin also reduce the overgrowth?<br />
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"Pinealectomy (PNX) alters growth plate morphologies by enlarging the bone-forming surface. A bone-forming surface exists in front of the cartilage ossification with intermittent penetration of metaphyseal vessels. Papillae of degenerated hypertrophic chondrocytes extend into the metaphysis with osteoblasts on the surface forming primary bone trabeculae in a direction parallel to bone growth. <b>In PNX chickens, osteoblast coverage at the ossification front is enlarged.</b> Some of the osteoblasts align perpendicular to bone growth. Enlargement of the calcein-labeled hypertrophic zone and higher numbers of proliferative chondrocytes are seen."<br />
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PNX increased the hypertrophic zone area. Longitudinal bone growth was not labeled in this study however. But "“The unique paradigm of rapid bone growth” is more pronounced following PNX, suggesting longitudinal over-growth."<br />
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"In the growth plates of mammals, the ossification front is essentially straight because of the simultaneous replacement of hypertrophic chondrocytes by bone in a transverse plane and is solely composed of eroded surface. The majority of longitudinal bone growth results from advancing the whole plate by newly synthesized primary spongiosa, ie, cell proliferation and matrix synthesis at the top of the plate is more or less matched by resorption, thus the thickness of the growth plate stays reasonably constant. In the growth plates of chickens, metaphyseal vessels invade the zone of hypertrophy at intervals and resorption does not occur synchronously across the plate and a bone-forming surface exists in the chondro-osseous junction. Growth plate cartilage becomes included within the newly formed bone and the chondro-osseous junction undulates. <b>A bone-forming surface exists and the subjacent region is temporarily protected from further resorption (protected regions)</b>. Primary spongiosa is not produced where endochondral bone is produced in direction perpendicular to longitudinal growth. <b>The increase in thickness of the growth plate with reduced metaphyseal bone production considerably contributes to rapid longitudinal bone growth</b>{can we mimic this in humans?}. <b>Following PNX in chickens, activated osteoclasts and osteoblasts enlarge endochondral bone coverage. The subjacent region is protected from further resorption, resulting in the increase in thickness of the growth plates</b>"<br />
<br />
"at 6 days following PNX we found histological changes that were seen after activated osteoclasts and/or chondroclasts to a large extent phagocytized degenerating chondrocytes leaving a minimal amount of cartilage matrix. Activated osteoblasts, losing their scaffolding for bone formation, directly cover the hypertrophic cells. The enlarged endochondral bone coverage further minimizes metaphyseal bone production, leading to a rapid and marked loss of cancellous bone volume, and would accelerate bone elongation economically. Where endochondral bone covers the cartilage, the subjacent region is temporarily protected from further resorption"<-maybe a surgery can be developed to inject endochondral bone into the growth plate preventing growth plate resorption.<br />
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Let's look at the genes produced in the chicken growth plate to see if there are any that could be linked to these protected growth plate regions i.e. <b>eternal growth plate formation without fusion</b>.<br />
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<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3648502/"><b>Screening of differentially expressed genes in the growth plate of broiler chickens with Tibial Dyschondroplasia by microarray analysis.</b></a><br />
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"Tibial dyschondroplasia (TD) is a common skeletal disorder in broiler chickens. It is characterized by the presence of a non-vascularized and unmineralized cartilage in the growth plate{so we get an even better idea of genes that might protect from resorption}. Previous studies have investigated differential expression of genes related to cartilage development during latter stages of TD. The aim of our study was to identify differentially expressed genes (DEGs) in the growth plate of broiler chickens, which were associated with early stage TD. We induced TD using tetramethylthiuram disulfide (thiram) for 1, 2, and 6 dayss. <br />We identified 1630 DEGs, with 82, 1385, and 429 exhibiting at least 2.0-fold changes at days 1, 2, and 6, respectively. These DEGs participate in a variety of biological processes, including cytokine production, oxidation reduction, and cell surface receptor linked signal transduction on day 1; lipid biosynthesis, regulation of growth, cell cycle, positive and negative gene regulation, transcription and transcription regulation, and anti-apoptosis on day 2; and regulation of cell proliferation, transcription, dephosphorylation, catabolism, proteolysis, and immune responses on day 6. The identified DEGs were associated with the following pathways: neuroactive ligand-receptor interaction on day 1; synthesis and degradation of ketone bodies, terpenoid backbone biosynthesis, ether lipid metabolism, JAK-STAT, GnRH signaling pathway, ubiquitin mediated proteolysis, TGF-β signaling, focal adhesion, and Wnt signaling on day 2; and arachidonic acid metabolism, mitogen-activated protein kinase (MAPK) signaling, JAK-STAT, insulin signaling, and glycolysis on day 6."<br />
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"thiram-induced TD is not produced through an increase in chondrocyte multiplication in the transition zone, nor by altering the expression of genes causing the arrest of chondrocytes in a pre-hypertrophic state. It acts by creating metabolic dysfunction that leads to the destruction of blood capillaries in the transition zone chondrocytes. Thiram could promote chondrocyte proliferation in the growth plate of chickens, and disturbs the regulation of endochondral calcification and development of normal cartilage. This results in prehypertrophic cell accumulation, angionecrosis, abnormal extracellular matrix synthesis, deferred endochondral calcification, and bone resorption"<br />
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" the expression level of secreted frizzled-related protein 4 (sfrp4) was upregulated 2.8-, 73.5-, and 11.6-fold on days 1, 2, and 6, respectively. The expression level of cadherin 1 (cdh1) was upregulated 31.4- and 10.9-fold on days 2 and 6, respectively. Similarly, expression of enolase 2 (eno2) was upregulated 2.3-, 10.5-, and 4.0-fold on days 1, 2, and 6, respectively."<br />
<br />
"lysyl oxidase (lox), which was upregulated, participates in crosslinking of extracellular collagen via oxidative deamination of lysine or hydroxylysine"<br />
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"Downregulation of prostaglandin E receptor 4 (subtype EP4) (ptger4) and arginine vasopressin receptor 2 (avpr2) on day 1 directly influenced signal transduction and blood vessel elasticity. On day 2, downregulation of a variety of synthases altered the production of lipid compounds that are precursors of hormones, vitamin D, PTGD, and PTGE, all of which likely have an important role in angiogenesis, regulation of transcription and cell proliferation, and bone development."<br />
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Detailed comparison of these genes to LSJL genes to be done. Unfortunately, I could not find a comparison of normal chicken to human growth plates.<br />
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There was a weight loading study that <a href="http://www.heightquest.com/2010/03/compression-versus-distraction-in.html">weight loading in young chicks increased bone resorption but decreased longitudinal bone growth</a>. Maybe weight loading destroys the protected areas of the growth plate. If this were true, then that study would not be relevant to humans as humans do not have the protected zones of the growth plate.<br />
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Does Tybial dyschondroplasia cause overgrowth in chickens?<br />
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<b>Changes in the tibial growth plates of chickens with thiram-induced dyschondroplasia.</b><br />
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"Tibial dyschondroplasia (TD) is a metabolic cartilage disease of young poultry in which endochondral bone formation is disrupted leading to the retention of a non-calcified, avascular plug of cartilage in the tibial growth plate. Chicks aged 7 days were fed either a control diet or one containing thiram 100 ppm for 48 h to induce TD. Cell multiplication in the growth plate was determined thereafter with bromodeoxyuridine (BrdU) labelling, and metabolic changes by measuring alkaline phosphatase (ALP), tartrate-resistant acid phosphatase (TRAP), and glutathione (GSH) activities. The effect on chondrocyte maturation was examined. Terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) and DNA fragmentation were used to determine the effects of thiram on cell survival. Thiram-induced TD was not due to the multiplication of cells in the post-proliferative zones. Thiram did not affect ALP activity, which would have indicated a loss of calcification potential, but it reduced both TRAP and the glutathione concentrations, suggesting that the growth plate metabolism and remodelling functions were adversely affected. Thiram appeared to have no effect on the expression of type X collagen, transglutaminase, RUNX2, or matrix metalloproteinase-2 (MMP) genes suggesting that it did not alter the maturation potential of chondrocytes. On the contrary, the expressions of MMP-13 and vascular endothelial growth factor (VEGF) genes were "up-regulated," suggesting that thiram has pro-angiogenic activity. Thiram induced endothelial cell apoptosis in the capillary vessels of the growth plates, as early as 10 days of age, when TD was not visually evident. The vascular death increased on subsequent days accompanied by massive death of chondrocytes in the transition zone of the growth plate. The induction of apoptosis in the growth plate was also demonstrated by DNA fragmentation. Thiram induced TD not through an increase in the multiplication of chondrocytes in the transition zone and not by altering the expression of genes causing the arrest of chondrocytes in a prehypertrophic state, but by creating a metabolic dysfunction which led to the destruction of blood capillaries in the transition zone chondrocytes."<br />
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Thiriam also depleted Guthione levels.<br />
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<img alt="Full-size image (36 K)" border="0" class="imgLazyJSB figure large" data-fulleid="1-s2.0-S0021997505000228-gr1.jpg" data-fullheight="170" data-fullwidth="483" data-loaded="true" data-thumbeid="1-s2.0-S0021997505000228-gr1.sml" data-thumbheight="44" data-thumbwidth="125" height="170" src="http://ars.els-cdn.com/content/image/1-s2.0-S0021997505000228-gr1.jpg" style="display: inline; height: 170px; width: 483px;" width="483" /><br />
"Typical morphology of growth plates from control and thiram-fed chickens aged 16 days. (a) Control growth plate. (b) Growth plate with TD severity score of 1 from a thiram-fed chicken. (c) Growth plate with a severity score of 2 from a thiram-fed chicken."<-C looks overgrown but I can't say for sure. Tibial dyschondroplasia is associated with rapied chicken growth but we can't say in which way is the causal direction.<br />
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However, in instances where there are protected regions of the growth plate inhibiting ossification may increase and induce longitudinal bone growth. This may be the reason for the deformity as only some areas are protected thus only some areas have overgrowth thus resulting in deformity like in C.<br />
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<a href="http://ps.fass.org/content/79/7/994.long"><b>Chondrocytes and longitudinal bone growth: the development of tibial dyschondroplasia.</b></a><br />
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"Chondrocyte proliferation proceeds normally in TD, but markers of the differentiated phenotype, local growth factors, and the vitamin D receptor are abnormally expressed within the prehypertrophic chondrocytes above, and within, the lesion. Tibial dyschondroplasia is associated with a reduced incidence of apoptosis, suggesting that the lesion contains an accumulation of immature cells that have outlived their normal life span. Immunolocalization studies of matrix components suggest an abnormal distribution within the TD growth plate that is consistent with a failure of the chondrocytes to fully hypertrophy. In addition, the collagen matrix of the TD lesion is highly crosslinked, which may make the formed lesion more impervious to vascular invasion and osteoclastic resorption. "<br />
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"Abnormal, nonuniform bone growth within the area of the [TD] lesion leads to increased tibial plateau angle and tibial bowing"<-this deformity may be due to overgrowth.<br />
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So if we can recreate regions of the growth plate that can undergo longitudinal bone growth without needing the resorption phase like in some parts of the chicken then we can grow taller forever.Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com7tag:blogger.com,1999:blog-1013552121036660524.post-74742191834525865312013-06-10T16:40:00.000-07:002013-06-10T16:40:28.190-07:00Stannioncalcin 1 & 2: Two targets for inhibition for height growth<b> </b>STC1 and especially STC2 are two potent targets for inhibition during development enhancing height growth. So I open it up to brainstorming to try to find inhibitors.<br />
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<a href="http://www.jbc.org/content/281/8/5120.long"><b>Stanniocalcin 1 Acts as a Paracrine Regulator of Growth Plate Chondrogenesis</b></a><br />
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"During embryogenesis, the expression of mammalian stanniocalcin (STC1) in the appendicular skeleton suggests its involvement in the regulation of longitudinal bone growth. Such a role is further supported by the<b> presence of dwarfism in mice overexpressing STC1</b>. Yet, the STC 1 inhibitory effect on growth may be related to both postnatal metabolic abnormalities and prenatal defective bone formation. In our study, we used an organ culture system to evaluate the effects of STC on growth plate chondrogenesis, which is the primary determinant of longitudinal bone growth. Fetal rat metatarsal bones were cultured in the presence of recombinant human STC (rhSTC). After 3 days, rhSTC suppressed metatarsal growth, growth plate chondrocyte proliferation and hypertrophy/differentiation, and extracellular matrix synthesis. In addition, <b>rhSTC increased the number of apoptotic chondrocytes in the growth plate. In cultured chondrocytes, rhSTC increased phosphate uptake, reduced chondrocyte proliferation and matrix synthesis, and induced apoptosis</b>. All these effects were reversed by culturing chondrocytes with rhSTC and phosphonoformic acid, an inhibitor of phosphate transport. The rhSTC-mediated inhibition of metatarsal growth and growth plate chondrocyte proliferation and hypertrophy/differentiation was abolished by culturing metatarsals with rhSTC and phosphonoformic acid. STC1 inhibits longitudinal bone growth directly at the growth plate. Such growth inhibition, likely mediated by an increased chondrocyte phosphate uptake, results from suppressed chondrocyte proliferation, hypertrophy/differentiation, and matrix synthesis and by increased apoptosis. Last, the expression of both STC1 and its binding site in the growth plate would support an autocrine/paracrine role for this growth factor in the regulation of growth plate chondrogenesis. "<br />
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"sodium-dependent Pi (NaPi) transporter(s) may be a target of STC1 activity"<br />
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PFA is an additional inhibitor of phosphate transport also used in the study. STC decreased the hypertrophic or proliferatize zone height to an additional degree than PFA which had a relatively minor decrease. STC also decreased cartilage matrix synthesis to a much greater degree than PFA.<br />
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"100 ng/ml rhSTC significantly increased Pit-1 mRNA expression in the metatarsal growth plate, whereas it decreased mRNA expression of FGF23"<-<a href="http://www.heightquest.com/2012/06/pseudo-reactivation-of-growth-plates.html">FGF23 is involved in phosphate homeostasis and increases chondrocyte hypertrophy</a>.<br />
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"When compared with control mice, STC transgenic mice exhibited a 30-50% postnatal growth reduction."<br />
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"In a study on ADTC5 cells (a chondrogenic cell line), treatment with Pi and Ca2+ led to a decrease in the Bcl-2/Bax ratio, which is believed to disrupt the mitochondrial membrane and promote release of mitochondrial components, irreversibly engaging the cell toward apoptosis"<br />
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STC1 overexpression enhances osteoblast differentiation according to <a href="http://endo.endojournals.org/content/144/9/4134.long"><b>Stanniocalcin 1 stimulates osteoblast differentiation in rat calvaria cell cultures</b></a>.<br />
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<a href="http://mcb.asm.org/content/25/23/10604.long"><b>The murine stanniocalcin 1 gene is not essential for growth and development.</b></a><br />
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"Stc1 function is not essential for growth or reproduction in the mouse."<br />
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STC1 null mice had improved bone density but does that mean increased height? Weight growth was lower in STC1 null mice but no measurements of longitudinal bone growth were provided but they did say that growth was normal.<br />
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STC2 deletion however does increase growth according to <a href="http://endo.endojournals.org/content/149/5/2403.long">The murine stanniocalcin 2 gene is a negative regulator of postnatal growth</a>.<br />
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More on STC1 and STC2: <a href="http://ajpendo.physiology.org/content/288/1/E92.long"><b>Human stanniocalcin-2 exhibits potent growth-suppressive properties in transgenic mice independently of growth hormone and IGFs</b></a>.Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com5tag:blogger.com,1999:blog-1013552121036660524.post-47638174889530600632013-05-16T15:17:00.001-07:002014-10-30T14:44:34.099-07:00Growth Plate RegenerationThis is from the Google Preview of the Book <a href="http://books.google.com/books?hl=en&lr=&id=prGV1sM4I9wC&oi=fnd&pg=PA259&dq=%22ectopic+growth+plate%22&ots=1X-0WLSMLo&sig=rTsT_aDp8msxmMDBZ5mGDAAT4Vw">Bone: Fracture Repair and Regeneration</a>. Specifically the chapter: <b>Prospects of Regeneration of Growth Plates in Mammals</b> written in 1992. <br />
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The author Richard M. Libbin is old. I believe he is still alive in New York but I couldn't find contact info. The book was available for $8 so I bought it so I'll have more information from it.<br />
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Overall the book doesn't have new revolutionary information but it makes several statements that provide evidence for the possibility of height increase by LSJL or other mechanical means.<br />
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One interesting theory he presents is that the osseous bridge formed during growth plate fracture decreases height by decreasing blood flow to the growth plate. Blood flow has been shown to affect growth plate and height growth via genes like <a href="http://www.heightquest.com/2011/09/height-increase-by-inhibiting-hsp90.html">HSP90</a>.<br />
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The author mentions a regrowth of the hemiephysis occurring in some instances but "physeal regeneration does not occur innately in the distal humerus of the rat."<br />
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"Physeal regeneration [sites may be] formed via chondrocyte reorganization within the junctional cartilage."<br />
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"Regions of physeal regrowth were observed in the cartilage which had formed distal to the skeletal transection surfaces, and also within the junctional cartilage proximal to them."<br />
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"Proliferation of periosteal cartilage similar in morphology to fracture callus is the starting point for physeal regeneration"<br />
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"Regeneration of growth plate cartilage does not occur at forelimb amputation sites of rats [because] while exuberant periosteal chondrogenesis rapidly encloses the hindlimb bone ends within a mass of hyaline cartilage, in the forelimb the equivalent process occurs less frequently and less vigrous, newly formed cartilage rarely extending beyond the plane of amputation. The failure of rat forelimb growth plate cartilage to regenerate may reflect a deficiency in the chondrogenic potential of its periosteum."<br />
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On page 274, he mentions an argument that states that regenerative capacity is never completely lost in higher level vertebrates. In frogs, which can regenerate as tadpoles but not as full frogs the lack regenerative capacity as adults because<b> cells lose the ability to dedifferentiate</b>. Maybe this relates to genes such as OCT4, Sox2, Klf4, and Myc. Once dedifferentiation was induced through trauma, regeneration was achieved. Maybe LSJL can help induce dedifferentiation. Dedifferentiation may be a key step before neo-growth plates can be formed.<br />
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"In [instances of] regrown junctional cartilage, [that cartilage] now contained extended regions of growth plate cytoarchitechture, suggesting that <b>physeal organization is not restricted to the ends of long bones, but may be provoked to occur at other sites as well</b>."<br />
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On page 280, it's mentioned that cartilage formed off the periosteum is very similar to the growth plate in terms of cellular organization.<br />
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"<b>Any cartilage or cartilage forming tissue may be able to reform a growth plate</b>."<-MSCs and the periosteum is cartilage forming tissue. The problem with MSCs is the microenvironment of the adult bone. The goal with LSJL is induce mesenchymal condensation thus allowing MSCs to become cartilage forming tissue.<br />
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"<b>Physeal cartilage may be provoked to form anywhere along the length of the bone</b>"<br />
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"growth plate cartilage phenotype may be expressed wherever cartilage is present"<br />
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"After complete physeal ablation following division of the limb, it is periosteal cartilage which forms the regenerate, the characteristic ordered arrangement of growth plate chondrocytes appearing within an expanse of nonphyseal, hyaline cartilage as had occurred during the development of bone in fetal and neonatal life."<br />
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Mention of voluntary muscle at the skeletal end being important to cartilage regrowth. This is a place of cutoff so when I get the book, I'll analyze it.<br />
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Other Chapters:<br />
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<b>Synthesis and Stability during Fracture Repair</b><b><br /></b><br />
<b><br /></b>
"[A lack of blood vessals may not lead] to chondrogenesis because some large, sinusoid-like vessels [was detected] in the cartilage of rat tibial fractures.<b>"</b><br />
<b><br /></b>
"[Some] areas of cartilage, or chondroid bone, are transient, persisting for only a few days, and so the proteoglycans may not mature to their normal levels of sulfation."<b><br /></b><br />
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<b>Regeneration of the growth plate. </b><br />
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"in 5 different series of experiments reported between 1950 and 1986 regeneration of injured parts of growth plates in long bones of rabbits and pigs could be demonstrated. The 1st series implied partial X-ray injury of growth plates in rabbits aged 3–6 weeks.The 2nd series implied autotransplantation of the head of the fibula in rabbits aged 10–21 days. The 3rd, 4th and 5th series implied transplantation of autologous fat grafts into provoked defects of growth plates in rabbits and pigs. The findings show that regeneration of a growth plate occurs when a part of it is injured in such a manner that a bone bridge is not formed between the epiphysis and the metaphysis. Regeneration of a plate is much faster in relation to the growth in length of the bone in the rabbit than in the pig. The 1st and 2nd series suggest that regeneration takes place by interstitial proliferation of cells from the germinal layer of the uninjured parts of the plate. Signs of partial regeneration of growth plates have been seen in radiographs after operation for partial closure of growth plates in children. "<br />
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Interesting that fat tissue was implanted to prevent bone fusion.<br />
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<b><a href="http://uknowledge.uky.edu/cgi/viewcontent.cgi?article=1058&context=gradschool_theses">IGF-I RELEASING PLGA SCAFFOLDS FOR GROWTH PLATE REGENERATION</a></b><br />
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"rat bone marrow cells (BMCs) [were seeded] on the top of IGF-I encapsulated PLGA scaffolds, and the results showed an increase in cell multiplication and glycosaminoglycan content. " They were then implanted into injured growth plates. Of course, the question is what would be the effect of this implantation in a bone with no active growth plate.<br />
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"The practical difficulty in the use of IGF-I is due to its short biological half life. Encapsulation of IGF-I with PLGA protects the bioactivity and stability of IGF-I."<br />
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"Stacks of chondrocytes were observed in the case of the native growth plate. In the regenerated growth plate the chondrocytes were not found in the usual stacked manner. Single chondrocytes were distributed in the extra cellular matrix in the regenerated growth plate."<-maybe this is due to lack of some chemicals like BMP-2 or Ihh?Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com21tag:blogger.com,1999:blog-1013552121036660524.post-86871611336134743462013-05-13T21:37:00.000-07:002013-05-20T15:41:15.380-07:00Lateral Synovial Joint Loading Supplement GuideIn an earlier post, I estimated that <a href="http://www.heightquest.com/2011/01/lateral-synovial-joint-loading-three.html">you can gain 1/4" every two months from lateral synovial joint loading</a>. This seems to be going along with how <a href="http://www.lsjl.info/st-it-s-progress-log-t33.html">St.it</a>(He reported gains of about 0.5 cm for 2 months so about 1/5") and <a href="http://www.lsjl.info/r-f-s-progress-thread-t39.html">RT</a>(gains of about 1 cm in a month and a half) have reported gaining on the LSJL forum. Now, what LSJL is good at is good at is inducing <a href="http://www.heightquest.com/2011/02/is-it-possible-to-grow-taller-by.html">chondrogenic differentiation which can cause height growth</a>. But anything anabolic that can accelerate the rate of cellular proliferation can make this height growth occur faster like <a href="http://www.heightquest.com/2010/02/effects-of-growth-hormone-on-gaining.html">HGH</a>. <br />
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And incorporating <a href="http://www.heightquest.com/2010/06/can-height-be-increased-with-ultrasound.html">LIPUS</a> and electromagnetic fields(which are important as shown by the pizeoeletric current and the <a href="http://www.heightquest.com/2011/01/grow-taller-by-manipulating-opgrankl.html">OPG/RANKL</a> gradient).<br />
<br />
I'm not going to be going into things like supplement purity and supplement forms(yet). That's something that will come with time. Note that all supplements and dosages are at your own risk. I only study the possible effects of supplements on height increase. All the information I have on the supplements is based on the studies I present on this blog. This means that there are possible interactions and side effects that I may overlook. This list is intended to inspire discussion about the possibility of supplements to increase height and to inspire discussion about possible risks and side effects. I do not vouch for the safety of any supplements nor do I provide any dosages. If you want vouches of safety than look to the manufacturer or to an organization such as the FDA.<br />
<br />
DNA Protectors like Sam-e may not be necessary with a normal diet but as you do more anabolic activities or take more anabolic supplements your need for these supplements may increase.<br />
<br />
I'm will be including supplements like <a href="http://www.heightquest.com/2010/10/grow-taller-with-viagra.html">Viagra</a> and <a href="http://www.heightquest.com/2010/11/can-you-grow-taller-with-lithium-salts.html">Lithium</a> that are only available by prescription. Because if people are aware of the height increasing potential of certain supplements that might increase the availability. <br />
<br />
Dosages of each supplement likely vary based on diet, weight, and activity level.<br />
<br />
<span style="background-color: white;">Basic Lateral Joint Loading Routine(Lateral Loading of the Epiphysis):</span><br />
-Increases cellular differentiation stem cells to chondrocytes which leads to height growth.<br />
-Increases TGF-Beta, Wnt, and ECM pathways(Hyaluronic Acid).<br />
<br />
<a href="http://www.heightquest.com/2010/11/grow-taller-with-ultrasound.html" style="background-color: white;">LIPUS</a><span style="background-color: white;">:</span><br />
-Need more TGF-Beta1. Won't increase height without <a href="http://www.heightquest.com/2010/12/get-taller-stature-with-tgf-beta1.html">TGF Beta</a>.<br />
-Increases Aggrecan Expression.<br />
-Inhibits GSK-3Beta increasing cellular proliferation(which is why it makes bone fractures heal faster).<br />
<br />
<a href="http://www.heightquest.com/2010/06/being-taller-due-to-pemf.html">PEMF</a>:<br />
Increases TGF-Beta release.<br />
<br />
<span style="background-color: white;">Axial Loading(Heavy Weightlifting):</span><br />
-Increases TGF-Beta<br />
-Increases all kinds of anabolic hormones(net gain in cellular proliferation resulting in more need for anti-oxidants and DNA methylaters)<br />
-Increases need for calories<br />
<br />
<span style="background-color: white;">Endurance Training:</span><br />
-Can increase <a href="http://www.heightquest.com/2010/09/grow-tall-by-lengthening-your-telomeres.html">VO2 max which can lengthen telomeres</a><br />
-Increases sensitivity to <a href="http://www.heightquest.com/2010/03/what-is-real-cause-of-gigantism-part-ii.html">Growth Hormone</a>.<br />
<br />
<span style="background-color: white;">Now the Supplements:</span><br />
<span style="background-color: white;"><br /></span>
<span style="background-color: white;"><b>c-Fos inhibitors:</b></span><br />
<span style="background-color: white;"><b><br /></b></span>
-<a href="http://www.heightquest.com/2012/08/apigenin-another-promising-height.html">Apigenin</a><br />
<span style="background-color: white;"><br /></span>
<span style="background-color: white;"><b>Beta-Catenin inhibitors:</b></span><br />
<span style="background-color: white;"><b><br /></b></span>
<span style="background-color: white;">-<a href="http://www.heightquest.com/2011/09/grow-taller-with-sopharae-beans.html">Quercetin</a></span><br />
<span style="background-color: white;"><br /></span>
<span style="background-color: white;"><b>EstrogenReceptorAlpha inhibitors:</b></span><br />
<span style="background-color: white;"><b><br /></b></span>
-<a href="http://www.heightquest.com/2012/08/royal-jelly-has-lot-of-potential-to.html">Royal Jelly</a><br />
<br />
<b style="background-color: white;">ECM(Extracellular Matrix) Protectors:</b><br />
<br />
-As your shear strain increases your need for more ECM increases so endurance training, sprinting or other exercises that cause shear strain on chondrocytes. You'll notice that your bones will crack more after endurance training(not like a chiropractic crack but more of a dry crack).<br />
<br />
So the more you run the more of these you'll need-<br />
-<a href="http://www.heightquest.com/2010/04/grow-taller-with-glucosamine-and.html">Chondroitin & Glucosamine</a><br />
-<a href="http://www.heightquest.com/2010/12/height-gaining-with-hyaluronic-acid.html">Hyaluronic Acid</a> <-More Important than Chondroitin & Glucosamine for growing taller<br />
<br />
<a href="http://www.heightquest.com/2011/11/grow-taller-with-seaweed-and-beta.html">Seaweed and Beta-Glycerophosphate</a>:<br />
Beta-Glycerophosphate may play a role in allowing endochondral ossification without periosteum. Seaweed may help increase ECM levels.<br />
<br />
<a href="http://www.heightquest.com/2011/10/can-forskolin-help-with-increasing.html">Forskolin</a>:<br />
Increases proteoglycan syntehesis and aggrecan mRNA.<br />
<br />
Glucosamine may only have benefits if you engage in a lot of joint taxing exercises whereas hyaluronic acid and chondroitin can help you grow taller during puberty or while performing LSJL.<br />
<br />
<b>DNA Protectors:</b><br />
<b><br />
</b><br />
-B6, <a href="http://www.heightquest.com/2010/12/increase-your-height-with-vitamin-b12.html">B12</a>, Folic Acid(<-The need for these increases the more anabolic activities you engage in or the more anabolic supplements intake)<br />
<br />
-<a href="http://www.heightquest.com/2010/09/grow-taller-with-folinic-acid.html">Folinic Acid</a> may provide additional protection for DNA. It should also be noted that Folinic Acid produced an observable increase in growth plate morphology and a non-significant increase in longitudinal bone growth.<br />
<br />
-<a href="http://www.heightquest.com/2010/09/increase-your-height-with-s-adenosyl.html">Sam-e</a>(<-You only need this if B6, B12, and Folic Acid are not performing their jobs which they do in most people)<br />
<br />
-Telomere Length(<a href="http://www.heightquest.com/2010/11/super-growth-boosting-with-igh-1.html">Astragalus Membranaceous</a> which also doubles as an anti-oxidant)<br />
<br />
-<a href="http://www.heightquest.com/2012/06/inflammation-to-grow-tall.html">Anakrina and Entarnercept</a>(prescription only substances that act to inhibit TNF-alpha and IL-1Beta, those two compounds are produced endogenously by growth plate chondrocytes and reduce growth)<br />
<br />
<b style="background-color: white;">Increase Cellular Proliferation(May not always increase final adult height but results in faster gains in LSJL and doesn't hurt):</b><br />
<b><br />
</b><br />
-Examples are HGH, Myostatin Inhibitors, IGF-1, Testosterone. The higher your cellular proliferation rate the more DNA protectors and anti-oxidants you need. Use all supplements as directed(Niacin must be taken at a specified large dose). Remember, that anabolic supplements increase non-bone cells as well such as skin cells, muscle cells, etc. Usually, adipogenic differentiation is inhibited though.<br />
<br />
-<a href="http://www.heightquest.com/2010/10/natural-height-increase-with-creatine.html">Creatine</a>(inhibits Myostatin)<br />
<br />
-<a href="http://www.heightquest.com/2010/11/add-some-inches-to-your-height-with.html">Lactoferrin</a>(increases chondrocyte proliferation, also available in milk)<br />
<br />
The below two supplements are testosterone boosters and have a role in the nitric oxide pathway which can increase height growth:<br />
<br />
-<a href="http://www.heightquest.com/2010/10/growing-tall-with-protodioscin.html">Tribulus Terristris</a><br />
<br />
-<a href="http://www.heightquest.com/2010/09/grow-taller-with-horny-goat-weed.html">Horny Goat Weed</a><br />
<br />
-<a href="http://www.heightquest.com/2010/08/increase-growth-hormone-levels-with.html">Niacin</a>(enhances the bodies response to HGH when taken in large doses)<br />
<br />
-<a href="http://www.heightquest.com/2010/08/increase-non-long-bones-height-with.html">Puerarin</a>(increases cellular proliferation by the PI3K pathway)<br />
<br />
-<a href="http://www.heightquest.com/2010/05/increase-height-with-irs-1-and-mapks.html">Leptin</a>(increases cellular proliferation)<br />
<br />
<a href="http://www.heightquest.com/2010/11/can-you-grow-taller-with-lithium-salts.html">Lithum</a>:<br />
-Increases cellular proliferation and hypertrophy be inhibiting GSK3Beta however may have negative effects on height<a href="http://www.heightquest.com/2012/05/genes-involved-in-growth-plate.html"> like stabilizing Beta-Catenin</a>. However, <a href="http://www.heightquest.com/2011/06/grow-taller-by-increasing-chromatin.html">inactivation of Beta Catenin & overexpression of Sox9 has been shown to reduce height</a>. <a href="http://www.heightquest.com/2010/02/factors-that-affect-chondrocyte_24.html">Methylation of Sox9 by CARM1</a> inhibits Beta-Catenin degradation so upregulating Beta-Catenin may not be needed in some circumstances.<br />
<br />
<a href="http://www.heightquest.com/2011/09/grow-taller-with-sopharae-beans.html">Sophorae Beans</a>:<br />
Increases TGF-Beta and IGF-1 levels.<br />
<br />
<a href="http://www.heightquest.com/2011/08/grow-taller-with-cnidium.html">Cnidium</a>:<br />
Increases bFGF, IGF-1, and BMP-2 levels.<br />
<br />
<a href="http://www.heightquest.com/2010/09/will-alfalfa-really-help-you-grow.html">Alfalfa(Ipriflavone)</a>:<br />
Increases IGF-1 and Type II Collagen levels.<br />
<br />
<span style="background-color: white;">Growth Plate regulation(Endochondral Ossification Pathways):</span><br />
<br />
<a href="http://www.heightquest.com/2010/06/can-your-height-increase-with.html">Teriparatide</a>:<br />
<a href="http://www.heightquest.com/2010/11/can-zinc-make-me-taller.html">Parathyroid hormone antagonizes Ihh, Runx2, and TypeX Collagen differentiation plus upregulates CyclinD1</a>. So basically Parathyroid Hormone delays terminal differentiation and increases chondrocyte proliferation. <a href="http://www.heightquest.com/2012/05/genes-involved-in-growth-plate.html">PTH also stimulates Nkx3.2 which increases type II collagen(cartilage) and GAG production</a>. Parathyroid Hormone is pro-chondrogenic.<br />
<br />
<a href="http://www.heightquest.com/2010/10/grow-taller-with-viagra.html">Viagra</a>:<br />
PDE5 inhibitor and stimulates the Nitric Oxide pathway. The Nitric Oxide Pathway and CNP both increase cGMP levels thus like <a href="http://www.heightquest.com/2010/04/growing-taller-with-natriuretic.html">CNP</a> may increase longitudinal growth. Viagra is a far more effective NO pathway stimulator than something like <a href="http://www.heightquest.com/2010/10/grow-taller-with-arginine.html">arginine</a>, as Viagra targets a NO pathway inhibitor(PDE5) and so may be less susceptible to negative feedback mechanisms than something like Arginine.<br />
<br />
<a href="http://www.heightquest.com/2011/03/increase-your-height-with-ecdysterone.html">Ecdysterone</a>:<br />
Stimulates NO pathway.<br />
<br />
<a href="http://www.heightquest.com/2011/02/increasing-height-with-acteoside-and.html">Harpogoside</a>:<br />
Inhibits NFKappaB which inhibits height growth in active growth plates. In bones with no growth plates, NF-kappaB may cause apoptosis of bone cells and stimulate stem cells. So you shouldn't take Harpogoside if you have active growth plates.<br />
<br />
<b>Anti-Oxidants:</b><br />
<b><br />
</b><br />
<a href="http://www.heightquest.com/2011/12/grow-taller-with-ascorbic-acidvitamin-c.html">Vitamin C</a>:<br />
Vitamin is pro-chondrogeneic. It is unclear whether levels of Vitamin C above requirements would help increase height however Vitamin C deficiency reduces height. <a href="http://www.amazon.com/gp/product/B003FW4UME/ref=as_li_ss_tl?ie=UTF8&tag=thequ01-20&linkCode=as2&camp=1789&creative=390957&creativeASIN=B003FW4UME">Vitafusion Power C, Gummy Vitamins For Adults, 150-Count</a><img alt="" border="0" height="1" src="http://www.assoc-amazon.com/e/ir?t=thequ01-20&l=as2&o=1&a=B003FW4UME" style="border: none !important; margin: 0px !important;" width="1" />.<br />
<br />
<span style="background-color: white;">-Pretty much all anti-oxidants are good except for </span><a href="http://www.heightquest.com/2011/01/grow-taller-with-anti-oxidants.html" style="background-color: white;">NAC</a><span style="background-color: white;"> which inhibits free radicals that are essential for height growth(NADPH).</span><br />
<br />
<a href="http://www.heightquest.com/2010/07/melatonins-affect-on-height.html">Melatonin</a>:<br />
Increases levels of TGF-Beta in addition to scavenging free radicals. Note that Melatonin increases levels of CYP1A2 which metabolizes Melatonin. Therefore it may be necessary to cycle Melatonin. Also note, that most doses of Melatonin may be too high and may increase CYP1A2 levels higher than a low dose for the same beneficial effects. Many studies have found 0.3mg of Melatonin to be effective versus the 3mg in most supplement tablets. Here's 0.5mg Melatonin: <a href="http://www.amazon.com/gp/product/B00166FXY0/ref=as_li_ss_tl?ie=UTF8&tag=thequ01-20&linkCode=as2&camp=1789&creative=390957&creativeASIN=B00166FXY0">Pure Encapsulations Melatonin 0.5 mg - 180 capsules</a><img alt="" border="0" height="1" src="http://www.assoc-amazon.com/e/ir?t=thequ01-20&l=as2&o=1&a=B00166FXY0" style="border: none !important; margin: 0px !important;" width="1" />.<br />
<br />
-<a href="http://www.heightquest.com/2010/05/grow-taller-with-acai-berry-and-lithium.html">Acai Berry</a> has been shown to be a highly effective anti-oxidant and it is available in foods(Acai berry enhanced smoothies)<br />
<br />
<b>Diet:</b><br />
<br />
<a href="http://www.heightquest.com/2010/12/grow-taller-with-beer.html">Silicon Reduced Diet</a>:<br />
-Silicon Deficiency may have possibility to inhibit growth plate closure and increase longitudinal growth.<br />
-Silicon seems to be pro-bone rather than pro-cartilage. Thus, a silicon deficiency may be favorable to increased chondrogenesis.<br />
<br />
<span style="background-color: white;">So if you want to grow taller faster with LSJL. First, look at what physically can you do that's anabolic like cardio and weight training. Then make sure as you increase your activity level increase your levels of chondrocyte protectors as necessary. Also increase your levels of DNA protectors and anti-oxidants.</span><br />
<br />
With each supplement that's anabolic you try up your anabolic and DNA protector supplement content as well. For safety, whenever possible go for water soluble supplements like Vitamin C.Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com43tag:blogger.com,1999:blog-1013552121036660524.post-37893196187225377732013-05-02T15:49:00.001-07:002022-09-17T21:15:53.609-07:00Grow taller with Collagen HydrolysatesCollagen Hydrolysates are available for sale: <br />
<a href="http://www.amazon.com/gp/product/B00546EMCC/ref=as_li_ss_tl?ie=UTF8&camp=1789&creative=390957&creativeASIN=B00546EMCC&linkCode=as2&tag=thequ01-20">Alfa Vitamins Collegen Hydrolysate Nutrition Supplement, 120 Count</a><img alt="" border="0" height="1" src="http://www.assoc-amazon.com/e/ir?t=thequ01-20&l=as2&o=1&a=B00546EMCC" style="border: none; margin: 0px;" width="1" /><br />
<br />
This makes it a very promising supplement but the cost of the dosage ratios recommended would be insane but could be up to 25% additional height. There are 120 pills for $10. A 50lb kid would take 25 a day to meet the dosage requirements. So that would be about $2.50 a day. Which I guess is not that bad. <br />
<br />
<b>Porcine Skin Gelatin Hydrolysate Promotes Longitudinal Bone Growth in Adolescent Rats.</b><br />
<br />
"Collagen hydrolysates (CHs) are mixtures of peptides obtained by partial hydrolysis of gelatin that are receiving scientific attention as potential oral supplements for the restoration of osteoarticular tissues. The aim of this study was to evaluate the effectiveness of CHs for promoting longitudinal bone growth in growing rats. An in vitro study was carried out in osteoblast-like MG63 cells and the most effective CH on bone formation was selected among 36 various CHs. An in vivo study confirmed the functional effects of a selected CH with molecular weight of <3 kDa on longitudinal bone growth. <b>CHs dose-dependently promoted the longitudinal bone growth and height of the growth plate in adolescent male rats</b>, whereas gelatin failed to affect longitudinal bone growth. Insulin-like growth factor-1 and bone morphogenetic protein-2 in the CH treated group were highly expressed in the growth plate."<br />
<br />
"Collagen is the major constituent of the connective tissues in vertebrates, comprising 30% of total body protein. The denatured form of collagen is referred to as gelatin and is commonly used in foods, pharmaceuticals, cosmetics, and others. To increase the solubility of gelatin, partially hydrolyzed gelatin products have been prepared and are referred to as collagen hydrolysates (CHs)." <br />
<br />
3-Week old male Sprague-Dawley rats were used.<br />
<br />
"Longitudinal bone growth in normal adolescent male rats was 404.0±11.6 μm/day, and administration of 50 and 250 mg/kg gelatin failed to promote the longitudinal bone growth. However, treatment with 250 mg/kg of CH significantly increased the longitudinal bone growth exhibiting 468.4±27.4 μm/day."<-The dosage for the alfa vitamins collagen above is 1000mg. So maybe a human should actually take a larger dosage. 250mg/kg is actually pretty insane dosage in terms of cost but growth was over 25% more. That's 550mg/lb. So a 200lbs individual would have to take 100 pills a day. 50mg/kg still increased height just not statistically significantly.<br />
<br />
Here's the growth plate under Collagen Hydrolysate(growth plate height was increased by 11%).<br />
<img alt="http://online.liebertpub.com/na101/home/literatum/publisher/mal/journals/content/jmf/0/jmf.ahead-of-print/jmf.2012.2461/20130430/images/large/figure3.jpeg" class="decoded" height="498" src="http://online.liebertpub.com/na101/home/literatum/publisher/mal/journals/content/jmf/0/jmf.ahead-of-print/jmf.2012.2461/20130430/images/large/figure3.jpeg" style="cursor: -moz-zoom-in;" width="423" /><br />
"CHs with molecular weights <3000 Da that is able to increase IGF-1 and BMP-2 protein expression in growth plate, and consequently promote longitudinal bone growth in growing rats."<-the molecular weight of the supplement above is not listed. Looking it up Collagen Hydrolysate has an average molecular weight of 2000-5000 Da so it's possible that the molecular weight here is over the threshold but humans may be able to tolerate the higher moleculate rate than rats.<br />
<br />
Food consumption doesn't seem to be measured but gelatin could serve as sort of a control to that.<div><br /><b>Biological effect of hydrolyzed collagen on bone metabolism</b><br /> </div><div><b><br /></b></div>"an increase in the overall metabolism of collagen can lead to severe dysfunctions and a more fragile bone matrix and because orally administered collagen can be digested in the gut, cross the intestinal barrier, enter the circulation, and become available for metabolic processes in the target tissues, one may speculate that a collagen-enriched diet provides benefits for the skeleton."<div><br /></div><div>couldn't get full study</div><div><br /></div>Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com24tag:blogger.com,1999:blog-1013552121036660524.post-15719194951952812242013-05-02T15:27:00.001-07:002022-08-20T20:23:50.524-07:00The osteochondral endplateThe osteochondral endplate is the place where the articular cartilage meets the bone. What we've learned about <a href="http://www.heightquest.com/2013/01/increase-your-stature-with-plastic.html">plastic deformation</a> is that is a threshold strain that must be achieved to induce longitudinal growth in the bone. Studies with <a href="http://www.heightquest.com/2010/08/comparison-of-epiphyseal-distraction.html">epiphyseal distraction</a> have shown that stretching the growth plate rarely increases height without fracturing the bone.<br />
<br />
<i><u><b>Directly stretching the growth plate did not increase height unless there was fracture or the distraction caused an increase in growth plate activity. Since stretching the growth plate region does not directly increase height it is unlikely that the growth plate region increases height by stretching that region. If growth plate increased height by stretching the bone shouldn't a mechanism of stretching like epiphyseal distraction also increase height?</b></u></i><br />
<i><u><b></b></u></i><br />
<br />
We also know that the amount of tensile strain to induce a longitudinal stretch in the cortical bone is extreme and unlikely to be generated by the growth. <a href="http://www.heightquest.com/2010/12/physics-of-growing-taller-via-your.html">The growth plates must induce a physical mechanism of growing taller</a>, otherwise cartilage would just transform into bone and your bones would not grow longer. I propose that this method involves a force against the osteochondral endplate.<br />
<br />
<br />
The epiphysis is weaker than the diaphysis of the bone. The epiphysis is not cylindrical shaped so it is less stable. This is a picture of the tibia:<br />
<br />
<img height="320" id="irc_mi" src="http://content.answcdn.com/main/content/img/oxford/Oxford_Sports/0199210896.tibia.1.jpg" style="margin-top: 24px;" width="196" /><br />
<br />
What if the mechanism of growing taller was just to push away the osteochondral endplate and then the stronger cortical bone grows around it?<br />
<br />
<b>The Cartilage-Bone Interface</b><br />
<br />
"Mature articular cartilage is integrated with subchondral bone through a 20 to 250 μmthick layer of calcified cartilage. Inside the calcified cartilage layer, perpendicular chondrocyte-derived collagen type II fibers become structurally cemented to collagen type I osteoid deposited by osteoblasts. <b>The mature mineralization front is delineated by a thin 5 μm undulating tidemark structure that forms at the base of articular cartilage. Growth plate cartilage is anchored to epiphyseal bone, sometimes via a thin layer of calcified cartilage and tidemark{so the tidemark that is at the same at the osteochondral endplate is similar to that of growth plate cartilage},</b> while the hypertrophic edge does not form a tidemark and undergoes continual vascular invasion and endochondral ossification (EO) until skeletal maturity upon which the growth plates are fully resorbed and replaced by bone. <b>The tidemark can be regenerated through a bone marrow-driven growth process of EO near the articular surface</b>."<br />
<br />
"In the developing knee, epiphyseal bone will continue to expand into the cartilage anlage until the cartilage interface forms a thin calcified layer that arrests vascular invasion. Calcified cartilage forms at the base of the articular cartilage, and in certain growth plate reserve zones"<br />
<br />
"Growth plate hypertrophic cartilage (HTC) does not form a tidemark. This interface is actually a mixture of cartilage and bone, by definition of the primary spongiosa,where newbone is deposited on the cartilage trabeculae carved out by invading blood vessels and marrow"<br />
<br />
"Like articular cartilage, the growth plate hypertrophic zone also contains collagen type X and alkaline phosphatase, but a tidemark is notably absent. The tidemark that forms at the base of mature articular cartilage develops slightly below the region of chondrocytes expressing collagen type X. Mineral deposits form in the neonatal calcified layer of the articular cartilage in line with the collagen fibers."<br />
<br />
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<a href="https://3.bp.blogspot.com/-9xp_WVmrs2E/W2z5GBTj_zI/AAAAAAAABjc/nRsBAyeIZ4gNHC7Otl02rWHCM4o2wAPdQCEwYBhgL/s1600/Screenshot%2B%25285%2529.png" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="1024" data-original-width="1280" height="256" src="https://3.bp.blogspot.com/-9xp_WVmrs2E/W2z5GBTj_zI/AAAAAAAABjc/nRsBAyeIZ4gNHC7Otl02rWHCM4o2wAPdQCEwYBhgL/s320/Screenshot%2B%25285%2529.png" width="320" /></a></div>
<br />
<br />
<br />
According to this diagram the articular cartilage grows by appositional growth so you should be able to grow taller with no growth plates by appositional growth in the articular cartilage.<br />
<br />
"A distinct and more advanced EO process is going on during postnatal articular cartilage growth(►Fig. 1E and H). In 3- to 6-month-old rabbit articular cartilage,most chondrocytes are no longer proliferating, and a tidemark has formed at the base ofthehypertrophiczone.23 Bone is not being deposited along cartilage trabeculae,i thas developed layer-by-layer to form a thick osteoid around blood vessels subjacent to the calcified cartilage layer. Only small patches of cartilage persist in the subchondral bone (EO, ►Fig. 1E). The remnants of GAG and collagen type II in trabecular bone are the hallmarks of EO"<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
</div>
"The calcified cartilage layer is semipermeable and permits passage of small molecules (<500 Da) from the subchondral bone to the articular cartilage layer"<br />
<br />
"Thickening of the calcified cartilage in OA could be expected to reduce the flow of small solutes from the vascularized subchondral bone to the deep zone chondrocytes."<-Maybe this could be part of the reason that <a href="http://www.heightquest.com/2011/10/why-dont-people-with-osteoarhritis-grow.html">people with osteoarthritis don't grow taller</a>?<br />
<br />
"Once formed, the tidemark and calcified cartilage layer persist as dynamic structures that can change and remodel over time. Below mature articular cartilage, the mineralization front is a relatively smooth and undulating plate-like surface"<-Maybe this remodeling of the tidemark and calcified cartilage layer plays a role in height growth<br />
<br />
"growth plates develop a relatively stable reserve zone-epiphyseal bone interface, with a purely collagen type II GAG-rich cartilage phase, and a mixture of collagen type I and collagen type II in the newly forming primary spongiosa. Calcified cartilage becomes established at the edges of a “permanent” epiphyseal bone layer (i.e., proximal reserve zone and articular cartilage hypertrophic zone), and the tidemark serves as a barrier to vascular invasion and calcification of hyaline cartilage."<-maybe we can induce tidemarks to prevent growth plate resorption. <br />
<br />
"The mineral front at the base of the growth plate corresponds with the vascular bone and newly deposited collagen type I. In the growth plate hypertrophic zone, calcification of the collagen type II matrix is much delayed compared with the articular cartilage calcified layer. This is because after<br />
birth, the mammalian joints require a suitable mechanically stable articular surface, while growth plates in the long bones are continually expanding, even beyond sexual maturity. <b>Cartilage calcification is therefore only occurring at the end-stage of cartilage growth.</b> After reaching skeletal maturity, growth plates are completely resorbed and replaced by collagen type I–positive mineralized bone."<-So it's possible that the tidemark is both the limiting factor for the articular cartilage and the growth plate.<br />
<br />
"Calcified cartilage becomes established at the edges of a “permanent” epiphyseal bone layer (i.e.,<br />
proximal reserve zone and articular cartilage hypertrophic zone), and the tidemark serves as a barrier to vascular invasion and calcification of hyaline cartilage."<-So if you cause advancement of the tidemark you may create a signal for the bone to grow longer.<br />
<br />
<a href="https://www.blogger.com/blogger.g?blogID=1013552121036660524" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"></a>"In the calcified cartilage layer of normal human femoral condyles, chondrocytes are quiescent[not dividing] and present at a much lower density compared with hyaline cartilage (average of 51 cells/mm2 versus 152 cells/mm2).The calcified cartilage layer is flanked by an undulating tidemark, and an even more irregular cement line adjacent to the bone"<br />
<br />
"the ratio of calcified cartilage to total cartilage thickness [is] relatively constant." Calcified cartilage layer thins with age and older adults can experience tidemark advancement.<br />
<br />
" Repetitive knee microtrauma in a rabbit model during 9 weeks of loading was shown to lead to a mean 25% increase in the proximal tibial calcified cartilage layer thickness, and tidemark duplication, with no change in mean articular cartilage thickness"<br />
<br />
"Tidemark duplication could be related to uneven load-sharing following softening of a focal area of damaged cartilage"<br />
<br />
"The tidemark is a 5 μm thick structure that appears at the cartilage-calcified cartilage junction"<br />
<br />
"A significant correlation was observed between increasing tidemark duplication, mineral density, and carbonate content in primates. Repetitive knee microtrauma in a rabbit model during 9 weeks of loading was shown to lead to a mean 25% increase in the proximal tibial calcified cartilage layer thickness, and tidemark duplication, with no change in mean articular cartilage thickness"<br />
<br />
"chondrogenic foci will spontaneously form in drill or microfracture holes generated in skeletally mature knee cartilage defects"<br />
<br />
"In some rabbit cartilage repair models involving complete debridement[removal] of the calcified cartilage layer, <b>subchondral bone plate advancement beyond the native tidemark in flanking cartilage has been observed after 3 to 9 months of repair</b>."<-so it may be the calcified cartilage layer that allows for height growth and not the tidemark<br />
<br />
"the calcified layer is undergoing continual resorption and endochondral advancement over time"<br />
<br />
"the epiphyseal blood vasculature in skeletally immature knees has active endothelial cell proliferation while adult vasculature has postmitotic endothelia and the subchondral bone no longer contains osteoclasts."<-Can LSJL induce endothelial cell proliferation and osteoclast differentiation in adult epiphysis?<br />
<br />
I've always said there is nothing that inhibits the formation of
growth plates in adult epiphysis. This study presents two factors that
could inhibit adult growth plate formation: lack of proliferating
epithelia and no osteoclasts.<br />
<br />
According to <b>Early growth response 2 negatively modulates osteoclast differentiation through upregulation of Id helix-loop-helix proteins</b>., egr2(which LSJL upregulates) downregulates osteoclasts by transactivating Id2 however LSJL downregulates Id2.<br />
<br />
"All cartilage-bone interfaces develop from an initially cartilaginous
structure that undergoes coordinated invasion by blood vessels and
osteoblasts. <b>Formation of a tidemark anatomically stabilizes the
cartilage-bone interface and arrests cartilage calcification and blood
vessel invasion. </b>Vascularization of the calcified cartilage
layer and subchondral bone plate is an important feature of a healthy
cartilage-bone interface." <br />
<br />
"Calcified cartilage and osteoid in the adult subchondral bone have a similar mineral level."<br />
<br />
"Bone plate advancement could be a consequence of delayed or failed tidemark regeneration during bone marrow-driven EO below hyaline-like repair tissue."<br />
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<img border="0" height="320" src="https://2.bp.blogspot.com/-P4FooyclV5o/UYLoLCzaLYI/AAAAAAAAA_k/h_nWRpQUDi4/s320/growth+plate.jpg" width="213" /></div>
<br />
<br />
"The growth plate-epiphyseal bone interface sometimes includes a layer of calcified cartilage and a tidemark in the reserve zone (A, proximal trochlea), and in other areas is devoid of calcified cartilage<br />
or tidemark and fused to a more vascular bone (B, distal trochlea). Representative decalcified transverse sections from 4-month-old rabbit trochlear growth plates stained with hematoxylin and eosin are shown, from N ¼ 7 distinct New Zealand white rabbit femurs, 4 months old. TM, tidemark (white arrows); BV, blood vessels; CC, calcified cartilage; EO, endochondral ossification (cartilage remnant)."<-Growth for New Zealand White Rabbits really starts to taper off at 19 weeks of age.<br />
<br />
Here's the study related to the advancement of the subchondral bone past the tidemark:<br />
<br />
<b>Observations of subchondral plate advancement during osteochondral repair: a histomorphometric and mechanical study in the rabbit femoral condyle.</b><br />
<br />
"Osteochondral defects, 3mm diameter by 3mm deep, were made by controlled drilling through the articular surface into the subchondral bone in femoral condyles of 33 rabbits. The repair response was examined at 8, 16 and 32 weeks post surgery. <br />
At 8 weeks, the level of reparative subchondral bone was 0.79+/-0.36 mm below the native tidemark. <b>By 16 weeks, reformed subchondral plate was irregular, showing that 76.5% of the plate had extended beyond the native tidemark</b> (0.13+/-0.05 mm) whilst 16.9% of the plate remained below (0.19+/-0.15 mm). The repaired surface non-osseous layer became thinner than the adjacent cartilage (0.23+/-0.08 vs 0.38+/-0.11 mm, P<0.05). This persisted up to 32 weeks. The repaired surface layers showed disappearance of safranin-O staining, increased separation splits at the boundary, and eventual degradation. General histological scores were similar across 8, 16 and 32 weeks although the scores of defect filling and restoration of osteochondral junction were decreased from 8 to 16 weeks. Mechanically, repaired defects had lower contact pressure and greater indentation than the normal controls at all time. Indentations of the cartilage adjacent to the defects were also greater than the normal at 8 and 32 weeks."<br />
<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="http://4.bp.blogspot.com/-gAknRXuTTCM/UYLnl3dApDI/AAAAAAAAA_c/QRakeF_LkPQ/s1600/osteochondral.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="258" src="https://4.bp.blogspot.com/-gAknRXuTTCM/UYLnl3dApDI/AAAAAAAAA_c/QRakeF_LkPQ/s320/osteochondral.jpg" width="320" /></a></div>
<br />
The bone here is taller! If this had occurred in all the longitudinal ends of the bone you would have a longer bone. The arrow is pointing to the subchondral bone advancement.<br />
<br />
"<b>In [some osteochondral] defects, new marrow-derived cartilage underwent endochondral ossification, forming bone on the surface of calcified cartilage cores.</b> In the depths of the defects, new bone formed directly from osteoblasts derived from marrow mesenchymal cells. The new bone is initially woven, eventually becoming lamella, with the subchondral region modified to form a compact bone plate and a reformed tidemark. However, histological architecture of the reconstituted bone plate and cancellous bone was not identical to the original, and the new tidemark and subchondral bone advanced beyond the native level."<br />
<br />
"contact pressure [is the] pressure between the articular surface and the flat circular surface of the transducer."<br />
<br />
"contact pressures of reparative articular surfaces were either higher or lower than normal controls, and suggested these differences were related to thickness variation of repaired surface tissue and the presence or absence of an abnormally thick subchondral plate."<br />
<br />
There isn't a tidemark for the hypertrophic chondrocytes of the epiphyseal growth plate. What if the tidemark serves as both the limiting factor for both the articular cartilage and longitudinal bone growth? With removal of the tidemark/calcified cartilage layer there was advancement of the subchondral bone. Thus, maybe the growth plate exerts a force causing an advancement of the tidemark allowing for new longitudinal bone growth.<br />
<br />
In this model, growth plates would produce upward force(contact pressure) pushing the tidemark upwards allowing for new bone growth.Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com2tag:blogger.com,1999:blog-1013552121036660524.post-73164681789564596462013-04-29T14:28:00.002-07:002021-01-28T08:47:58.761-08:00Flurbiprofen(Grow Taller by manipulating Lymphocyte count) This is a compliment to the analysis by <a href="http://www.naturalheightgrowth.com/2013/04/06/increase-height-and-grow-taller-using-flurbiprofen-breakthrough/">Natural Height Growth on Flurbiprofen</a>.<br />
<br />
What's interesting about Flurbiprofen is that usually things that increase growth plate height as a result of inhibiting cartilage or bone degraders usually decrease growth such as MMP13 inhibitors.<br />
<br />
My hypothesis is that it alters bone growth by inhibiting lymphocyte(immune cell type) activity. There needs to be an equilibrium amount of lymphocyte activity as confirmed by the highest dose of Flurbiprofen decreasing longitudinal bone growth. Based on whether the amount of lymphocytes you have is above or below equilibrium taking Flurbiprofen will either increase or decrease your height.<br />
<br />
Lymphocytes can be measured on a blood sample. Unfortunately, we don't know the optimal lymphocyte count for maximizing height growth so we don't know what the target goal would be with Flurbiprofen.<br />
<br />
<b>Flurbiprofen-induced stimulation of periosteal bone formation and inhibition of bone resorption in older rats.</b><br />
<br />
"The skeletal effects of flurbiprofen (Fb), a nonsteroidal anti-inflammatory drug, was studied by histomorphometry in 9-month-old retired female breeder, Sprague-Dawley rats. Flurbiprofen was given subcutaneously at 0, 0.2, 0.1, 0.5, 2.5, or 5 mg/kg/d for 21 days. <b>Flurbiprofen had no effect on longitudinal growth, but stimulated radial growth (+200%){maybe this could give a little skull and calcaneus height?} over controls. In the tibial shaft, Fb stimulated the mineral apposition rate (+25%), mineral bone formation rate (+100%), and periosteal labeling length (+64%) at the 2.5 and 5.0 mg Fb/kg dose levels, and had no effect on marrow cavity size compared to controls.</b> However, these changes were insufficient to increase cortical bone mass. In the proximal tibial metaphysis,<b> Fb suppressed osteoclasts/mm2 of metaphyseal tissue (-47%), osteoclasts/mm of bone surface (-46%), and the osteoclast/osteoblast ratio (-50%), increased the calcified cartilage core population (+100%), and had no effect on osteoblast numbers at all dose levels{<a href="http://www.heightquest.com/2010/04/osteoclasts-increase-height.html">osteoclasts</a> may be good for height during development and may allow for the formation of cartilage canals to form new growth plates}</b>. There was an insignificant increase in metaphyseal cancellous bone mass. Flurbiprofen-stimulated periosteal bone growth was due to direct stimulation of osteoblast recruitment and activity independent of longitudinal bone growth."<br />
<br />
"retired female breeder, Sprague-Dawley rat, with a 5 mcm/day longitudinal growth rate of the proximal tibia and a 3.6 mcm/day periosteal bone apposition rate of the tibia) shaft ."<-I'm not sure what mcm is relative to units of measurement but 9 month old rats are still growing.<br />
<br />
"increased longitudinal bone growth and growth plate thickness in the weanling rat [who took flurbiprofen], while the size of the hypertrophic cells and the cartilage cell production rate did not differ from the controls ."<br />
<br />
In older rats, there was an increase in the size of the calcified cartilage core.<br />
<br />
<b>Flurbiprofen enhances growth and cancellous and cortical bone accumulation in rapidly growing long bones.</b><br />
<br />
"The effects of flurbiprofen, a non-steroidal anti-inflammatory drug, on bone growth was studied by static and dynamic histomorphometry in immature (28 days old) male Sprague-Dawley rats. Flurbiprofen at 0, 0.02, 0.1, 0.5 or 2.5 mg/kg/d doses was given subcutaneously daily for 21 days. <b>The 0.1 and 0.5 mg/kg/d doses were most effective in stimulating longitudinal and radial bone growth and enhancing the accumulation of cancellous and cortical bone{so it seems there is an equilibrium quantity}.</b> Proximal tibial longitudinal bone growth rate, growth plate thickness, and periosteal bone formation rate were increased 30-40%, while cortical bone (tibial shaft) and cancellous bone (proximal tibial metaphysis) accumulated 12% and 90% more bone than controls, respectively. Enhanced accumulation of cortical bone was attributed to stimulated periosteal bone formation without accompanying marrow cavity enlargement. Enhanced accumulation of cancellous hard tissue was postulated to be due to reduced trabecular bone resorption and no effect on bone formation. The cell counts support these conclusions. There was a decrease in osteoclast numbers (-62 to -70%), an insignificant decrease in osteoblast numbers (-5 to -30%) per mm of bone surface and a decrease in osteoclast to osteoblast ratio (-35 to -56%). The findings presented are compatible with the conclusion that flurbiprofen, induced changes in rapidly growing long bones by reducing osteoclast activity and recruitment, stimulating longitudinal and radial growth, increasing the cortical bone mass by stimulated periosteal bone growth and depressed endosteal resorption, and increasing cancellous bone mass by depressed trabecular bone resorption without affecting bone formation."<br />
<br />
The increase in longitudinal growth was fairly significant from about 165 mcm/day to 204 mcm/day for 0.5mg/d group. The longitudinal growth was virtually the same from 0.1mg/d to 0.5mg/d. The percentage of increase of growth plate height was approximately the same as the increase in longitudinal growth about 25%. The trends of maximal chondrocyte hypertrophy size and rate of chondrocyte proliferation were less consistent and dramatic. Longitudinal growth was less at 2.5mg per day than control 159 mcm/day to 165 mcm/day.<br />
<br />
Here's a drug that's sort of the inverse to Flubiprofen:<br />
<br />
<a href="http://content.lib.utah.edu/utils/getfile/collection/etd1/id/686/filename/1582.pdf"><b>Effects of phytohemagglutinin-P (PHA-P) on bone of the growing rat.</b></a><br />
<br />
"The effects of phytohemagglutinin-P, (PHA-P), a mitogen known to selectively stimulate cells of hematogenous or lymphoid monocytic origin, 25 and 50 mg/kg/day administered for 15 days on proximal tibiae of growing male Sprague-Dawley rats, were studied. The general effect of PHA-P was to decrease the amount of cartilage, hard tissue, and longitudinal growth in the proximal tibial metaphysis. A decrease in longitudinal bone growth, in the number of chondrocytes, in the thickness of cartilage plate, in the metaphyseal mass of hard tissue, in the percentage of calcified cartilage core, and in the number of osteoblasts per mm of bone surface was observed. Additionally, PHA-P increased the number of osteoclasts, the number of labeled osteoclastic nuclei, and the average number of nuclei per osteoclast. There was a significant decrease in the time to the first appearance of labeled osteoclastic nuclei as the dose of PHA-P increased. Thus, PHA-P treatment leads to the dominance of osteoclastic over chondroblastic and osteoblastic activity and results in a hard tissue deficit in a growing skeleton. The data indicate that PHA-P administration selectively increases osteoclast numbers by elevating osteoclastic progenitor cell proliferation and enhancing their fusion and differentiation to osteoclasts."<br />
<br />
So PHA-P decreases osteoblasts and increases the number of osteoclasts and decreases longitudinal bone growth. PHA-P is part of the red kidney bean. PHA-P stimulates proliferation of lymphocytes.<br />
<br />
According to <b>Flurbiprofen and immunosuppression of Trypanosoma brucei infection in the goat</b>., Flurbiprofen inhibits T-lymphocytes.<br />
<br />
This study provides a possibly model for how lymphocytes may affect longitudinal bone growth:<br />
<br />
<a href="http://jcb.rupress.org/content/149/4/983.long"><b>Growth plate compressions and altered hematopoiesis in collagen X null mice.</b></a><br />
<br />
"A variable skeleto-hematopoietic phenotype was observed in collagen X null mice which mirrored the defects in transgenic (Tg) mice with dominant interference collagen X mutations. Specifically, perinatal lethality was seen in approximately 10.8% of null mutants at week three after birth, and in another subset by 12 wk. In perinatal lethal mutants, growth plates were compressed, trabecular bone reduced, and hematopoietic aplasia and erythrocyte-filled vascular sinusoids were apparent in marrows. Lymphatic organs, reduced to approximately 80% that of controls, displayed altered architecture and lymphocyte content. In thymuses, a paucity of cortical CD3(+)/CD4(+)/CD8(+) lymphocytes was consistent with the marrow's inability to replenish maturing T cells. In spleens, an unaltered T cell distribution was coupled with diffuse staining for IgD(+)/B220(+) B cells, whose reduction was prominent in poorly organized lymphatic nodules. Disorderly arrays of splenic macrophages surrounding periarteriolar lymphatic sheaths and a red pulp depletion further complemented the Tg perinatal lethal phenotype. Moreover, <b>subtle growth plate compressions and hematopoietic changes were seen in all null mice{this is inconsistent with the larger growth plates seen in flurbiprofen treated mice}</b>."<br />
<br />
So either lymphocytes are not the cause of flurbiprofen elevated height growth or there is an equilibrium quantity of lymphocytes for optimal height growth(supported by there being an optimal dosage of flurbiprofen).<br />
<br />
Inflammatory cytokines may have effects like lymphocytes.<br />
<br />
<b>Interleukin-6 modulates trabecular and endochondral bone turnover in the nude mouse by stimulating osteoclast differentiation.</b><br />
<br />
"We have chosen the immunologically compromised athymic mouse, which demonstrate sclerotic features in its trabecular bone, as the animal model for assessment of possible modulation effects of interleukin-1alpha (IL-1alpha) and interleukin-6 (IL-6) on bone and cartilage metabolism. The cytokines were applied by daily subcutaneous injections for 3 consecutive days. Histomorphometry, measuring epiphyseal trabecular bone volume (ETBV), metaphyseal trabecular bone volume (MTBV), and the width of the growth plate, and tartrate-resistant acid phosphatase (TRAP) histochemistry were used to assess parameters of bone turnover in the proximal tibia. IL-6, but not IL-1alpha, reduced ETBV and MTBV. B<b>oth IL-6 and IL-1alpha reduced the width of the growth plate. IL-6, but not IL-1alpha, increased the number of chondroclasts and osteoclasts in the primary spongiosa of the proximal tibia, as well as the number of nuclei.</b> The resultant bone resembled that of the wild-type mouse. The results point to IL-6 as a possible regulator of bone turnover in vivo. It is suggested that the athymic mouse has a deficiency somewhere in the cascade of events leading to the production of IL-6 or, alternatively, that<b> IL-6 replaces other factors that are supplied by T lymphocytes directly or indirectly.</b> As T lymphocytes interact with B lymphocytes it is suggested that the athymic mouse might be appropriate for studying the in vivo effects of the immune system on normal bone metabolism."<br />
<br />
"hematopoietic cells and lymphocytes residing in the bone marrow may have effects on bone, especially in the pathological state."<br />
<br />
On lymphocytes affecting height:<br />
<br />
<b>Growth patterns in pubertal HIV-infected adolescents and their correlation with cytokines, IGF-1, IGFBP-1, and IGFBP-3.</b><br />
<br />
"This study aims to describe the final adult height (FAH) and pubertal growth patterns in human immunodeficiency virus (HIV)-infected adolescents and to compare these to an age-matched population of seroreverting HIV-exposed, uninfected (HEU) adolescents. It further aims to evaluate the interplay of proinflammatory cytokines with insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), and IGFBP-1 during the pubertal growth spurt. Methods: HIV-infected and HEU adolescents who had achieved FAH were evaluated. Auxologic data, viral load, CD4+ T-lymphocyte (CD4) count, and the use of highly active antiretroviral therapy were obtained via a retrospective chart review. Serum interleukin (IL)-1α, IL-6, tumor necrosis factor (TNF)-α, IGFBP-1, IGFBP-3, and IGF-1 were assessed. <b>The mean FAH standard deviation score for the HIV-infected group was -0.78 (±1.1) compared to 0.05 (±0.78) for the HEU{so being exposed to HIV but not being infected slightly increased height}.</b> <b>There was a positive correlation between CD4 count and FAH{But this correlation occur indefinately}.</b> The mean age and magnitude of peak growth velocity (GV) was within normal limits. IL-1α, IL-6, TNF-α, IGFBP-3, and IGF-1 were not significantly correlated with HIV RNA or height. IGFBP-1 was detectable in 100% of poorly controlled HIV-infected patients and 25% of the HEU cohort. The FAH of HIV-infected patients was significantly shorter than that of HEU patients, and it positively correlated with CD4 count. Our cohort demonstrated normal timing and magnitude of peak GV during puberty."<br />
<br />
Adult Height Achieved was linearly correlated to CD4+ lymphocyte count to 2000.Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com6tag:blogger.com,1999:blog-1013552121036660524.post-46971916337101794562013-04-22T19:42:00.008-07:002022-12-25T07:39:50.575-08:00Bone lengthening in response to stress?<b>Presented are the findings that tennis players do have longer stroke arms than the contralateral arm. This does not seem to be due to a selection bias as the mean contralateral arm of the tennis player is the same as the control arm for non-players. Thus there does not seem to be a selection bias for arm length as there does for say basketball and height.</b><br />
<br />
<b>The changes in the tennis player seem to be throughout the entire bone rather than just the ends of the bones. If the changes were due to the growth plate you'd expect the changes to be constrained to near to the ends of the bones but since the changes are throughout the entire bone it's more consistent with <a href="http://www.heightquest.com/2013/01/increase-your-stature-with-plastic.html">plastic deformation</a>. </b><br />
<br />
<b>However, the changes in bone length are small and it's hard to create a serving/throwing motion with your legs or spine. And the studies are not perfect for our purposes as we'd want to look at more longitudinal studies and people without present growth plates.</b><br />
<b><br /></b>
<b>This still provides evidence that very high forces could generate active tensile induced longitudinal growth in bone. However, the difficult in reproducing the throwing/serving motion in other bones and the relatively minor amount of growth in general means that such a method is not a practical method of gaining height.</b><br />
<br />
Basepall pitcher's pitching arm tends to be longer than their non-pitching arms. Many have speculated that this may be due to the stress that pitching arm undergoes. However, many have retorted that people with one arm longer than the other may just be better pitchers. That problem does not exist with instrument players. Longer fingers do not make people better guitar or violin players.<br />
<br />
I found this as a science fair project for the California state science fair. Looks like students are the only ones willing to do height increase research thanks to the fact that grow taller is a dirty phrase.<br />
<br />
<a href="http://www.usc.edu/CSSF/History/2004/Projects/J1025.pdf">The Fingers of Isaac Stern: Will Constant Stress Affect the Development of Phalanges?</a><br />
<br />
<a href="http://www.sciencebuddies.org/science-fair-projects/project_ideas/Music_p014.shtml#summary">Here's a page</a> that considers a similar project.<br />
<br />
Objectives/Goals<br />
The objective is to determine if violinists have longer phalanges in their left hand than their right hand compared to non-violinist. I believe violinists have longer left hand fingers due to the stress on the bones.<br />
Methods/Materials<br />
Methods: 6 steps: 1)Design a questionnaire 2)Define samples. 3)Select two groups: violinists and control group,each with twenty four people,divide evenly into four sub-groups: male, female, adult and young adult.(12 & up) 4)Define uncontrolled variables. 5)Conduct a personal interview and measure the index, middle, ring finger & pinky. 6)Analyze data.<br />
Materials: A specially made ruler is used. It has a moveable piece of cardboard on the ruler for easy reading and maximum accuracy.<br />
Results<br />
<b>The violinist group has much longer phalanges in their left hand by as much as 0.6 cm.</b> The non-violinists left hand four fingers are significantly shorter than the right hands' by as much as 0.9 cm. The data show no significant difference between both adults and young adults, male and female group.<br />
Conclusions/Discussion<br />
Conclusions: My hypothesis is correct. The violinists' left hand fingers are longer than their right hand. This might be due to the stress they put on their bones during years of practice.<br />
Next question: I would like to know if my research would help any medical study. Especially for the handicapped with two legs of different length.<br />
<br />
Now, unlike the baseball pitcher, longer fingers do not make for better violin players. The non-violinists had longer fingers in their right hand and since most people are right handed, using a hard more would indicate finger length. There is still the possibility that left handed people may be better violin players and that left handed people have longer left hands that right hands.<br />
<br />
What is interesting is that playing the violin there are no microfractures and there are no epiphyseal distraction forces. The phalanges are long bones in the finger. The mechanism as to how playing the violin would result in long bone lengthening is unknown. One would wonder what the effect of bone lengthening would be in regards to typing which puts the same kind of stresses on finger bones, doesn't select versus right or left hand(okay qwerty is more left handed and dvorak is more right handed), and also doesn't cause microfractures or major distraction forces.<br />
<br />
Unfortunately this one kids research paper is the only piece of information I could find on the subject. Hopefully this kid will became an important scientist and help us find way to grow taller naturally.<div><br /></div><div><a href="https://guitarunit.com/does-playing-guitar-make-your-fingers-longer/#:~:text=Final%20Words%201%20playing%20guitar%20will%2C%20indeed%2C%20make,overall%20size%20of%20your%20fingers%2C%20also%20More%20items">According to this article guitar </a>makes your fingers longer: "Playing guitar does make the fingers of a fretting hand longer" There are other articles that say otherwise.</div><div><br /></div><div>According to this publication playing guitar/violin does increase finger length</div><div><br /></div><div><b>Do the “Spreadability” and Finger Length of Cellists and Guitarists Change Due to Practice?</b></div><br />"It is a widely held opinion among musicians that extreme joint positions increase the flexibility in the corresponding joints. <b>There are also occasional views that extensive use of the fingers starting in childhood may lead to increased finger length</b>. These opinions have implications for teaching methods; however, in spite of extensive examinations of the shapes of musicians’ hands, to date there have been almost no objective findings. There have been large-scale examinations of the angle of supination of the left elbow of violinists, with the finding that primarily genetic factors are responsible. In order to answer the question whether external factors can influence joint configurations of the hand as well as finger length, the active finger spreads and finger lengths of 210 subjects (cellists, guitarists, and control subjects) were measured. The working hypothesis was that there would be an increase in finger spread in the left hand fingers compared with the right if the frequent extreme positions taken on the fingerboard did in fact influence finger spread. The nonmusician control group, however, would not be expected to show this difference, or at least not to the same extent as in the musicians. Similar differences should apply to finger length, if this is influenced by long-term practicing on these instruments. <b>A majority of the measurements of all three groups demonstrated a greater spreadability of the fingers of the left hand than of the right</b>. In contrast to the comparison groups, there was a significantly greater span between the left hand index and small fingers of cellists. This span was not measured in the guitarists because it does not apply in their playing as it does for cellists. In addition, the measurements of the right-left differences in <b>the finger lengths of the cellists when compared with the nonmusician group showed significantly longer fingers on the left than the right.</b> <b>This difference is probably caused by better-developed fingertips of the cellists</b>. Further research is needed to discern whether the spreadability could be improved through specific training programs."<div><br /></div><div><-so they give a non-bone lengthening related possibility i.e. fingertip thickness. But the science experiment phalanges themselves were actually longer.<br /><div><br /><div>
<b>Mechanical stresses and endochondral ossification in the chondroepiphysis.</b><br />
<div>
<br /></div>
<div>
"The ossific nucleus appears in an area of high shear (deviatoric) stresses; The edge of the advancing ossification front (zone of Ranvier or ossification grove) also experiences high shear stresses; and <b>the joint surface, where articular cartilage forms, is exposed to high-magnitude hydrostatic compression</b>. <b>Intermittently applied shear stresses (or strain energy) promote endochondral ossification and that intermittently applied hydrostatic compression inhibits or prevents cartilage degeneration and ossification."</b></div>
<div>
<b><br /></b></div>
<div>
LSJL likely applies both types of stresses which is why it is both pro-chondrogenic and pro-endochondral ossification.</div>
<div>
<br /></div>
<div>
"<b>Pressure caused cartilage formation in the perichondrium and periosteum as did tensile stresses acting at right angles to the perichondrium fiber direction</b>."<-Note that the mature periosteum can form cartilage and not just the developmental perichondrium.</div>
<div>
<br /></div>
<div>
"Pressure and tensile stresses imposed on cartilage caused the “disintegration of the hyaline substance and its replacement by a fibrillar system”"</div>
<div>
<br /></div>
<div>
"adventitious cartilage arises in response to intermittent pressure and tension accompanied by movement. Immobilization caused the transformation of this cartilage into “bonelike” tissue."</div>
<div>
<br /></div>
<div>
"mechanical pressure and avascularity have similar effects in that both conditions favor differentiation</div>
<div>
of cartilage rather than bone from precursor cells."</div>
<div>
<br /></div>
<div>
"Deviatoric (distortional or shear) stresses cause material distortions with no change in volume. Dilatational (hydrostatic) stresses are pure hydrostatic (compression or tension) stresses that do not distort but will cause volume changes if the material is compressible. The stored strain energy is the sum of the deviatoric and dilatational energy. Materials like cartilage, which are nearly incompressible, will store negligible dilatational energy since negligible volume change occurs, regardless of the magnitude of the dilatational stress. In such materials, therefore, the shear stress distributions will reflect the distribution of strain energy density."</div>
<div>
<br /></div>
<div>
"deviatoric stresses (which are accompanied by elongation or tensile strains in some direction) [are] a specific stimulus for the development of collagenous fibrils and hydrostatic pressure [is] responsible for chondrogenesis."</div>
<div>
<br /></div>
<div>
"The vascular supply pattern to the femoral head was found to correlate with regions that were not exposed to high magnitudes of intermittent hydrostatic compression."</div>
<div>
<br /></div>
<div>
Hydrostatic stress places stress more directly into the epiphysis of the bone than other forms of stress.<br />
<br />
<b>Short-term and long-term site-specific effects of tennis playing on trabecular and cortical bone at the distal radius</b><br />
<b><br /></b>
"Epiphyseal bone enduring longitudinal growth showed a great capacity to respond to mechanical loading in children"<br />
<br />
"In children, no significant difference was observed between the dominant and nondominant forearm lengths (21.6 cm on both sides). In adults, the respective values were 25.3 ± 1.6 cm and 25.0 ± 1.6 cm, with a significant side-to-side difference"<br />
<br />
<b>Stimulation of Bone Growth Through Sports: A Radiologic Investigation of the Upper Extremities in Professional Tennis Players</b><br />
<br />
"<b>Can any differences be found in longitudinal growth of the bones of the forearm and hand in professional tennis players between the stroke arm and the contralateral arm</b>? An investigation<br />
was conducted involving 20 high-ranking professional tennis players (12 male and eight female players) between 13 and 26 years of age as well as 12 controls of the same age range. [Examination] of the bones of the forearm and hand yielded an increase in density of bone substance and bone diameter as well as <b>length in the stroke arm as compared with the contralateral arm.</b> This change in bone structure and size can be attributed to mechanical stimulation and hyperemia{increase in blood flow} of the constantly strained extremity."<br />
<br />
"Significant difference in ulnar length between the two arms in the tennis players [ranging] from 0.2 to 1.3 cm"<br />
<br />
The mean difference in ulna length in control group was 0.17mm but this could be a correlational rather than causal relationship. People with a dominant longer arm may select tennis as a sport.<br />
<br />
The mean length for the contralateral arm was 270mm which was the same as the control group but the mean length for the stoke arm was 278mm.<br />
<br />
They also found an increase in the length of the second metacarpal of the playing arm of the hand of 4.1mm. Average lengthening of the second metacarpal was 2.7mm.<br />
<br />
In all likelihood, I think it's more likelihood that the tennis caused the overgrowth rather than being a correlational effect. <br />
<br />
<b>The phenomenon of twisted growth: humeral torsion in dominant arms of high performance tennis players</b><br />
<br />
There's a lot of stuff in this article about the physics of the forces generated during a serve.<br />
<br />
"twisted humeral geometry at different stages of development could be attributed to muscle forces inducing a torsional load."<br />
<br />
"characteristic twisted bone growth profile was found in tennis players, baseball pitchers and handball players." <br />
<br />
"Predominant axial loading by deltoid induces humeral hypertrophy with pronounced bone growth along the longitudinal axis."<br />
<br />
"During ball impact, muscle forces are aligned with the longitudinal axis of the humerus."<br />
<br />
"During the serve, the entire upper limb is subject to tremendous loads"<br />
<br />
<img src="http://www.tandfonline.com/na101/home/literatum/publisher/tandf/journals/content/gcmb20/2009/gcmb20.v012.i01/10255840802178046/production/images/medium/gcmb_a_317971_o_f0006g.gif" /><br />
Right arm versus left arms of professional tennis player. You can kind of see a twisted nature of the bone and the twist seems to go throughout the whole bone and not just the growth plate region.<br />
<br />
According to <b>Humeral torsion and passive shoulder range in elite volleyball players</b>, "the dominant arm [is] on average 9.6° more retroverted than the non-dominant arm" for volleyball players.</div><div><br /></div><div><b><a href="https://online.boneandjoint.org.uk/doi/epdf/10.1302/0301-620X.62B2.6988435">morphological effects of torsion applied to growing bone</a></b></div><div><br /></div><div>Interesting no significant different in the epiphysis on the torsion side. The trabeculae became angled. After a period of no torsion the angled trabeculae become removed.</div><div><br /></div><div>Longitudinal bone growth between the two seemed to be equal.</div><div><br /></div><div><b>Effect of Starting Age of Physical Activity on Bone Mass in the Dominant Arm of Tennis and Squash Players</b></div><div><br /></div>"To determine in female tennis and squash players the effect of biological age (that is, the starting age of playing relative to the age at menarche) at which tennis or squash playing was started on the difference in bone mineral content between the playing and nonplaying arms."<-this will help us know if torsional forces can increase bone height in adults.</div></div></div><div><br /></div>"Bones of the playing extremity clearly benefit from active tennis and squash training, which increases their mineral mass. The benefit of playing is about two times greater if females start playing at or before menarche rather than after it."<div><br /></div><div>According to <b>Long-term unilateral loading and bone mineral density and content in female squash players, </b>"The bone changes are greatest in the humerus which gives us some hints on what loading is beneficial torsional.</div><div><br /></div><div><b>Bone Modeling Response to Voluntary Exercise
in the Hindlimb of Mice</b></div><div><b><br /></b></div><div>"The functional adaptation of juvenile
mammalian limb bone to mechanical loading is necessary to maintain bone strength. Diaphyseal size and
shape are modified during growth through the process
of bone modeling. Although bone modeling is a well documented response to increased mechanical stress
on growing diaphyseal bone, the effect of proximodistal
location on bone modeling remains unclear. Distal limb
elements in cursorial mammals are longer and thinner,
most likely to conserve energy during locomotion
because they require less energy to move. Therefore, distal elements are hypothesized to experience greater mechanical loading during locomotion and may be expected
to exhibit a greater modeling response to exercise. In
this study, histomorphometric comparisons are made
between femora and tibiae of mice treated with voluntary exercise and a control group. We find that
<b>femora of exercised mice exhibit both greater bone
growth rates and growth areas than do controls. </b>The femora of exercised mice also have significantly greater cortical area, bending rigidity, and torsional rigidity, although bending and torsional rigidity are comparable when standardized by
bone length. Histomorphometric and cross-section geometric properties of the tibial midshaft of exercised and
control mice did not differ significantly, although <b>tibial
length was significantly greater in exercised mice</b>. Femora of exercised mice were able to adapt to
increased mechanical loading through increases in compressive, bending, and torsional rigidity. No such adaptations were found in the tibia. It is unclear if this is a
biomechanical adaptation to greater stress in proximal
elements or if distal elements are ontogenetically constrained in a tradeoff of bone strength of distal elements
for bioenergetic efficiency during locomotion"</div><div><br /></div><div>"Most mammals exhibit limb tapering with
greater muscle and bone mass concentrations proximally, and thinner, elongated elements distally"</div><div><br /></div><div>"bone may primarily be added periosteally to increase resistance
to bending with new growth diminishing distally
along the proximodistal axis"</div><div><br /></div><div>They hypothesize: "Bone growth in response to loading will be
greater in the femur than tibia to minimize the
addition of bone mass distally."</div><div><br /></div><div>"Twenty virgin female house mice (Mus musculus) of the
inbred strain C57BL/6J were used in this experiment"</div><div><br /></div><div>"The femora of exercised mice have significantly larger areas of bone growth both periosteally and endosteally than controls"</div><div><br /></div><div class="separator" style="clear: both; text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgerJSfrCZQgeIENMu3gLMDYAkOCM5rTMUIRuCVhNP44uOIL6UFEP_2E3XhowytlRWQqY3n2-h8bg8ZURgHyoT1nB4I5koJ9OMhVuFMoXuTKgDwQA9s2wiR25tM1QhZs3N1l-AxekR8k7YTlpnes4YudsL0e0fuWYB9bWELhK3cGlQ37el1kDWAU_Dr/s1101/EXERCISE%20length%20difference.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="299" data-original-width="1101" height="121" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgerJSfrCZQgeIENMu3gLMDYAkOCM5rTMUIRuCVhNP44uOIL6UFEP_2E3XhowytlRWQqY3n2-h8bg8ZURgHyoT1nB4I5koJ9OMhVuFMoXuTKgDwQA9s2wiR25tM1QhZs3N1l-AxekR8k7YTlpnes4YudsL0e0fuWYB9bWELhK3cGlQ37el1kDWAU_Dr/w443-h121/EXERCISE%20length%20difference.png" width="443" /></a></div><div class="separator" style="clear: both; text-align: left;">That is a huge difference in length. Like 10%.</div><div class="separator" style="clear: both; text-align: left;"><br /></div><div class="separator" style="clear: both; text-align: left;">"exercise-treated mice ran an average of 7.8 km/day
with a standard deviation of 1.19 km/day during
the 4-week experiment."</div><br /><div><br /></div><ul class="c-article-author-list c-article-author-list--short js-no-scroll" data-component-authors-activator="authors-list" data-test="authors-list" style="background-color: #fcfcfc; box-sizing: inherit; color: #333333; display: inline; font-family: -apple-system, BlinkMacSystemFont, "Segoe UI", Roboto, Oxygen-Sans, Ubuntu, Cantarell, "Helvetica Neue", sans-serif; font-size: 1rem; list-style: none; margin-block-start: 48px; margin: 0px 8px 0px 0px; padding: 0px; scroll-behavior: auto; width: 100%;"></ul>Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com6tag:blogger.com,1999:blog-1013552121036660524.post-5564208074482579132013-04-16T13:17:00.001-07:002022-08-20T20:39:27.714-07:00Increase your Stature with Plastic Deformation<b> Recently, someone asked if it was possible to grow taller while running with ankle weights and <a href="http://www.naturalheightgrowth.com/2013/02/24/would-a-tibia-subjected-to-high-intensity-dynamic-mechanical-tensile-loading-fracture-or-elongate-through-stretching-first/">natural height growth recently posted about tensile stress for height growth</a>. The goal for tensile stress for height growth is to induce enough stress in the bone to induce plastic deformation in the bone to make it longer. The point at which this occurs is the yield stress. Cortical bone is the limiting factor for this to occur. Ultimate stress is the point where the bone breaks. According to <a href="http://www.engin.umich.edu/class/bme456/bonefunction/bonefunction.htm">this engineering page</a>, the ultimate stress for bone is 133MPa whereas the yield stress is 115MPa. It would be hard to generate this kind of stress in the bone but it's possible that there may be some residual strain that occurs at the nanometer level. Can we generate enough residual strain via tensile forces on the bone to eventually reach the plastic deformation range? According to<a href="http://www.asbweb.org/conferences/2011/pdf/147.pdf"> LOAD TRANSFER ACROSS THE PELVIC BONE DURING NORMAL WALKING</a>, 20-67MPa stresses were generated in the hip bone during walking. So it's conceivable that a tensile force of 115MPa could be generated by a physiological loading regime. I couldn't find how much tensile stress is generated by running.</b><br />
<div>
<br /></div>
Plastic deformation refers to residual strain whereas elastic strain refers to strain that has no residual strain. So a potential treatment would involve using say a <a href="http://www.heightquest.com/2010/09/grow-taller-with-tensile-strain.html">tensile strain</a> mechanism to stretch the bone to such a degree that it retains some of the stretch after the load is removed.<br />
<br />
Plastic deformation seems to take a high level of strain to occur. <br />
<br />
<b>Orientation dependence of progressive post-yield behavior of human cortical bone in compression.</b><br />
<br />
"[We] determine the effect of loading direction on the evolution of post-yield behavior of bone using a progressive loading protocol. To do so, cylindrical compressive bone samples were prepared each in the longitudinal, circumferential and radial directions, from the mid-shaft of cadaveric femurs procured from eight middle-aged male donors (51.5 ± 3.3 years old). These specimens were tested in compression in a progressive loading scheme. The elastic modulus, yield stress, and energy dissipation were significantly greater in the longitudinal direction than in the transverse (circumferential and radial) directions. However, no significant differences were observed in the yield strain as well as in the successive plastic strain with respect to the increasing applied strain among the three orientations. <b>The initiation and progression of plastic strain are independent of loading orientations</b>, thus implying that the underlying mechanism of plastic behavior of bone in compression is similar in all the orientations."<br />
<br />
Therefore we can see what loads are required in other orientations like compressive loading and use those some loads to induce tensile strain to such a degree as to induce plastic strain.<br />
<br />
"the post-yield behavior of bone is associated with an exponential decay of elastic modulus (microdamage accumulation), <b>linear plastic deformation</b>, and an acute saturation of viscous behavior of the tissue"<br />
<br />
<b>Cooperation of length scales and orientations in the deformation of bovine bone.</b><br />
<br />
"Combined wide angle X-ray diffraction and small angle X-ray scattering were used together with in situ tensile testing to investigate the deformation and failure mechanisms of bovine cortical bone at three material levels: (1) the atomic level, corresponding to the mineral crystal phase; (2) the nano level, corresponding to the collagen fibrils; (3) the macroscopic level. Deformation was linear at all three levels up to a strain of 0.2% in the longitudinal tensile direction. At this critical strain a sudden 50% decrease in the fibrillar and mineral strains was observed. The presence of partial local damage leads to inhomogeneous strain distributions within the probed gauge volume. This gives rise to diffraction peak broadening in the mineral phase, as well as strain relaxation at the nanoscale. Above the critical strain the longitudinally oriented strains below the nanoscale remained constant at a reduced level until failure. The lateral orientation of the nanostructures toughens the bone, while a higher material level dominated the subsequent deformation process, either by sliding between the lamellar layers or by the growth of microcracks. The bone has compressive residual stress in the crystal phase."<br />
<br />
"At low stresses the bone behaves linear elastically with stiffness primarily coming from the mineral phase. Physiological loading generally falls in this elastic region. The mineral phase that provides rigidity is proposed to carry the load, while the soft matrix transfers the load to neighboring mineral crystals by shear. Yielding is known to be the start of damage, when strain reaches a critical level and starts initiating crack formation. In the post-yield region cortical bone experiences large plastic deformation while absorbing large amounts of energy prior to fracture"<br />
<br />
"<b>The post-yield deformation involves a combination of slippage at cement lines</b>, which reduces strain energy and slows down crack propagation by deflecting the crack path, and discontinuity of microcracks, that greatly reduces the stress intensity at the crack tip. At the nanoscopic level, breaking of sacrificial bonds at the fibrillar level dissipates energy, while long mineral platelets delocalize the crack-tip deformation"<-maybe inducing other forms of slippage of cement lines will also permanently make the bone grow longer without the high levels of tensile strain required for plastic strain.<br />
<br />
" Upon tensile loading the gap zones between the fibrils were stretched and the change in the dimensions of the gap zones is a measure of fibrillar strain."<br />
<br />
<br />
<img alt="Full-size image (18 K)" border="0" class="imgLazyJSB figure large" data-fullheight="239" data-fullsrc="http://ars.els-cdn.com/content/image/1-s2.0-S1742706111000766-gr9.jpg" data-fullwidth="333" data-loaded="true" data-thumbheight="157" data-thumbsrc="http://ars.els-cdn.com/content/image/1-s2.0-S1742706111000766-gr9.sml" data-thumbwidth="219" height="239" src="http://ars.els-cdn.com/content/image/1-s2.0-S1742706111000766-gr9.jpg" style="display: inline; height: 239px; width: 333px;" width="333" /><br />
"Fracture surface of the bone captured by an optical camera during tensile testing."<-So the stretching did induce microfractures in such a way as to kind of lengthen the bone.<br />
<br />
<b>How tough is bone? Application of elastic-plastic fracture mechanics to bone.</b><br />
<br />
"bone contains a high volumetric percentage of organics and water that makes it behave nonlinearly before fracture. We applied elastic-plastic fracture mechanics to study bone's fracture toughness. The J integral, a parameter that estimates both the energies consumed in the elastic and plastic deformations, was used to quantify the total energy spent before bone fracture. Twenty cortical bone specimens were cut from the mid-diaphysis of bovine femurs. Ten of them were prepared to undergo transverse fracture and the other 10 were prepared to undergo longitudinal fracture. The specimens were prepared following the apparatus suggested in ASTM E1820 and tested in distilled water at 37 degrees C. The average J integral of the transverse-fractured specimens was found to be 6.6 kPa m, which is 187% greater than that of longitudinal-fractured specimens (2.3 kPa m). The energy spent in the plastic deformation of the longitudinal-fractured and transverse-fractured bovine specimens was found to be 3.6-4.1 times the energy spent in the elastic deformation. The toughness of bone estimated using the J integral is much greater than the toughness measured using the critical stress intensity factor."<br />
<br />
"bone contains water that can affect the properties of collagen"<br />
<br />
"60% of water was bonded to collagen [in dog bones]"<br />
<br />
<b>Mechanisms of short crack growth at constant stress in bone.</b><br />
<br />
"Slow, stable crack growth occurred at a rate and angle which were dependent on the orientation of the sample: tests were conducted with the loading axis both parallel and perpendicular to the longitudinal axis of the bone. All cracks showed intermittent growth in which periods of relatively rapid propagation alternated with periods of temporary crack arrest or relatively slow growth. In some cases crack arrest could be clearly linked to microstructural features such as osteons or Volkmann's canals, which acted as barriers to crack growth. Crack-opening displacement increased over time during the arrest periods. The growth of small cracks in bone at constant stress, [involves] microstructural barriers, time-dependent deformation of material near the crack tip and strain-controlled propagation."<br />
<br />
<b>Progressive post-yield behavior of human cortical bone in shear. </b><br />
<br />
" the shear modulus of bone decreased with respect to the applied strain, but the rate of degradation was about 50% less than those previously observed in compression and tension tests. In addition, a quasi-linear relationship between the plastic and applied strains was observed in shear mode, which is similar to those previously reported in tension and compression tests. However, the viscous responses of bone (i.e. relaxation time constants and stress magnitude) demonstrated slight differences in shear compared with those observed in tension and compression tests."<br />
<br />
<a href="http://www.blogger.com/blogger.g?blogID=1013552121036660524" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"></a><a href="http://www.blogger.com/blogger.g?blogID=1013552121036660524" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"></a>"After a preload of 10 N in compression, each specimen was loaded using the cyclic loading protocol. In each cycle, the specimens were loaded under the displacement control with a rate of 0.005 mm/s, held at the displacement level for 120 s, unloaded to 25 N, and held at the 25 N for 120 s. The dwelling time (120 s) was determined through pilot studies to ensure that the specimens reach to a quasi-equilibrium condition"<br />
<br />
"The shear yield strain and yield stress of the bone specimens were 0.88 ± 0.18% and 35.7 ± 9.88 MPa, respectively"<-These were bones from 80 year olds though.<br />
<br />
" the yield strain in shear observed in this study was about 0.88 ± 0.18% (N = 6), which is higher than those in compression (0.71 ± 0.07%, N = 8) and in tension (0.39 ± 0.03%, N = 8) "<br />
<br />
<a href="http://www.blogger.com/blogger.g?blogID=1013552121036660524" style="clear: right; float: right; margin-bottom: 1em; margin-left: 1em;"></a><b>Traumatic plastic deformation of the tibia: case report and literature review. </b><br />
<br />
" a 10-year-old girl who, after falling down a slope, came to a sudden stop when her right foot hit a rock. This resulted in a fracture of the fibula and bowing of the tibia."<br />
<br />
"Plastic deformation refers to the deformation of a bone, without fracture of its cortices, that persists once the deforming force has been removed. It has been reported most commonly in the forearm, with 58 of a review of 74 cases involving the forearm."<br />
<br />
<b>Mechanical and morphological aspects of experimental overload and fatigue in bone </b><br />
<br />
"long bone fatigue is produced in 30 pairs of dog ulnas by applying opposing forces at both extremities thereby causing a strain. On a force-deformation curve the force axis indicates a zone of load, an intermediate zone of fatigue and a zone of overload; the deformation axis shows an elastic zone and a plastic zone"<br />
<br />
"the plastic phase is short for dense cortical bone"<b> </b><br />
<br />
<b>Guided growth: recent advances in a deep-rooted concept. </b><br />
<br />
"Guiding growth by harnessing the ability of growing bone to undergo plastic deformation is one of the oldest orthopaedic principles."<br />
<br />
"Bracing for adolescent idiopathic scoliosis does not influence vertebral development."<br />
<br />
<b>Damage accumulation in vertebral trabecular bone depends on loading mode and direction.</b><br />
<div>
<br /></div>
"251 cylindrical samples (8×18-25mm) were obtained from 50 male and 54 female fresh frozen human vertebrae (T1-L3) of 65 (21-94) years. Vertebrae were randomly assigned to three groups cranial-caudal, anterior-posterior and latero-lateral. Specimens were mechanically loaded in compression, tension or torsion in five load steps at a strain rate of 0.2%/s. Three conditioning cycles were driven per load step. Stress-strain curves were reconstructed from the force-displacement or from the moment-twist angle curves. Damage accumulated from 0 to 86% in compression, from 0 to 76% in tension and from 0 to 86% in torsion through the five load steps. Residual strains accumulated from 0 to -0.008mm/mm in compression,<b> 0 to 0.006mm/mm in tension</b> and 0 to 0.026rad/rad in torsion. <b>Significantly less damage but not residual strains accumulated in transverse directions</b>."<br />
<br />
Lots of alterations were made to the bone so that may have had effects on physiological loading properties.<br />
<br />
"Cortical bone shows qualitatively similar damaging behaviour as trabecular bone"<br />
<br />
"substantial damage occurs at the nanometer level "<br />
<br />
"Cracks and diffuse damage that accumulate within trabeculae cause reductions in apparent modulus prior to failure of whole trabeculae"<-see above where the scientists stated that cortical bone has similar damaging properites as trabecular bone.<br />
<br />
<br />
<b>Comparison of the elastic and yield properties of human femoral trabecular and cortical bone tissue</b><br />
<b><br /></b>
"Effective tissue modulus and yield strains were calibrated for cadaveric human femoral neck specimens taken from 11 donors, using a combination of apparent-level mechanical testing and specimen-specific, high-resolution, nonlinear finite element modeling. The trabecular tissue properties were then compared to measured elastic modulus and tensile yield strain of human femoral diaphyseal cortical bone specimens obtained from a similar cohort of 34 donors. Cortical tissue properties were obtained by statistically eliminating the effects of vascular porosity. Results indicated that <b>mean elastic modulus was 10% lower (p<0.05) for the trabecular tissue (18.0±2.8 GPa) than for the cortical tissue (19.9±1.8 GPa){so it actually doesn't take that much more stress to induce plastic deformation in the cortical bone than in the trabecular bone(cortical bone is the limiting factor for lengthening)}</b>, and the 0.2% offset tensile yield strain was 15% lower for the trabecular tissue (0.62±0.04% vs. 0.73±0.05%, p<0.001). The tensile–compressive yield strength asymmetry for the trabecular tissue, 0.62 on average, was similar to values reported in the literature for cortical bone. We conclude that while the elastic modulus and yield strains for trabecular tissue are just slightly lower than those of cortical tissue, because of the cumulative effect of these differences, <b>tissue strength is about 25% greater for cortical bone</b>."<br />
<div>
<br /></div>
<div>
The yield modulus is the point where looking for as that is when the bone deforms plastically.</div>
<div>
<br /></div>
<div>
0.2% offset yield stress (MPa) for cortical bone <span class="Apple-tab-span" style="white-space: pre;"> </span>107.9±12.3</div>
<div>
<br /></div>
<div>
Offset yield means that the extract stress needed is inexact.</div>
<div>
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<div>
107.9 MPa is equal to 107.9N/millimeter^2. So the larger area over which the force is applied, the less force overall is generated.</div><div><br /></div><b>Stress Fracture of a Radius Resulting in Malunion: A Case Report</b><div><b><br /></b></div>"Stress fractures are the result of repetitive and abnormal stresses on bone and are commonly divided into two basic categories, those due to extrinsic factors that primarily involve the type and intensity of the physical activity and intrinsic factors that are related to the individual's age, weight, and medical conditions that weaken bone strength, such as osteoporosis and osteopenia. <b>Common examples are an enlarged humerus seen in some professional baseball players and an enlarged radius seen in some competitive tennis players. When stress loading is not gradual and exceeds the elastic range of the bone, plastic deformation occurs.{So by the existence of plastic deformation there must be an alternative to limb lengthening surgery}</b> Stress fractures in the upper extremities are far less common and in two large series accounted for 2.8% to 7.6% of all stress fractures. In adults, they have been reported in the humerus, mainly in baseball pitchers, with 12 cases in one study of injuries in a men's over 30 baseball league. Solitary reports of humeral stress fractures have been reported in other sports as well, including tennis, body building, and weightlifting. Stress fractures also occur in the forearm, more commonly in the ulna than radius, and have been reported following a wide variety of sports activities, including fast-pitch softball, tennis, golf, bowling, and competitive ice-dancing. Most are localized to the diaphysis of the bone that has been shown to have the smallest diameter and the thinnest cortices on computed tomography and is the most vulnerable site for repetitive torque forces that rotation of the radius exerts on the relatively immobile ulna.20 Stress fractures of the radius are exceedingly rare and only six cases have been reported in the English language literature that were confirmed by magnetic resonance imaging (MRI) or radiographs. The first case reported in 1980 involved bilateral fractures in a 23-yearold British naval recruit whose training included "field gun running," that required him and his fellow recruits to straddle a 900-pound gun barrel across their forearms while running through a series of obstacles. The other two cases were unilateral fractures: a 15-year-old high school wrestler whose fracture in the middle third of the diaphysis was confirmed on MRI that showed periosteal bone reaction adjacent to a sclerotic fracture line and a 12-year-old boy who repetitively practiced "wheelies" in which he would lift the front wheel of his bicycle, ride on the rear wheel for a short distance, and then slam the front wheel down on the pavement with all his force. The mechanisms of injury in the other three cases were not from weightbearing activities but from repetitive muscle forces acting on the radius."<div><br /></div>"When stress loading is not gradual and exceeds the elastic range of the bone, plastic deformation occurs. Rather than the bone having the opportunity to gradually remodel and hypertrophy, there is bone resorption that at a certain point results in microfractures. The microfractures generally progress to small cortical cracks in the bone and, if the physical activity continues at the same intensity and there is no medical intervention to splint the bone, the result is usually an obvious clinical fracture."<div><br /></div>"In children who have not reached skeletal maturity, stresses are more likely to affect the epiphyseal growth plate of a particular bone than the bone itself."Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com11tag:blogger.com,1999:blog-1013552121036660524.post-62865816688548718852013-04-11T17:50:00.000-07:002013-04-11T15:36:20.428-07:00Do fats and sugars affect your height gain? <b>Considering that there are several <a href="http://www.heightquest.com/2012/06/genes-associated-with-human-height.html">Vitamin D related genes that influence height</a> but there are some instances where <a href="http://www.heightquest.com/2010/05/grow-taller-with-vitamins.html">Vitamin D intake does not affect adult height</a>. Although, the levels of glucose consumed versus starch and fructose affect the pathways related to Vitamin D rather than just Vitamin D levels. Therefore, it is likely that glucose versus starch and fructose consumption may affect adult height rather than just a temporary decrease in growth rate.</b><br />
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<b>Eating high glucose foods versus high fructose and to a much less extent high starch foods will only affect people with open growth plates but could result in a little bit more adult height.</b><br />
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People are always looking for a quick fix. Rather than hard, strenuous exercise to increase height people want to take some height increase pill. In this blog entry, I'm going to look at if dietary factors can affect human height.<br />
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Now, I'm considering "normal" foods. Anything that you put in your body could be considered part of your body. The definition of diet as per this article is any chemical that could be found regularly in food(so no supplements, although they do have chondroitin and glucosamine in liquid form now but it still isn't what I would consider mainstream food).<br />
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<b>High-fat, sucrose diet impairs geometrical and mechanical properties of cortical bone in mice.</b><br />
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"Exposure to diets <b>high in fat and sucrose can induce hyperinsulinaemia, affect Ca and Mg metabolism, and alter bone mineralisation and mechanical properties</b>."<br />
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One possible explanation for how diets high in fat and sucrose alter bone mechanical properties is that unesterified long-chain saturated fatty acids have a melting point above body temperature and, with sufficient calcium in the intestinal lumen, form insoluble calcium soaps.<br />
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So, sugar and fat competes with bone for calcium absorption. So, a very high diet with high fat and glucose levels could impair height gain. Remember, that <a href="http://www.heightquest.com/2010/11/boost-height-with-insulin.html">reduced sensitivity to insulin</a> has been associated with possible height gain.<br />
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<b><span style="color: black; font-size: small;"><span style="font-weight: normal;">"</span><span style="font-size: small;"><span style="font-family: inherit;">The present study assessed morphological and mechanical changes in a murine model exposed to a high-fat/sucrose (HFS) diet, as well as corresponding molecular and endocrine markers of bone turnover.</span></span></span><span style="color: black; font-family: inherit; font-size: small;"><span style="font-weight: normal;"> "</span></span></b><br />
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<span style="font-family: inherit;">Bone turnover however doesn't necessarily have an affect on human height. The old confusion between bone modeling and remodeling(neither of which can increase height) is an example of how things can be misconstrued. Bone turnover can affect the rate at which microfractures heal however and microfractures in the cortical bone can be possibly used to help you grow taller.</span><br />
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"Both body mass and percentage body fat were greater in mice fed HFS diet. After adjusting for body mass, tibial structural and morphological properties were adversely affected in the HFS cohort. <b>Cortical thickness, cross-sectional area,</b> and load at maximum were all significantly lower in mice fed HFS diet. Receptor activator of nuclear factor kappabeta ligand <b>(RANKL) mRNA was significantly upregulated in HFS mice, but osteoprotegerin/RANKL mRNA ratio remained unchanged between cohorts[So OPG increased to compensate for the increase in RANKL leading to a change in bone turnover] .</b> Moreover, cyclo-oxygenase-2[also known as COX2] mRNA tended to be increased in HFS. Thus, ingestion of an HFS diet had a significant adverse effect on mouse bone morphology and mechanics, and these effects were<b> likely due to elevated osteoclast activity associated with the inflammatory state of obesity</b>, and not necessarily osteoclast recruitment/proliferation."<br />
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The investigators in this study theorized that obesity caused the change in cortical thickness not the high fat/fructose diet. Any diet with a caloric surplus could have potentially caused the same effect. A high caloric diet may be beneficial but a high fat diet may cause additional inflammatory factors that can be bad for height growth.<br />
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<span style="font-size: small;"><b>Study on the effect of T-2 toxin combined with low nutrition diet on rat epiphyseal plate growth and development.</b></span><br />
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<span style="font-size: x-large;"><span style="font-size: small;">"</span></span>The purpose of this study was to observe early lesions of rat epiphyseal plates and metaphysis caused by T-2 toxin and T-2 toxin combined with a low nutrition diet to determine possible pathogenic factors of Kashin-Beck disease (KBD). Ninety Wistar rats were divided into three groups. Group A was fed with a normal diet as control; group B was fed with a normal diet and T-2 toxin; and group C was fed with a low nutrition diet and T-2 toxin."<br />
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T-2 toxin is a mold byproduct of a fungus.<br />
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"After two weeks, the epiphyseal plate showed necrosis of chondrocytes in groups B and C. After four weeks, more obvious chondrocyte necrosis appeared. The positive rate of Lamellar necrosis in group C was significantly higher than that in groups B and A (P < 0.01). Metaphyseal trabecular bone showed sparse disorder and disruption in group C. T-2 toxin combined with a low nutrition diet could lead to more serious chondrocyte necrosis in the epiphyseal plate and disturb metaphyseal trabecular bone formation."<br />
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So, the T-2 toxin has the potential to decrease height by destroying chondrocytes. Chondrocytes are the basis for height growth in the growth plates. This shows you how detrimental toxins can be in terms of growing taller.<br />
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<b><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835657/?tool=pubmed">Dietary patterns in Canadian men and women ages 25 and older: relationship to demographics, body mass index, and bone mineral density</a>.</b><br />
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<span style="font-size: small;">"</span><span style="font-size: small;">The objective of the study was to determine whether dietary patterns in men (ages 25-49, 50+) and women (pre-menopause, post-menopause) are related to femoral neck bone mineral density (BMD) independently of other lifestyle variables, and whether this relationship is mediated by body mass index."</span><br />
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The BMI is a perfect example of how people cling to something because it's the popular thing rather than because it's the correct thing. The BMI is only useful for populations as the deviations average out. Their is too much internal differences in bone size within individuals for a tool like the BMI to be useful. Further, the BMI doesn't account for things like on average people's wingspans being larger than their height.<br />
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"We identified two underlying dietary patterns using factor analysis and then derived factor scores. The first factor (nutrient dense) was most strongly associated with intake of fruits, vegetables, and whole grains. The second factor (energy dense) was most strongly associated with intake of soft drinks, potato chips and French fries, certain meats (hamburger, hot dog, lunch meat, bacon, and sausage), and certain desserts (doughnuts, chocolate, ice cream). The energy dense factor was associated with higher body mass index independent of other demographic and lifestyle factors, and body mass index was a strong independent predictor of BMD. Surprisingly,<b> we did not find a similar positive association between diet and BMD</b>. In fact, when adjusted for body mass index, each standard deviation increase in the energy dense score was associated with a BMD decrease of 0.009 (95% CI: 0.002, 0.016) g/cm2 for men 50+ years old and 0.004 (95% CI: 0.000, 0.008) g/cm2 for postmenopausal women. In contrast, for men 25-49 years old, each standard deviation increase in the nutrient dense score, <b>adjusted for body mass index, was associated with a BMD increase of 0.012</b> (95% CI: 0.002, 0.022) g/cm2."<br />
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BMD density was measured by dual x-ray absorptiometry so bone size could have been increased by increased diet. Eating more was associated with increased BMD. Now BMD may not be a causal way to increase height but it is a good measure of anabolism in the bone. The reason that age had the affect of lowering BMD instead of racing BMD with energy dense score could possibly be that men over 50 had lower activity levels.<br />
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<b>Regulation of Mesenchymal Stem Cell Chondrogenesis by Glucose through Protein Kinase C/Transforming Growth Factor Signaling.</b><br />
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<input id="gwProxy" type="hidden" /><input id="jsProxy" onclick="jsCall();" type="hidden" />"The extent of chondrogenesis of hMSCs previously cultured with different concentrations of glucose was evaluated. Transforming growth factor-beta (TGF-β) signaling molecules and protein kinase C (PKC) were analyzed to identify the role of these molecules in the regulation of glucose on chondrogenesis. In addition, hMSCs in high-glucose expansion culture were treated with the PKC inhibitor to modulate the activity of PKC and TGF-β signaling molecules.<br />
<b>High-glucose maintained hMSCs were less chondrogenic than low-glucose maintained cells upon receiving differentiation signals</b>. High-glucose culture increased the phosphorylation of PKC and expression of type II TGF-β receptor (TGFβRII) in pre-differentiation hMSCs. However, <b>low-glucose maintained hMSCs became more responsive to chondrogenic induction with increased PKC activation and TGFβRII expression than high-glucose maintained hMSCs during differentiation.</b> <b>Inhibiting the PKC activity of high-glucose maintained hMSCs during expansion culture upregulated the TGFβRII expression of chondrogenic cell pellets, and enhanced chondrogenesis.</b>"<br />
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"During chondrogenic induction, high-glucose medium enhances chondrogenesis of chick mesenchymal cells, in comparison with low-glucose medium"<br />
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"high-glucose expansion culture reduces the proliferation of hMSCs"<br />
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"TGF-β ligand binds to type II TGF-β receptor (TGFβRII) to form a heterodimeric complex with type I TGF-β receptor (TGFβRI), which phosphorylates downstream signaling molecule Smad2/3. Phosphorylated Smad2/3 forms a heteromeric complex with Smad4, acting as a transcriptional activator to regulate the activity of TGF-β-responsive genes, including Sox9 for chondrogenesis"<br />
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"Human MSCs transfected with the TGF-β1 or TGF-β2 gene have been shown to induce chondrogenesis with the production of cartilage-related collagen type II."<br />
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"Human bone marrow-derived MSCs were isolated from femoral heads of 3 patients between 25 to 50 years of age who underwent total hip arthroplasty"<br />
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"[The human MSCs] expressed CD73, CD90, and CD105, but not CD34 and CD45"<br />
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"HGMCs grew slower than LGMCs"<br />
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"at day 9, the levels of mRNA expression of cartilage-related markers Sox9 and aggrecan of HGMC pellets were significantly downregulated, and at day 22, the expression levels of aggrecan and collagen type II of HGMC pellets were also significantly decreased, compared to those of LGMC pellets."<br />
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During differentiation TGFBRI expression was barely detectable in either mesenchymal group and TGFBRII was downregulated in the High-Glucose group versus the Low-Glucose group. Smad3-p and PKC-p were lower in HGMC pellets than LGMC.<br />
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Pre-differentiation PKC-p was actually higher in HGMC than LGMC. Inhibition of PKC during pre-differentiation culture can increase PKC and TGFBRII levels during chondrogenesis. At 14 days of chondrogenesis, pre-differentiation chondrocytes treated with PKC inhibitor had higher levels of Acan, Col2, and Col9.<br />
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"high-glucose chondrogenic culture is essential for maintaining matrix structural integrity"<br />
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<b><a href="http://www.frontiersin.org/Bone_Research/10.3389/fendo.2012.00153/full">Glucose: an energy currency and structural precursor in articular cartilage and bone with emerging roles as an extracellular signaling molecule and metabolic regulator.</a></b><br />
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"Glucose is vital for osteogenesis and chondrogenesis, and is used as a precursor for the synthesis of glycosaminoglycans, glycoproteins, and glycolipids. Glucose sensors are present in tissues and organs that carry out bulk glucose fluxes (i.e., intestine, kidney, and liver). <b>The beta cells of the pancreatic islets of Langerhans respond to changes in blood glucose concentration by varying the rate of insulin synthesis and secretion</b>. Neuronal cells in the hypothalamus are also capable of sensing extracellular glucose. Glucosensing neurons use glucose as a signaling molecule to alter their action potential frequency in response to variations in ambient glucose levels. Bone cells can influence (and be influenced by) systemic glucose metabolism. Cartilage and bone cells are sensitive to extracellular glucose and adjust their gene expression and metabolism in response to varying extracellular glucose concentrations."</div>
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"The transport of sugar across the plasma membrane of mammalian cells is mediated by members of the GLUT/SLC2A family of facilitative sugar transporters and the SGLT/SLC5A family of Na+-dependent sugar transporters"</div>
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"GLUT1, GLUT3, and GLUT4 are high-affinity transporters whereas GLUT2 is a low-affinity transporter; GLUT5 is primarily a fructose carrier " GLUT1 is expressed in articular cartilage and IVD cells.</div>
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"IVD is anatomically and functionally very similar to cartilage although in contrast to cartilage it develops from notocordal cells rather than mesenchymal cells"</div>
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"chondrocytes express multiple isoforms of the GLUT/SLC2A family"</div>
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"Chondrocytes are capable of adjusting to high and low glucose concentrations by changing the protein levels of GLUT1"</div>
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"OA chondrocytes exposed to high glucose were unable to down-regulate GLUT1. OA-derived chondrocytes accumulated more glucose and produced more ROS."</div>
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GLUT1 and GLUT4 are expressed in murine endochondral bone formation.</div>
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"high d(+)glucose may alter RANKL-induced osteoclast formation by inhibiting redox-sensitive NF-kappaB activity through an anti-oxidative mechanism."</div>
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"Mature osteoclasts rely on the citric acid cycle and mitochondrial respiration to generate high levels of ATP production for acid secretion and bone resorption."</div>
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" glucose metabolism is increased during osteoclast differentiation resulting in a metabolic shift toward accelerated glucose metabolism at an early stage of RANKL-stimulated osteoclast differentiation. Increased mitochondrial oxidative phosphorylation will then result in elevated ATP production and enhanced osteoclast differentiation."</div>
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"osteocalcin{up in LSJL} [is a] regulator of pancreatic insulin production and glucose metabolism"</div>
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"osteocalcin deficiency in knockout mice leads to decreased insulin and adiponectin secretion, insulin resistance, higher serum glucose levels, and increased adiposity"<br />
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<b>Perinatal maternal dietary supplementation of ω3-fatty acids transiently affects bone marrow microenvironment, osteoblast and osteoclast formation, and bone mass in male offspring.</b><br />
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[Omega3-fatty acids]</div>
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"[Does] maternal supplementation with ω3-polyunsaturated fatty acids (n3FA) [improve] offspring bone growth and adult bone mas?. Female rats were fed a diet containing 0.1% (control, n = 10) or 1% (n3FA, n = 11) docosahexanoic acid (DHA) during pregnancy and lactation. Offspring were weaned onto a control rat chow diet. Tibial growth plate and metaphysis structure, osteoblast/osteoclast density and differentiation, and gene expression were assessed in offspring at 3 wk (weaning), 6 wk (adolescent), and 3 months (adult). <b>Maternal n3FA supplementation elevated offspring plasma n3FA levels at 3 and 6 wk</b>. Although <b>total growth plate heights were unaffected at any age, the resting zone thickness was increased in both male and female offspring at 3 wk</b>. In n3FA males, but not females, bone trabecular number and thickness were increased at 3 wk but not other ages. The wk 3 n3FA males also exhibited an increased bone volume, an increased osteoblast but decreased osteoclast density, and lower expression of osteoclastogenic cytokines receptor activator of nuclear factor-κB ligand, TNF-α, and IL-6. No effects were seen at 6 wk or 3 months in either sex. Thus, perinatal n3FA supplementation is associated with increased bone formation, decreased resorption, and a higher bone mass in males, but not in females, at weaning; <b>these effects do not persist into adolescence and adulthood and are unlikely to produce lasting improvements in bone health</b>."</div>
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"Despite n3FA supplementation being ceased at weaning, increased DHA and total n3FA levels persisted until 6 wk of age but had returned to control levels by 3 months of age."</div>
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"maternal n3FA supplementation did not alter body length or body weight of the offspring at the ends of critical growth periods (3 wk, 6 wk, and 3 months of age)."</div>
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"eicosapentaenoic acid (EPA) and DHA are never completely absent from breast milk, and the level is largely determined by the mother's diet"</div>
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"feeding postweaning male Fisher rats DHA substantially increased bone marrow cell number"<-more bone marrow cells means more possibilities for mesenchymal condensation and more ability to induce chondrogenesis.<br />
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<b><a href="http://www.ingentaconnect.com/search/download?pub=infobike%3a%2f%2fcog%2fct%2f2011%2f00000020%2f00000006%2fart00003&mimetype=text%2fhtml">Glucose reduction prevents replicative senescence and increases mitochondrial respiration in human mesenchymal stem cells.</a></b><br />
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"During in vitro expansion of MSCs, replicative senescence may occur and will compromise the quality of the expanded cells. Because calorie restriction has been shown to effectively extend the life span of various organisms, the purpose of this study is to investigate the effect of glucose reduction on MSCs and the coordinated changes in energy utilization. It was found that the frequency of cycling cells was significantly increased, while senescence markers such as β-galactosidase activities and p16(INK4a) expression level were markedly reduced in MSCs under low-glucose culture condition. MSCs [maintained chondrogenic differentiation potential] after low-glucose treatment. Interestingly, the ability of osteogenic lineage commitment was improved, while the ability of adipogenic lineage commitment was delayed in MSCs after glucose reduction. We observed decreased lactate production, increased electron transport chain complexes expression, and increased oxygen consumption in MSCs after glucose reduction treatment. Increased antioxidant defensive responses were evidenced by increased antioxidant enzymes expression and decreased superoxide production after glucose reduction. MSCs utilize energy more efficiently under restricted glucose treatment and exhibit greater self-renewal and antisenescence abilities, while their <b>differentiation potentials remain unaffected</b>."<br />
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"CR induces SIR2 family gene expression to regulate the downstream stress resistance reaction and to slow the aging processes"<br />
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"during cell proliferation an increase in lactate production will occur when there is excessive amount of glucose"<br />
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<a href="http://2.bp.blogspot.com/-mrP6I9Hqzok/UO7_dDwKmHI/AAAAAAAAAvo/v2ybWOv5fo8/s1600/glucose+chondroinduction.gif" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="320" src="http://2.bp.blogspot.com/-mrP6I9Hqzok/UO7_dDwKmHI/AAAAAAAAAvo/v2ybWOv5fo8/s320/glucose+chondroinduction.gif" width="205" /></a></div>
E and F are chondroinduction metrics to progressively higher concentrations of glucose(left to right).<br />
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<b>(*NEW*)</b><br />
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<b>Excessive fructose intake causes 1,25-(OH)2D3-dependent inhibition of intestinal and renal calcium transport in growing rats. </b><br />
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"chronic high fructose intakes by lactating rats prevented adaptive increases in rates of active intestinal Ca2+ transport and in levels of 1,25-(OH)2D3, the active form of vitamin D. Since sufficient Ca2+ absorption is essential for skeletal growth, our discovery may explain findings that excessive consumption of sweeteners compromises bone integrity in children. We tested the hypothesis that 1,25-(OH)2D3 mediates the inhibitory effect of excessive fructose intake on active Ca2+ transport. First, compared with those fed glucose or starch, <b>growing rats fed fructose for 4 wk had a marked reduction in intestinal Ca2+ transport rate as well as in expression of intestinal and renal Ca2+ transporters that was tightly associated with decreases in circulating levels of 1,25-(OH)2D3, bone length</b>, and total bone ash weight but not with serum PTH.<b> Dietary fructose increased the expression of 24-hydroxylase (CYP24A1) and decreased that of 1α-hydroxylase (CYP27B1), suggesting that fructose might enhance the renal catabolism and impair the synthesis, respectively, of 1,25-(OH)2D3. Serum FGF23, which is secreted by osteocytes and inhibits CYP27B1 expression, was upregulated</b>, suggesting a potential role of bone in mediating the fructose effects on 1,25-(OH)2D3 synthesis. Second, 1,25-(OH)2D3 treatment rescued the fructose effect and normalized intestinal and renal Ca2+ transporter expression. The mechanism underlying the deleterious effect of excessive fructose intake on intestinal and renal Ca2+ transporters is a reduction in serum levels of 1,25-(OH)2D3."<br />
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"1,25-(OH)2D3 is one of the key hormones controlling intestinal active Ca2+ transport, mainly by regulating TRPV6 and CaBP9k expression"<br />
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"Expression levels of TRPV5 and CaBP28k decreased in the fructose-fed compared to the glucose- and starch-fed rats"<br />
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The glucose fed group had the highest Vitamin D and PTH levels.<br />
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Glucose had the most bone length. 34.4mm for glucose versus 32.4mm for fructose. Although we can't be sure if this decrease in growth rate translates into decreased adult height.<br />
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Glucose diet was slightly superior than starch diet as well.<br />
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Foods high in Glucose:<br />
Vegetables, Fruits, Breads, Grains, Dairy, Meats<br />
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Foods high in fructose:<br />
Mostly processed foods<br />
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Foods high in starch:<br />
Potatoes, bread, rice, cereal, <br />
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Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com5tag:blogger.com,1999:blog-1013552121036660524.post-31115082003695237452013-04-05T09:52:00.000-07:002014-01-09T16:10:23.557-08:00Micro-Growth Plates by LSJLIt's unlikely that LSJL can re-establish a whole entire new growth plate. It's far more probable that LSJL can produce smaller growth plates that can each contribute a little to longitudinal bone growth. Here I present a study that provides evidence of the microgrowth plate theory.<br />
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<a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0058865"><b>The Interplay between Chondrocyte Redifferentiation Pellet Size and Oxygen Concentration.</b></a><br />
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"Chondrocytes dedifferentiate{in endochondral ossification <a href="http://www.heightquest.com/2011/06/becoming-taller-with-chondrocyte.html">chondrocytes die out rather than transdifferentiate into bone type cells</a> so it's unlikely that there's any remnants of dedifferentiated or transdifferentiated chondrocytes that retain some chondrocyte epigenetic material, for LSJL we have to rely on regular mesenchymal stem cells} during ex vivo expansion on 2-dimensional surfaces. Aggregation of the expanded cells into 3-dimensional pellets, in the presence of induction factors, facilitates their redifferentiation and restoration of the chondrogenic phenotype. <b>Typically 1×10(5)-5×10(5) chondrocytes are aggregated, resulting in "macro" pellets having diameters ranging from 1-2 mm.</b> These macropellets are commonly used to study redifferentiation, and recently macropellets of autologous chondrocytes have been implanted directly into articular cartilage defects to facilitate their repair. However, diffusion of metabolites over the 1-2 mm pellet length-scales is inefficient, resulting in radial tissue heterogeneity. <b>The aggregation of 2×10(5) human chondrocytes into micropellets of 166 cells each{it's probable to be able to induce an aggregate of 166 cells with LSJL stimuli, likely more cells are needed as we are dealing with MSCs rather than dedifferentiated chondrocytes}, rather than into larger single macropellets, enhances chondrogenic redifferentiation.</b> The thousands of micropellets were manufactured using the microwell platform, which is an array of 360×360 µm microwells cast into polydimethylsiloxane (PDMS), that has been surface modified with an electrostatic multilayer of hyaluronic acid and chitosan to enhance micropellet formation{Both <a href="http://www.heightquest.com/2012/06/height-increase-with-chitosan.html">chitosan</a> and <a href="http://www.heightquest.com/2011/05/does-hyaluronic-acid-supplementation.html">hyaluronic acid</a> are supplements, whether they can help create some kind of basement membrane or scaffold for growth is unclear}. Such surface modification was essential to prevent chondrocyte spreading on the PDMS. Sulfated glycosaminoglycan (sGAG) production and collagen II gene expression in chondrocyte micropellets increased significantly relative to macropellet controls, and redifferentiation was enhanced in both macro and micropellets with the provision of a hypoxic atmosphere (2% O2). <b>Once micropellet formation had been optimized, micropellets could be assembled into larger cartilage tissues</b>{so micro-growth plates can combine to become larger growth plates}."<br />
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"The reduced diameter of the micropellets[100 micrometers each] mitigated diffusion gradients, enhanced MSC chondrogenic differentiation and generated a more uniform cell product"<br />
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"Hypoxic micropellets assembled into macrotissues. Alcian blue staining for hypoxic micropellets assembled at different time points (indicated days). The total culture duration was 21 days. Scale bars: 100 µm."<br />
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Key Differences between this study and LSJL:<br />
*Articular Cartilage was used and not Growth Plate cartilage<br />
*Dedifferentiated Chondrocytes were used and not mesenchymal stem cells.<br />
*The micro-cartilage was uniform here. In LSJL, the microgrowth plates would not be uniform. <br />
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Regardless it still provides evidence that <b>MSCs could potentially form microgrowth plates and those growth plates could combine to form larger growth plates</b>. It seems that the higher oxygen concentration was of a more endochondral rather than chondral environment which is good considering that adult bone is vascularized.<br />
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Here's some evidence that micro growth plates can undergo endochondral ossification:<br />
<br />
<b>Delayed endochondral ossification in early medial coronoid disease (MCD): A morphological and immunohistochemical evaluation in growing Labrador retrievers. </b><br />
<br />
"Early micromorphological changes [occur] in articular cartilage and to describe the postnatal development of the medial coronoid process (MCP) before MCD develops. Three litters of MCD-prone young Labrador retrievers were purpose-bred from a dam and two sires with MCD. Comparisons of the micromorphological appearance of the MCP in MCD-negative and MCD-positive joints demonstrated that MCD was initially associated with a disturbance of endochondral ossification, namely a delay in the calcification of the calcifying zone, without concurrent abnormalities in the superficial layers of the joint cartilage. Cartilage canals containing patent blood vessels were only detected in dogs <12weeks old. <b>Retained hyaline cartilage might ossify as the disease progresses, but weak areas can develop into cracks between the retained cartilage and the subchondral bone, leading to cleft formation and fragmentation of the MCP.</b>"<br />
<br />
That scattered growth plates could undergo endochondral ossification bodes well that micro growth plates could undergo endochondral ossification. <br />
<br />
"Osteochondrosis is characterized by a disturbance of endochondral ossification that leads to an area of retained cartilage"<-osteochondrosis could be key to our understanding of microgrowth plates.<br />
<br />
The arrows are pointing to cartilage canals<br />
<br />
<img alt="Full-size image (90 K)" border="0" class="imgLazyJSB figure large smallImg" data-fulleid="1-s2.0-S1090023313001925-gr6.jpg" data-fullheight="319" data-fullwidth="645" data-loaded="true" src="http://ars.els-cdn.com/content/image/1-s2.0-S1090023313001925-gr6.jpg" data-thumbeid="1-s2.0-S1090023313001925-gr6.sml" data-thumbheight="108" data-thumbwidth="219" style="display: inline;" />Cartilage canals dissappeared at 12 weeks of age.<br />
<br />
<b>Pathogenesis of epiphyseal osteochondrosis. </b><br />
<br />
"Osteochondrosis (OC) of the articular epiphyseal cartilage complex (AECC) is a developmental disease that is present in the first weeks of life. It is characterized by focal chondronecrosis and <b>retention of growth cartilage due to failure of endochondral ossification</b>. Fissures may extend from the lesion through the overlying articular cartilage to create a cartilage flap and an osteochondral fragment. This articular form is known as osteochondritis dissecans (OCD). There have been many hypotheses about the etiopathogenesis of OC of the AECC including, amongst others, ischemia of growth cartilage or altered cartilage type II collagen metabolism. The ischemia theory proposes that <b>necrosis of the vessels in the cartilage canals of the sub-articular growth cartilage leads to necrosis of chondrocytes and retention of necrotic cartilage{so re-establishing these vessels in the cartilage canals could be critical to forming new growth plates}</b>. Several studies have measured biomarkers in serum and synovial fluid to demonstrate a consistent increase in type II collagen synthesis in young animals of different species. Although these changes could represent lesion reparative events, there is no comparable increase in the synthesis of cartilage matrix proteoglycan molecule. It is therefore speculated that an altered type II collagen metabolism may be involved in the early changes associated with OC. Further studies of OC susceptible animals in utero and the first weeks of life are required to elucidate the cause of vessel necrosis and the exact role of type II collagen structure and metabolism in OC."<br />
<br />
"The bones of diarthrodial joints develop from mesenchymal cells that condense and differentiate into chondrocytes to form a cartilage template. Following formation of the primary ossification center in the diaphysis, the chondrocytes of the central area of the epiphysis proliferate, hypertrophy and undergo cell death. A complex sequence of molecular signals orchestrates these events. The hypertrophic chondrocytes themselves secrete type X collagen and alkaline phosphatase that contribute to calcification of the adjacent matrix. The mineralized cartilaginous septae, between the cell lacunae, undergo proteolytic digestion by septoclasts . Proteinases, such as matrix metalloproteinases (MMPs), cathepsins and gelatinases, degrade the mineralized type II-collagen-rich network to allow blood vessel invasion. The invading vessels are a source of mesenchymal stem cells and bone progenitors that differentiate into osteoblasts, secrete osteoid and promote ossification of the secondary center of ossification in the epiphysis" <-Our goal is to induce the mimicing of these events via LSJL to form new growth plates.<br />
<br />
<b>Osteochondrosis of the proximal phalanx of the hallux in adolescent footballers. </b><br />
<br />
"We report two cases with radiographic appearances of osteochondrosis in the proximal phalanx of the big toe in adolescent footballers. The radiological findings were those of initial fragmentation with subsequent healing of the epiphysis. This is the first report of osteochondrosis at this site. Local pain was accompanied by swelling with restriction of dorsiflexion of the metatarsophalangeal joint of the big toe. The condition was self-healing over a 2-4-year period. It needs to be included in the differential diagnosis of painful hallux in adolescent footballers."<br />
<br />
Unfortunately I could not get this full study. It'd be interesting to see the healing of the epiphysis. Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com12tag:blogger.com,1999:blog-1013552121036660524.post-76868037830420446472013-04-04T11:48:00.001-07:002022-09-24T07:44:32.155-07:00How they treat short stature in medicine<b>Clinical practice. Short stature in childhood--challenges and choices.</b><br />
<br />
"Treatment with recombinant human growth hormone can increase the adult height of children with idiopathic short stature by 1.2 to 2.8 in. (3.0 to 7.1 cm), with wide variation in the incremental gain."<-10,000 to $60,000 per patient per year<br />
<br />
"human growth hormone therapy in children with idiopathic short stature increases the growth rate and mean adult height by 1.2 to 2.8 in., or approximately 0.4 in. (1.0 cm) per year of human growth hormone treatment."<br />
<br />
"Human growth hormone is administered subcutaneously at a dose of 0.2 to 0.375 mg per kilogram of body weight per week. Daily administration of human growth hormone is superior to less frequent administration. Dose modulation may influence the effect; doses at the higher end of this range and adjustment of the dose to achieve high-normal IGF-I levels lead to faster growth and perhaps to taller adult height"<br />
<br />
"For short peripubertal[early stages of puberty boys, growth-promoting alternatives to human growth hormone are low-dose androgen therapy with injectable testosterone and low-dose androgen therapy with oral oxandrolone (e.g., 1.25 to 2.5 mg per day). Both regimens are relatively low in cost, and though they are not FDA-approved for growth acceleration, they increased the growth rate by 1.2 to 2.0 in. (3.0 to 5.1 cm) per year for 1 to 3 years in controlled trials."<br />
<br />
"To avoid accelerated estrogen-mediated epiphyseal maturation, oxandrolone (not aromatized to estrogen) is theoretically preferred over testosterone when the bone age is less than 11 years. Oxandrolone is usually discontinued after a documented increase in endogenous testosterone; long-term follow-up studies indicate that treatment is followed by normal pubertal growth and eventual attainment of an adult height equal to or slightly greater than the predicted height before treatment "<br />
<br />
"Aromatase inhibitors (which reduce estrogen production and delay skeletal maturation) have been used experimentally in boys to prolong pubertal growth and increase height, but they are more expensive and have less of a growth-accelerating effect than androgens, and actual adult height gains have fallen short of prior predictions of 1.6 to 2.4 in. (4.1 to 6.1 cm)."<br />
<br />
Few Notes:<br />
<br />* Pediatric Treatment is extremely narrow: Only HGH and Testosterone. This is likely because they want the most expensive option and don't want treatments that could additionally help by say 0.1cm.<br />
* Oxandrolone is the best testesterone supplement as it does not convert to estrogen<br />
* These studies look at a wholistic view i.e. how much does this supplement increase the final height rather than looking at what happens directly at the cellular level.Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com2tag:blogger.com,1999:blog-1013552121036660524.post-84188413488467797882013-04-02T11:00:00.002-07:002022-10-07T21:00:42.184-07:00CTGF(CCN2), height increase target gene<b> </b>CCN2 could increase adult height by accelerating the rate of endochondral ossification but keeping the epiphyseal growth plate the same size resulting in more growth. CCN2 is also associated with the height gene IGF2.<br />
<br />
CTGF meets the criteria for a height growth target where overexpression increases height and underexpression decreases height. However this was only for cartilage specific expression of CTGF. Overexpression of CTGF has been found to have catabolic effects on muscle.<br />
<br />
Glucosamine and <a href="http://www.heightquest.com/2012/10/grow-with-cla.html">CLA</a> are potential ways to increase CTGF levels however can a global increase of CTGF increase height like a cartilage specific one? Does anyone know any other supplements that can increase CTGF? Prefereably only in the cartilage. <br />
<br />
It should be noted that CTGF is only a promising target for people with open growth plates.<br />
<br />
<a href="http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0059226"><b>Cartilage–Specific Over-Expression of CCN Family Member 2/Connective Tissue Growth Factor (CCN2/CTGF) Stimulates Insulin-Like Growth Factor Expression and Bone Growth</b></a><br />
<br />
"CCN family member 2/connective tissue growth factor (CCN2) promotes the proliferation, differentiation, and maturation of growth cartilage cells in vitro. We generated transgenic mice overexpressing CCN2 and analyzed them with respect to cartilage and bone development. Transgenic mice were generated expressing a ccn2/lacZ fusion gene in cartilage under the control of the 6 kb-Col2a1-enhancer/promoter. Changes in cartilage and bone development were analyzed. Primary chondrocytes as well as limb bud mesenchymal cells were cultured and analyzed for changes in expression of cartilage–related genes, and non-transgenic chondrocytes were treated in culture with recombinant CCN2. <b>Newborn transgenic mice showed extended length of their long bones, increased content of proteoglycans and collagen II accumulation</b>. Transgenic bones indicated increases in bone thickness and mineral density. Chondrocyte proliferation was enhanced in the transgenic cartilage. In in vitro short-term cultures of transgenic chondrocytes, the expression of col2a1, aggrecan and ccn2 genes was substantially enhanced; and in long-term cultures the expression levels of these genes were further enhanced. Also, in vitro chondrogenesis was strongly enhanced. <b>IGF-I and IGF-II mRNA levels were elevated in transgenic chondrocytes, and treatment of non-transgenic chondrocytes with recombinant CCN2 stimulated the expression of these mRNA</b>. <b>The addition of CCN2 to non-transgenic chondrocytes induced the phosphorylation of IGFR, and ccn2-overexpressing chondrocytes showed enhanced phosphorylation of IGFR</b>. The observed effects of CCN2 may be mediated in part by CCN2-induced overexpression of IGF-I and IGF-II. <b>CCN2-overexpression in transgenic mice accelerated the endochondral ossification processes, resulting in increased length of their long bones.</b>"<br />
<br />
" At 8 weeks, the majority of the transgenic mice were about 12% larger than their wild-type littermates"<br />
<br />
"Safranin-O staining indicated consistently an enhanced density of proteoglycans in the transgenic cartilage in comparison with cartilage of wt littermates"<br />
<br />
"type II collagen [had] an enhanced reaction in resting chondrocytes and in the growth plate [of the transgenic mice]" CCN2 enhanced MMP9, Col10a1, VEGF, aggrecan, and Col2a1 expression.<br />
<br />
" the enhanced matrix deposition did not result in an increase in the size of the cartilaginous epiphysis; rather, the extended bone length was the result of an elongated bony shaft of the diaphysis."<br />
<br />
"Staining of the skeleton of transgenic embryos with type X collagen antibodies indicated that the hypertrophic zone was shorter in the transgenic embryos than in their wt littermates"<-So does CTGF Col2a1 specific overexpression increase adult height or just accelerate growth rate?<br />
<br />
"Chondrogenic differentiation of limb-bud mesenchymal cells from CCN2 transgenic animals was greatly enhanced as compared with that of their wild-type counterparts"<-this could result in increased adult height.<br />
<br />
Loss of function of CCN2 resulted in impaired endochondral ossification.<br />
According to <b>Magnesium supplementation prevents angiotensin II-induced myocardial damage and CTGF overexpression</b>., in one instance Magnesium inhibited CTGF.<br />
<br />
According to <b>Paracrine role for TGF-β-induced CTGF and VEGF in mesangial matrix expansion in progressive glomerular disease</b>., TGF-B induced upregulation of CTGF in one instance.<br />
<br />
According to <a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3364991/"><b>Performance of repetitive tasks induces decreased grip strength and increased fibrogenic proteins in skeletal muscle: role of force and inflammation</b></a>., exercise can increase CTGF levels. CTGF seemed to reach maximal levels of 6 weeks of the exercise in the exercise group of a high repetition, minimal force task(target reach rate of 4 reaches/min and <5% maximum pulling force). The other group with high repetition and high force(target rate of 4 reaches/min and 60% maximum pulling force. ) had higher increases in CTGF and continued even into the 9th week. The increase in CTGF seemed to be regulated by TNFa and TGFb. The increase in CTGF was inhibited by anti-inflammatory drugs.<br />
<br />
According to <b>Oral glucosamine increases expression of transforming growth factor β1 (TGFβ1) and connective tissue growth factor (CTGF) mRNA in rat cartilage and kidney: implications for human efficacy and toxicity</b>., <a href="http://www.heightquest.com/2010/04/grow-taller-with-glucosamine-and.html">glucosamine</a> increases CTGF in cartilage. The increase in CTGF was in articular but not growth cartilage. It wasn't huge but it was a significant increase 2.3-fold.<br />
<br />
In some cases, <a href="http://www.heightquest.com/2010/10/achieve-height-increase-by-modifying.html">mechanical load can decrease CTGF by decreasing MMP3</a>. <a href="http://www.heightquest.com/2011/10/tensile-strain-versus-lsjl-genes.html">Cyclic tension increased CTGF expression</a>.<br />
<br />
<b>CCN2/CTGF is required for matrix organization and to protect growth plate chondrocytes from cellular stress.</b><br />
<b><br /></b>
"The loss of CCN2 leads to perinatal lethality resulting from a severe chondrodysplasia. Upon closer inspection of Ccn2 mutant mice, we observed defects in extracellular matrix (ECM) organization and hypothesized that the severe chondrodysplasia caused by loss of CCN2 might be associated with defective chondrocyte survival. Ccn2 mutant growth plate chondrocytes exhibited enlarged endoplasmic reticula (ER), suggesting cellular stress. Immunofluorescence analysis confirmed elevated stress in Ccn2 mutants, with reduced stress observed in Ccn2 overexpressing transgenic mice. In vitro studies revealed that <b>Ccn2 is a stress responsive gene in chondrocytes. The elevated stress observed in Ccn2-/- chondrocytes is direct and mediated in part through integrin α5.</b> The expression of the survival marker NFκB and components of the autophagy pathway were decreased in Ccn2 mutant growth plates, suggesting that CCN2 may be involved in mediating chondrocyte survival. Absence of a matricellular protein can result in increased cellular stress and highlight a novel protective role for CCN2 in chondrocyte survival. The severe chondrodysplasia caused by the loss of CCN2 may be due to increased chondrocyte stress and defective activation of autophagy pathways, leading to decreased cellular survival. These effects may be mediated through nuclear factor κB (NFκB) as part of a CCN2/integrin/NFκB signaling cascade."<b><br /></b><br />
<b><br /></b>
"ER enlargement is a hallmark of defective protein folding and cellular stress. ER and other forms of cellular stress activate the Unfolded Protein Response (UPR), an adaptive mechanism to restore cell homeostasis and viability"<b><br /></b><b><br /></b>
"ER stress activates NFκB via tumor necrosis factor-α (TNF-α) receptor associated factor 2 (TRAF2) and inositol requiring enzyme 1 (IRE1) in vitro"<b><br /></b><br />
"CCN2 induces NFκB activity in ATDC5 chondrocytic cells through integrin αvβ3-mediated mechanisms to enhance migration"<br />
<br />
In this study CCN2 overexpression did not seem to result in increased height in rats. But the structure of the skeletons is different. The growth plate height in CCN2 mice was lower. The scientists did mention progressive overgrowth of cartilage elements.<br />
<br />
<a href="http://link.springer.com/article/10.1007%2Fs12079-013-0204-8/fulltext.html"><b>CCN2: a master regulator of the genesis of bone and cartilage. </b></a><br />
<br />
"CCN2 promotes the proliferation and differentiation of growth-plate chondrocytes"<br />
<br />
"the over-expression of CCN2 in cartilage stimulated the proliferation and differentiation of growth-plate chondrocytes, resulting in the promotion of endochondral ossification."<br />
<br />
Expression of CCN2 can be induced by TGF-Beta.<br />
<br />
In this study mice overexpressing CCN2 had longer bones on postnatal day 1.<br />
<br />
"In in vitro short-term cultures of chondrocytes prepared from the cartilage of ccn2-over-expressing mice, the expression of col2a1, aggrecan and ccn2 was substantially enhanced; and in long-term cultures the expression levels of these genes were further enhanced"<br />
<br />
"IGF-I and IGF-II mRNA levels were elevated in the transgenic chondrocytes, and treatment of non-transgenic chondrocytes with CCN2 stimulated the expression of these mRNAs"<br />
<br />
"phosphorylation of ERK1/2 by CCN2 is involved in chondrocyte proliferation, CCN2-BMP-2 treatment might promote chondrocyte differentiation by suppressing chondrocyte proliferation via decreased ERK1/2 phosphorylation."<div><br /><a href="https://link.springer.com/article/10.1007/s12079-011-0123-5"><b>The role of CCN2 in cartilage and bone development</b><br /></a></div><div><b><br /></b></div>"CCN2, a classical member of the CCN family of matricellular proteins, is a key molecule that conducts cartilage development in a harmonized manner through novel molecular actions. During vertebrate development, all cartilage is primarily formed by a process of mesenchymal condensation, while CCN2 is induced to promote this process. Afterwards, cartilage develops into several subtypes with different fates and missions, in which CCN2 plays its proper roles according to the corresponding microenvironments. The history of <b>CCN2 in cartilage and bone began with its re-discovery in the growth cartilage in long bones</b>, which determines the skeletal size through the process of endochondral ossification. <b>CCN2 promotes physiological developmental processes not only in the growth cartilage but also in the other types of cartilages</b>, i.e., Meckel’s cartilage representing temporary cartilage without autocalcification, articular cartilage representing hyaline cartilage with physical stiffness, and auricular cartilage representing elastic cartilage. Together with its significant role in intramembranous ossification, CCN2 is regarded as a conductor of skeletogenesis. During cartilage development, the CCN2 gene is dynamically regulated to yield stage-specific production of CCN2 proteins at both transcriptional and post-transcriptional levels. New functional aspects of known biomolecules have been uncovered during the course of investigating these regulatory systems in chondrocytes. Since <b>CCN2 promotes integrated regeneration as well as generation (=development) of these tissues</b>, its utility in regenerative therapy targeting chondrocytes and osteoblasts is indicated, as has already been supported by experimental evidence obtained in vivo."<div><br /></div>"CCN2, also known as connective tissue growth factor (CTGF)"<div><br /></div>"Meckel’s cartilage arises from mesodermal progenitor cells situated in close proximity to the zone of mineralization during mandibular bone formation"Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com5tag:blogger.com,1999:blog-1013552121036660524.post-71270714263638907162013-03-31T10:39:00.000-07:002014-06-02T15:49:34.583-07:00Creating a pro-chondrogenic microenvironment <b>Ctrl-F for (*NEW*) for the new information. Several times cellulose is used in biomaterial scaffolds to induce chondrogenesis. Cellulose is also known as fiber and is not digested. The question is can we ingest enough of it to build up enough fiber in the bone marrow to build a pro-chondrogenic microenvironment? Since fiber is something that is studied in the mainstream and not just in the bubble of height increase I open the subject to all of you.</b><br />
<b><br /></b>
<b>How much fiber can build up in the bone marrow?</b><br />
<br />
How do we create a pro-chondrogenic microenvironment within the epiphyseal bone marrow to allow for the formation of new growth plates? The goal of LSJL is to induce that environment.<br />
<br />
<b>Creation of an in vitro microenvironment to enhance human fetal synovium-derived stem cell chondrogenesis.</b><br />
<div>
<br /></div>
"[We] assess the feasibility of the sequential application of extracellular matrix (ECM) and low oxygen to enhance chondrogenesis in human fetal synovium-derived stem cells (hfSDSCs). Human fetal synovial fibroblasts (hfSFs) include hfSDSCs, as evidenced by their multi-differentiation capacity and the surface phenotype markers typical of mesenchymal stem cells. Passage-7 hfSFs were plated on either conventional plastic flasks (P) or ECM deposited by hfSFs (E) for one passage. Passage-8 hfSFs were then reseeded for an additional passage on either P or E. The pellets from expanded hfSFs were incubated in a serum-free chondrogenic medium supplemented with 10 ng/ml transforming growth factor-β3 under either normoxia (21% O(2)) or hypoxia (5% O(2)) for 14 days. Pellets were collected for evaluation of the treatments (EE21, EE5, EP21, EP5, PE21, PE5, PP21, and PP5) on expanded hfSF chondrogenesis. Compared with seeding on conventional plastic flasks, <b>hfSFs expanded on ECM exhibit a lower expression of senescence-associated β-galactosidase and an enhanced level of stage-specific embryonic antigen-4{The Extecellular Matrix has potential to reduce cellular senescence}</b>. <b>ECM-expanded hfSFs show increased cell numbers and an enhanced chondrogenic potentia</b>l. Low oxygen (5% O(2)) during pellet culture enhances hfSF chondrogenesis. The presence of stem cells in hfSFs, and modulation of the in vitro microenvironment can enhance hfSDSC chondrogenesis."<br />
<br />
The two elements of the microenvironment identified as being pro-chondrogenic are hypoxia and ECM. LSJL heavily upregulates ECM molecules.<br />
<br />
"Adult MSCs cultured in vitro lack telomerase activity"<-in contrast to fetal MSCs which have higher telomerase activity and longer telomeres.<br />
<br />
Group PE5 had the most positive chondrogenic markers. Which would be groups first plated on conventional plastic flasks than transferred to ECM by synovial fibroblasts in an hypoxic environment. EE5 which is ECM for the whole time also had positive measures on all chondrogenic factors.<br />
<br />
The reason that Plastic followed by ECM was better than pure ECM could be due to a catch-up growth phenomenon so ECM may be still better at all stages for chondrogenesis overall.<br />
<br />
Cellular Response to Hypoxia("Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus indicating lowered oxygen tension. Hypoxia, defined as a decline in O2 levels below normoxic levels of 20.8 - 20.95%, results in metabolic adaptation at both the cellular and organismal level. ") genes for mus musculus also altered in LSJL:<br />
Adam8{down}<br />
Gnb1{down}<br />
<br />
<b><a href="http://www.molbiolcell.org/content/23/18/3731.long">ECM stiffness primes the TGFβ pathway to promote chondrocyte differentiation.</a></b><br />
<div>
<br /></div>
<div>
"Chondrocytes generate an integrated response to ECM stiffness and transforming growth factor β (TGFβ), a potent agonist of chondrocyte differentiation.<b> Primary murine chondrocytes and ATDC5 cells{ATDC5 cells are progenitor cells to chondrocytes} grown on 0.5-MPa substrates deposit more proteoglycan and express more Sox9, Col2α1, and aggrecan mRNA relative to cells exposed to substrates of any other stiffness{0.5MPa is the optimal stiffness out of those tested to encourage chondrogenesis}</b>. The chondroinductive effect of this discrete stiffness, which falls within the range reported for articular cartilage, requires the stiffness-sensitive induction of TGFβ1. <b>Smad3 phosphorylation, nuclear localization, and transcriptional activity are specifically increased in cells grown on 0.5-MPa substrates{The benefits of this ECM stiffness may be due to an increase in Smad3 phosphorylation}</b>. ECM stiffness primes cells for a synergistic response, such that the combination of ECM stiffness and exogenous TGFβ induces chondrocyte gene expression more robustly than either cue alone through a p38 mitogen-activated protein kinase-dependent mechanism."</div>
<br />
"Upon integrin binding to ECM ligands and the generation of internal cell tension, cells develop focal adhesions, a highly ordered array of proteins including focal adhesion kinase (FAK), talin, vinculin, and α-actinin. These proteins interact with small GTPases (i.e., Rho, Rac) and other signaling pathways, facilitating changes in cytoskeletal organization, actinomyosin contractility, and cell shape with even small changes in matrix compliance"<br />
<br />
"The activated TβRI phosphorylates Smad2 and Smad3 on the C-terminal domain, causing heteromerization with Smad4 and preferential retention in the nucleus, where Smads act as transcription factors. In chondrocytes, phosphorylated Smad3 recruits CBP to activate Sox9-mediated transcription of Col2α1"<br />
<br />
"Cells respond to substrate stiffness by increasing internal cellular tension through stress fiber formation and cell spreading"<br />
<br />
"Rho and ROCK participate in stiffness sensing in part through stress fiber formation"<br />
<br />
"TGFβ rapidly activates the p38 pathway through the MAPK kinase kinase TAK1 activation of MKK3/6. Phospho-p38 was increased on 0.5-MPa substrates relative to plastic"<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="http://1.bp.blogspot.com/-VNHC5GEkDb8/UNtECIYfZ4I/AAAAAAAAArc/covRt_5x5ZM/s1600/stiffnessandchondroinduction.gif" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://1.bp.blogspot.com/-VNHC5GEkDb8/UNtECIYfZ4I/AAAAAAAAArc/covRt_5x5ZM/s320/stiffnessandchondroinduction.gif" height="260" width="320" /></a></div>
"there is an optimal level of ROCK activity on 0.5-MPa substrates that activates chondroinduction, in part, through the induction of TGFβ1 expression on compliant substrates."<br />
<br />
"BMP-inducible nuclear translocation of Smad1/5/8 requires sufficient ROCK-dependent cytoskeletal tension. ROCK can also enhance the activity of both Smad3 and Sox9 by phosphorylation of the Smad3 linker region or Sox9 on serine 181"<br />
<br />
<b>Mesenchymal stem cells and their microenvironment.</b><br />
<div>
<br /></div>
<div>
"MSCs are stromal-like cells that are characterized by a CD105+ /CD73+ /CD90+ /CD45- /CD34- /CD11b- /CD19- /HLA-DR- cell surface signature"</div>
<div>
<br /></div>
<div>
"MSCs [may] exist in a perivascular[near or around blood vessels] location and share a number of cell surface markers with pericytes"</div>
<div>
<br /></div>
<div>
"MSC show a greater propensity to differentiate to cartilage and bone, if they are bone marrow derived and to differentiate to fat, if isolated from adipose tissue"</div>
<div>
<br /></div>
<div>
"<b>In order to self renew, stem cells need to be protected from differentiation signals and from apoptosis, and the niche provides the adhesion molecules, soluble factors and conditions that allow this in a concerted fashion</b>. These soluble factors and ECM components activate various kinase cascades including the ERK1/2 MAPK and the PI-3K pathways"<-So not only do we need to induce differentiation signals to induce stem cells to chondrogenesis we need to protect them from differentiation signals that induce differentiation to other cell types.</div>
<div>
<br /></div>
<div>
"EGF, which stimulates the EGFR1 on MSCs, strongly activates the MAP kinases ERK1/2 and Jnk1, the Stat3 and PKC pathways and weakly stimulates the PI-3K pathway, and <b>high concentrations of EGF induce osteogenic differentiation in MSCs</b>"<-Thus we want to avoid high levels of EGF.</div>
<div>
<br /></div>
<div>
"High concentrations of covalently tethered EGF, which restrict signaling to the cell surface, result in increased osteogenic differentiation of MSCs, while <b>low concentrations of soluble EGF, which induce receptor internalization, are anti-osteogenic</b>"<-Reducing EGF levels may be part of the way to grow taller.</div>
<div>
<br /></div>
<div>
"<b>Concomitant PI-3K stimulation prevents ERK1/2-dependent osteogenic differentiation</b>."<-LSJL likely stimulates both PI3K and ERK1/2 which may be why it is more pro-chondrogenic than osteogenic.</div>
<div>
<br /></div>
<div>
"MSCs can produce VEGF, bFGF{up}, PDGF, angiopoietin, CXCL8/IL-8 and other angiogenic factors"</div>
<div>
<br /></div>
<div>
"[MSCs] express Oct4, Nanog, Sox2, SSEA3, SSEA4, Rex1, c-myc, nucleostemin, Nodal, Sca1{only expressed by mice and not humans}, Snail2"</div>
<div>
<br /></div>
<div>
"When chondrogenesis was assessed in cross-linked methacrylated hyaluronic acid hydrogels, the macromer density influenced MSC chondrogenesis: high density macromers resulted in increased chondrogenesis, but of inferior quality than seen with lower density gels"</div>
<div>
<br /></div>
<div>
"early MSC progenitors, defined by their smaller size and expression of podocalyxin-like protein (PODXL), selectively express alpha4 and alpha6 integrins, which are lost during culture. Freshly isolated MSC do not express the vitronectin receptor alphav beta5, but express low levels of the fibronectin receptor alpha5beta1 and the collagen receptors alpha1beta1, alpha2beta1 and alpha3beta1. Upon culture alphavbeta5 is up-regulated. Increased expression of alphavbeta5 and alpha5beta1 is observed during chondrogenic differentiation"</div>
<div>
<br /></div>
<div>
"MSCs do not seem to circulate in the vasculature under physiological conditions, it seems likely that they are released into the vasculature, when there is increased demand for these cells during any kind of tissue injury "</div>
<div>
<br /></div>
<div>
"Although MSCs accumulate in damaged tissue to some degree, recruitment of circulating MSC is very inefficient"</div>
<div>
<br /></div>
<div>
"MSCs seem to be resistant in general to certain apoptotic pathways perhaps due to very low expression of caspase 8 and caspase 9"</div>
<div>
<br /></div>
<div>
"all MSC express cell surface receptors for C3a and C5a"</div>
<div>
<br /></div>
<div>
"genes expressed in MSCs specifically involved in the HSC niche including galectin-1, fibronectin-1, osteopontin, CXCL12, thrombospondin-1 and -2, TGF-beta 2, Angiopoietin-1, ILGFBP-4, FGF-7, SFRP-1 and -2, VCAM-1, and BMPR type 1a"<br />
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<b>Redox regulation of stem/progenitor cells and bone marrow niche.</b><br />
<div>
<br /></div>
<div>
"Bone marrow (BM)-derived stem and progenitor cell functions including self-renewal, differentiation, survival, migration, proliferation, and mobilization are regulated by unique cell-intrinsic and -extrinsic signals provided by their microenvironment. Reactive oxygen species (ROS), especially hydrogen peroxide (H(2)O(2)), play roles in regulating stem and progenitor cell functions in various physiologic and pathologic responses.<b> The low level of H(2)O(2) in quiescent hematopoietic stem cells (HSCs) contributes to maintaining their "stemness," whereas a higher level of H(2)O(2) within HSCs or their niche promotes differentiation, proliferation, migration, and survival of HSCs or stem/progenitor cells.</b> <b>Major sources of ROS are NADPH oxidase and mitochondria</b>. In response to ischemic injury, <b>ROS derived from NADPH oxidase are increased in the BM microenvironment{mechanical loading stimulates ROS release from mitochondria creating a more hypoxic microenvironment}, which is required for hypoxia and hypoxia-inducible factor-1α expression and expansion throughout the BM</b>. This, in turn, promotes progenitor cell expansion and mobilization from BM, leading to reparative neovascularization and tissue repair. Excess amounts of ROS create an inflammatory and oxidative microenvironment, which induces cell damage and apoptosis of stem and progenitor cells."</div>
<div>
<br /></div>
<div>
"ROS such as O2•− and H2O2 are generated from a number of sources including mitochondria, NADPH oxidases (NOXs), xanthine oxidase, cytochrome P450, and nitric oxide synthase (through its uncoupling). Because O2•− is produced from oxygen, the oxygen concentration or hypoxic condition has a significant impact on the total amount of ROS. The O2•− reacts with nitric oxide (NO) to generate peroxynitrite (OONO−), thereby inhibiting endothelial function, whereas it can be quickly converted to H2O2 by superoxide dismutases (SODs) such as MnSOD (SOD2) or Cu/ZnSOD (SOD1) or extracellular SOD (SOD3). H2O2 is catalyzed by catalase, glutathione peroxidases (GPx′s), and the thioredoxin–peroxiredoxin system to nonreactive water"</div>
<div>
<br /></div>
<div>
"Growth factor signaling is mediated through H2O2 production."</div>
<div>
<br /></div>
<div>
"Different from phagocytic NADPH oxidase that is normally quiescent but generates a large burst of O2•− (the “oxidative burst”) upon activation, the NOXs constitutively produce low levels of O2•− or H2O2 intracellularly in the basal state and are further stimulated acutely by various agonists and growth factors. NOXs are now recognized to have specific subcellular localizations, which is required for localized H2O2 production and activation of specific redox signaling pathways to mediate various functions" NOXs are located in MSCs.</div>
<div>
<br /></div>
<div>
"Once O2•− is generated, it is immediately converted into H2O2 by MnSOD or Cu/ZnSOD"</div>
<div>
<br /></div>
<div>
"To avoid the potential damaging effects of H2O2, mitochondria express other antioxidant enzymes such as peroxiredoxin (Prx) 3 and Prx5 and glutathione peroxidase."</div>
<div>
<br /></div>
<div>
"hypoxic conditions increase mitochondrial ROS production, which stabilizes HIF-1α protein expression. "<br />
<br />
"optimal levels of ROS are required for normal responses, whereas excess or insufficient levels of ROS are associated with cellular dysfunction and reduced growth factor signaling, respectively"<-So we want to maximize ROS signaling before cellular dysfunction.<br />
<br />
"PTEN is a negative regulator of the PI3K–Akt pathway and contains catalytic cysteine residues that are highly susceptible to oxidation by H2O2. Therefore, PTEN inhibition stabilizes the active phosphorylated form of Akt. "<br />
<br />
<b>(*NEW*)</b><br />
<b>Directing chondrogenesis of stem cells with specific blends of cellulose and silk. </b><br />
<br />
"We systematically prepared cellulose, blends with silk at different compositions using a method based on ionic liquids as a common solvent. We tested the effect of blend compositions on the physical properties of the materials as well as on their ability to support mesenchymal stem cell (MSC) growth and chondrogenic differentiation. <b>The stiffness and tensile strength of cellulose was significantly reduced by blending with silk</b>. The characterised materials were tested using MSCs derived from four different patients.<b> Growing MSCs on a specific blend combination of cellulose and silk in a 75:25 ratio significantly upregulated the chondrogenic marker genes SOX9, aggrecan and type II collagen in the absence of specific growth factors{so the stiffness of this environment is likely optimal for chondrogenesis}.</b> This chondrogenic effect was not found with neat cellulose or cellulose/silk 50:50 blend composition. No adipogenic or osteogenic differentiation is detected on the blends suggesting that cellulose/silk 75:25 blend induces specific stem cell differentiation into the chondrogenic lineage without addition of the soluble growth factor TGF-β."<br />
<br />
"Cellulose is a linear homopolymer of glucose." Cellulose is also called fiber. It can't be digested so if you can get it to your bone marrow it may help create a pro-chondrogenic microenvironment.<br />
<br />
"Cellulose, which comprises three hydroxyl groups per repeating unit, is theoretically a good choice as an initiator of chondrogenesis" <br />
<br />
"Silane-treated glass surfaces functionalized with<b> carboxyl (–COOH) and hydroxyl (–OH) groups initiated chondrogenic marker mRNA expression in MSCs in the absence of chondrogenic growth factors</b>, whereas amine (–NH2) functional groups encouraged osteogenic differentiation of stem cells in the absence of osteogenic supplements"<br />
<br />
Compounds with Hydroxyl groups:<br />
Alcohol<br />
Sugars<br />
<br />
Compounds with Carboxyl groups:<br />
Sugars<br />
Vinegar<br />
Goat fat<br />
Breast milk<br />
Coconut/Palm/Peanut oil<br />
Nutmeg<br />
<br />
Amino acids contain the amine functional group.<br />
<br />
The study <b>Galactooligosaccharides improve mineral absorption and bone properties in growing rats through gut fermentation</b>. found that "Galactooligosaccharides (GOS), prebiotic nondigestible oligosaccharides derived from lactose" had no effect on femur length.<br />
<br />
According to <a href="http://jn.nutrition.org/content/109/6/1117.long"><b>Dietary cellulose, zinc and copper: effects on tissue levels of trace minerals in the rat.</b></a>, Fiber only increased tibia dry weight with a diet deficient in zinc and copper. Dry weight should but not necessarily correlate with bone length. The mice were below 9 weeks old so they were growing. The study was done in 1979 so there's no hope to contact for length data.<br />
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<b>The emergence of mechanoregulated endochondral ossification in evolution. </b><br />
<br />
"stable fractures with small gaps between bone ends can undergo intramembranous healing, involving ossification on a fibrous membrane; in larger fracture gaps and more straining mechanical environments, endochondral ossification is necessary for healing where a cartilage matrix is laid down which later, if the soft tissue succeeds in stabilising the fracture, provides a template for ossification. It is likely that endochondral bone emerged in evolution because it confers a greater fitness in a more demanding mechanical environment."<br />
<img alt="Full-size image (31 K)" border="0" class="imgLazyJSB figure large" data-fulleid="1-s2.0-S0021929012006823-gr2.jpg" data-fullheight="307" data-fullwidth="387" data-loaded="true" src="http://ars.els-cdn.com/content/image/1-s2.0-S0021929012006823-gr2.jpg" data-thumbeid="1-s2.0-S0021929012006823-gr2.sml" data-thumbheight="164" data-thumbwidth="206" height="307" style="display: inline; height: 307px; width: 387px;" width="387" />So we want shear strain and fluid velocity at an amount that causes cartilage tissue to form.</div>
</div>
Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com2tag:blogger.com,1999:blog-1013552121036660524.post-9879550597891125902013-03-28T15:26:00.000-07:002013-03-28T15:26:28.505-07:00Lengthening your Body with a Hyperbaric Chamber?<u><i><b>Request for help: Does anyone know of any athletes who regularly use hyperbaric chambers so we can study changes in their bone phenotype?</b></i></u><br />
<b> </b> <br />
The hyperbaric chamber makes you breathe solely oxygen and increases the atmospheric pressure surrounding you. Now cartilage is an avascular tissue but can hyperbaric chamber treatment increase chondroinduction or increase the growth from growth plates?<br />
<br />
Many athletes use hyperbaric chambers so if hyperbaric chambers could chondroinduce on their own there would be some sort of anecdotal evidence.<br />
<br />
Hyperbaric chambers may be an interesting possible way to enhance growth but are too cost prohibitive.<br />
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<b>The effect of hyperbaric oxygen and air on cartilage tissue engineering.</b><br />
<br />
"Under hyperbaric oxygen and air stimulation, the cell number of chondrocytes in cartilage matrix was not significantly increased, but the glycosaminoglycans syntheses markedly increased compared to the control group. The chondrogenic-specific gene expression of SOX9, aggrecan, and COL2A1 were compared respectively. Within the limitation of this study, it was concluded that 2.5 atmosphere absolute oxygen and air may provide a stress environment to help cartilage tissue engineering development."<br />
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"In approximately 2.5 ATA[absolute atmosphere] HBO–treated group, the SOX9 and aggrecan expressed significantly at days 9 and 12, but there was no increase with the type I collagen–related gene COL1A2. Alternately, in 2.5 ATA hyperbaric air–treated group, the SOX9 increased with the time and type II collagen–related gene COL2A1 showed significant over expression at days 6, 9, and 15, with no manifest increase with the COL1A2 "<br />
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Since hyperbaric chambers go to 2-3 times normal pressure maybe this would would be sufficient.<br />
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"Fifteen hASCs contained biocomposites and were equally separated into 3 groups and subsequently treated with 1 ATA air (as control), 2.5 ATA HBO, and 2.5 ATA hyperbaric air operations which were performed in a hyperbaric chamber (MEDITT, Republic of China). The duration of treatment was 1 hour a day for 5 days, and samples were observed at days 6, 9, 12, and 15, respectively, after induction."<br />
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<b>Equine peripheral blood-derived mesenchymal stem cells: isolation, identification, trilineage differentiation and effect of hyperbaric oxygen treatment.</b> states that hyperbaric oxygen increased the concentration of mesenchymal stem cells. Mesenchymal condensation is an important part of new growth plate formation. Increased MSC concentration would facilitate mesenchymal condensation.<br />
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<b>Osteodistraction of a previously irradiated mandible with or without adjunctive hyperbaric oxygenation: an experimental study in rabbits.</b> states that mandibular osteodistraction resulted in cartilagenous tissue in all the experimented groups. Only irradiation increased the size of chondroid islands and not hyperbaric oxygen.<br />
<br />
According to <b>Hyperbaric oxygen-stimulated proliferation and growth of osteoblasts may be mediated through the FGF-2/MEK/ERK 1/2/NF-κB and PKC/JNK pathways</b>., stimulates the growth and proliferation of osteoblasts but can that apply to chondrocytes or stem cells?<br />
<br />
<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3360870/"><b>Age-dependent response of murine female bone marrow cells to hyperbaric oxygen.</b></a><br />
<br />
"We treated 2- and 18-month old C57BL/6 female mice by HBO[Hyperbaric Oxygen]. Hematopoietic stem cells and progenitors, enumerated as colony-forming units in culture, were doubled only in peripheral leukocytes and BM cells of young mice receiving HBO. In old mice colony-forming unit fibroblast numbers, a measure of mesenchymal stromal cells (MSCs) from BM, were high but unaffected by HBO. To further explore this finding, in BM-MSCs we quantified the transcripts of adipocyte early-differentiation genes peroxisome proliferator-activated receptor-γ, CCAAT/enhancer binding protein-β and fatty-acid binding protein 4; these transcripts were not affected by age or HBO. However, osteoblast gene transcripts runt-related transcription factor 2, osterix (OSX) and alkaline phosphatase (AP) were twofold to 20-fold more abundant in MSCs from old control mice relative to those of young control mice. HBO affected expression of osteoblast markers only in old MSCs (OSX gene expression was reduced by twofold and AP expression was increased threefold)."<br />
<br />
Unfortunately no chondrogenic markers were measured. The study did say the HBO increased the mobilization of MSCs.Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com4tag:blogger.com,1999:blog-1013552121036660524.post-84752153046525976932013-03-25T14:50:00.003-07:002023-01-28T14:56:06.614-08:00Grow Taller by your periosteum?<b>I provide articles supporting <a href="http://www.naturalheightgrowth.com/2013/02/05/a-new-proposed-height-increase-and-grow-taller-method-from-periosteum-removal-breakthrough/">Natural Height Growth's theory that periosteal stripping could help increase height</a>. When cartilage first condenses in the embryo there is no periosteum therefore the periosteum could serve as a mechanism to inhibit growth related to maturity. Can rapid repetive loading(like via a chisel and hammer method) be akin to <a href="http://www.heightquest.com/2009/02/periosteal-stripping.html">periosteal stripping</a>? One of the papers mentioned in the aforementioned page is on adult rats and seems to possibly have longitudinal bone growth.</b><br />
<br />
We already know it's possible to grow taller by <a href="http://thequestforheight.blogspot.com/2010/03/growing-taller-by-increasing-periosteal.html">increasing the periosteal width</a> of your certain bones that have periosteum oriented in the longitudinal direction such as the flat bone of the skull . We also know that the periosteum is key in <a href="http://thequestforheight.blogspot.com/2010/04/limb-lengthening-surgery.html">distraction osteogenesis surgery</a>. Tissue damage is highly anabolic. How does muscular hypertrophy occur? By damage to the myosin-actin bridge. Does this damage just repair what was done before? No it increases the size of your muscle according to the cellular signals as regulated by myostatin(testesterone <a href="http://thequestforheight.blogspot.com/2010/05/inhibiting-myostatin-to-increase-your.html">inhibits myostatin</a>) plus other factors. Some of the cells that are released from damage to the muscle tissue go to repair but others go to build new muscle.<br />
<br />
There are studies that show that <a href="http://thequestforheight.blogspot.com/2010/03/gymnastics-and-microfractures.html">bone can increase in size</a>. Tissue damage is highly anabolic and bones can increase in size, the periosteum is a tissue and has been shown to be highly important in limb lengthening surgery, therefore the periosteum is likely to have anabolic effects on your bone. The periosteum contains progenitor cells which are like stem cells. <br />
<br />
Even though the progenitor cells from the periosteum are not as potent as the stem cells from trabecular, it still has anabolic effects. The periosteum also contains fibroblasts which are anabolic for connective tissues and what can possibly account for the <a href="http://thequestforheight.blogspot.com/2010/02/scientific-articles-related-to-our.html">increase in periosteal width in runners</a>.<br />
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One problem is the location of the most easily accessible periosteum(in the tibia) which damage to the tissues should only increase bone width unless the periosteal progenitor cells somehow differentiate into chondrocytes. Lateral Synovial Joint loading would definitely cause shear strain on the periosteum thus causing anabolic effects on the periosteum that way. However, it's unclear whether LSJL would cause hydrostatic pressure in the periosteum as the periosteum is far more malleable than the hard tissue of the bone surrounding the bone marrow.<br />
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Here's an article about the direct effect of the periosteum on growth plate development: <br />
<br />
<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824202/?tool=pubmed"><b><span class="highlight">Tissue</span> <span class="highlight">engineering</span> <span class="highlight">models</span> of <span class="highlight">human</span> <span class="highlight">digits</span>: <span class="highlight">effect</span> of <span class="highlight">periosteum</span> on <span class="highlight">growth</span> <span class="highlight">plate</span> <span class="highlight">cartilage</span> <span class="highlight">development</span>.</b></a><br />
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"<span class="highlight">Tissue</span>-engineered middle phalanx constructs of <span class="highlight">human</span> <span class="highlight">digits</span> were investigated to determine whether <b><span class="highlight">periosteum</span> wrapped partly about model midshafts mediated <span class="highlight">cartilage</span> <span class="highlight">growth</span> <span class="highlight">plate</span> formation</b>. <span class="highlight">Models</span> were fabricated by suturing ends of polymer midshafts in a <span class="highlight">human</span> middle phalanx shape with polymer sheets seeded with heterogeneous chondrocyte populations from bovine articular <span class="highlight">cartilage</span>. <b>Half of each midshaft length was wrapped with bovine <span class="highlight">periosteum{if periosteum was wrapped on the midshaft ends would the bone than grow longer?}</span></b>. Constructs were cultured, implanted in nude mice for up to 20 weeks, harvested and treated histologically to assess morphology and <span class="highlight">cartilage</span> proteoglycans. After 20 weeks of implantation, <b>chondrocyte-seeded sheets adjacent to <span class="highlight">periosteum</span>-wrapped midshaft halves established <span class="highlight">cartilage</span> <span class="highlight">growth</span> plates resembling normal <span class="highlight">tissue</span> in vivo</b>. <b>Sheets adjacent to midshafts without <span class="highlight">periosteum</span> had disorganized cells and no <span class="highlight">plate</span> formation</b>. Proteoglycans were present at both midshaft ends.<b> <span class="highlight">Periosteum</span> appears to guide chondrocytes toward <span class="highlight">growth</span> <span class="highlight">plate</span> <span class="highlight">cartilage</span> organization and <span class="highlight">tissue</span> <span class="highlight">engineering</span> provides means for carefully examining construct <span class="highlight">development</span> of this <span class="highlight">tissue</span></b>."<br />
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So the periosteum is needed to from growth plates. Chondrocytes not near periosteum will not form growth plates and will not make you taller. Adults have periosteum so this is a good sign for the potential for adult growth plates. There is usually no periosteum surrounding the epiphysis of the bone which could make it difficult to form growth plates there as an adult. But there is periosteum at the end of the epiphysis when it becomes the diaphysis, so it may be close enough to direct the formation of new growth plates.<br />
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"After 20 weeks of implantation, engineered human middle phalanx models were found to have glistening, firm and well defined cartilage on both ends of their individual midshaft regions. <b>The portion of midshaft covered with periosteum consisted of essentially clear tissue having a few red-colored areas over its surface indicative of vascular formation. The midshaft region left unwrapped was notably reddened and vascularized{</b>so the periosteum does not seem to have an effect on growth plate vascularization}. <b>X-ray radiography revealed marked mineral deposition within the midshafts of the models only where periosteum had been placed and sutured. No mineral formation was detectable in the cartilage regions at the ends of the models</b>.<a class="fig-table-link fig figpopup" href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824202/figure/F2/" style="text-decoration: none;"><span style="position: relative; text-decoration: none;"></span></a>"<br />
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So it could be the periosteum that affects the distinction between articular and growth plate cartilage. The reason that articular cartilage usually does not ossify could be that it's too far away from periosteum. <br />
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"Over identical implantation times, chondrocyte-seeded PGA sheets adjacent to the half of the same model midshafts left uncovered by periosteum had disorganized cells and no growth plate formation or mineralization"<-So you need both chondrocytes and periosteum to grow taller. And the chondrocytes need to be pretty close to the periosteum as the chondrocytes adjacent to the periosteum did not form growth plates.<br />
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"Periosteal tissue mediates growth plate cartilage formation, perhaps by synthesis and secretion of growth factors and other proteins that provide diffusion-limited regulation and control of neighboring cartilage."<-So we could mimic the benefits of periosteal tissue by increasing serum levels of growth factors and proteins. It would be hard to mimic the diffusion regulation and control of neighboring cartilage.<br />
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Shear Strain from lateral synovial joint loading may help spread periosteal growth factors to the epiphysis. Periosteum also has the ability to lengthen.<br />
<br />
The fact that LSJL targets height growth by stimulating cell differentiation in the epiphysis into chondrocytes and that chondrocytes will not form growth plates unless adjacent to periosteum(and the epiphysis usually has no periosteum) means that it is likely that the periosteum has to be addressed to maximize gains from LSJL.<br />
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Here's the diagram of the study of the portions of the bone attached to periosteum:<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="http://3.bp.blogspot.com/-NYJrCTwyjhs/TqcABoED_LI/AAAAAAAAAUg/CxBQdHnondo/s1600/periosteal+deposition.jpg" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="192" src="http://3.bp.blogspot.com/-NYJrCTwyjhs/TqcABoED_LI/AAAAAAAAAUg/CxBQdHnondo/s320/periosteal+deposition.jpg" width="320" /></a></div>
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Since the scientists attached the periosteum themselves it is likely that this does not completely represent a periosteal distribution pattern but you can see some periosteum at the very end of the epiphysis. Any stem cells that differentiate into chondrocytes at this end zone could have sufficient access to periosteum. Any other stem cells that differentiate in the remainder of the epiphysis will not form growth plates. Since only a small portion of the epiphysis is covered by periosteum, this makes only a small portion of stem cells successfully differentiated by LSJL increase height.<br />
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This could explain LSJL stagnation as well. In the beginning, individuals epiphysis may be well oriented to the periosteum making it easy for the chondrocytes to find surrounding periosteum. However, growing taller changes the epiphysis and periosteum thus perhaps making it harder for chondrocytes to be located next to periosteum.<br />
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Also, it was noted that people who performed LSJL got a larger epiphysis. It was then theorized that this could be due to chondrogenesis in the epiphysis. This is now not possible as growth plates cannot form unless adjacent to periosteum. The enlarged epiphysis is likely due to a direct increase in the width of individual osteons and direct bone deposition by osteoblasts.<br />
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There are two ingredients to growing taller: Stem Cells differentiating into chondrocytes and those chondrocytes being adjacent to periosteum. LSJL and some supplements that increase TGF-Beta1 and BMP-2 can help with the former, now we need to deal with the latter.<br />
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Here's a study that shows how the periosteum can cause bone regeneration:<br />
<br />
<b><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3324854/?tool=pubmed">A novel osteogenesis technique: The expansible guided bone regeneration</a></b><br />
<span style="background-color: white;"><br /></span>
<span style="background-color: white;">"</span><b style="background-color: white;">Guided bone regeneration is a unique osteogenesis technique that requires a barrier membrane under periosteum to create space for bone regeneration{if we extend the periosteum over the longitudinal ends of the bones and create a barrier membrane then we can grow taller, also we can grow taller when periosteum is already at the longitudinal location of the bone such as the flat bone of the skull}</b><span style="background-color: white;">. However, creating sizeable spaces is clinically not commonly feasible. A titanium plate and a thin silicone membrane were surgically layered on each calvaria of eight rabbits. Then, the periphery of the silicone membrane was fixed by a plastic ring to the underlying bone using titanium micro screws. After 1 week, a 5-mm-length titanium screw was used to elevate the titanium plate, which in turn elevated the silicone membrane together with overlying soft tissue in a rate of 1 mm/day for 5 days to create a secluded space. Animals were killed at 2 months (n = 4, group 1) and 4 months (n = 4, group 2) after the elevation. Histological and microradiographical analyses demonstrated creation of an amount of de novo bone formation (68.2 ± 22 mm3 in group 1 and 70.3 ± 14 mm3 in group 2) in the sizeable created spaces (207.1 ± 31 mm3 in group 1 and 202 ± 21 mm3 in group 2) without exposure of the device. This novel osteogenesis technique, “expansible guided bone regeneration,” created a substantial in vivo incubator without applying growth factors or osteoprogenitor cells. </span><b style="background-color: white;">Creating a growing space over the secluded surface allowed the development of normal biological healing process occurring on the bone surface into a regenerative process, generating bone outside the genetically determined skeletal bone{so what we can do is create a growing space between the articular cartilage and the subchondral ends of bone}</b><span style="background-color: white;">. This technique is a new tissue engineering approach stimulating endogenous tissue repair without applying cells or factors exogenously."</span><br />
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<br /></div>
"large volumes of bone can be produced in a predictive manner without exogenously applying the three key players, if the space is provided by injecting biocompatible gel under periosteum."<-space plus periosteum equals bone growth. The problem is there's no periosteum at the longitudinal ends of bones.<br />
<div>
<br /></div>
"More recently, we and others have been reported that gradual periosteum elevation creating a space over bone surface results in new bone formation in this space"<-How do we elevate and stretch the periosteum?<br />
<div>
<br /></div>
"the invasion of the created space with highly competitive nonosteogenic soft tissue and poor quality of the newly formed bone are the main drawbacks of this technique"<br />
<div>
<br /></div>
<div>
In the study they use an elevation screw to lift the periosteum. Maybe we can mimic this with mechanical stimuli somehow.</div>
<div>
<br /></div>
"Upon activation of bone surface, biological healing process taking place on the activated surface is kept confined to the surface during the first week. After that the elevation plate is set to move upward, the membrane is gradually elevated and the space attains its maximum size in 5 days."<br />
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Now we we need find mechanical stimuli that can stretch periosteum over the longitudinal ends of bones and that can elevate the periosteum.<br />
<br />
<div>
<b><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3178095/">The nature and role of periosteum in bone and cartilage regeneration.</a></b><br />
<br />
"[Can] periosteum from different bone sources in a donor [result] in the same formation of bone and cartilage? In this case, periosteum obtained from the cranium and mandible (examples of tissue supporting intramembranous ossification) and the radius and ilium (examples of tissues supporting endochondral ossification) of individual calves was used to produce tissue-engineered constructs that were implanted in nude mice and then retrieved after 10 and 20 weeks. Specimens were compared in terms of their osteogenic and chondrogenic potential by radiography, histology, and gene expression levels. By 10 weeks of implantation and more so by 20 weeks, <b>constructs with cranial periosteum had developed to the greatest extent</b>, followed in order by ilium, radius, and mandible periosteum. All constructs, particularly with cranial tissue although minimally with mandibular periosteum, had mineralized by 10 weeks on radiography and stained for proteoglycans with safranin-O red (cranial tissue most intensely and mandibular tissue least intensely). Gene expression of type I collagen, type II collagen, runx2, and bone sialoprotein (BSP) was detectable on QRT-PCR for all specimens at 10 and 20 weeks. By 20 weeks, the relative gene levels were: type I collagen, ilium >> radial ≥ cranial ≥ mandibular; <b>type II collagen, radial > ilium > cranial ≥ mandibular</b>; runx2, cranial >>> radial > mandibular ≥ ilium; and BSP, ilium ≥ radial > cranial > mandibular. The osteogenic and chondrogenic capacity of the various constructs is not identical and depends on the periosteal source regardless of intramembranous or endochondral ossification. Cranial and mandibular periosteal tissues appear to enhance bone formation most and least prominently, respectively."<br />
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Only the madible had no signs of cartilage proteoglycans.<br />
<br />
"These results indicate that osteoblasts and chondrocytes derived from sutured periosteum remain viable during implantation and migrate into the constructs. The cells proliferate and secrete matrix that leads to new bone and mineral formation (osteoblasts) and new cartilage (chondrocytes) in interior spaces of the scaffolds as well as in the tissue over the scaffolds"<-With LSJL we have no scaffold. We're trying to use endogenous tissues as a scaffold.<br />
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<div>
<b>Multiple exostosis: a short study of abnormalities near the growth plate.</b></div>
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<br /></div>
<div>
"The pathogenesis of multiple exostosis has been controversial with many theories put forward including the structural/mechanical theory, which emphasizes that the osteochondroma arises in the displaced growth plate cartilage penetrating a defective periosteum. Recently, molecular genetics has offered the neoplastic model with tumor suppressor genes implicated in the development and pathogenesis of exostosis. In this study, we demonstrated the spectrum of histological abnormalities in the developing exostosis present on the surface of the bone at the physis. Seven skeletally immature patients with multiple exostoses were used in this study. The patients' families were advised of and consented to the proposed study. Coincident with removal of symptomatic exostoses that was adjacent to the physis, a thin strip of bone with overlying periosteum was removed to include the edge of the physis. This was followed by formalin fixation and routine paraffin embedding. We demonstrated the earliest lesion as a microchondroma within the periosteum adjacent to the normal physis (also called the 'groove of Ranvier'). <b>More mature progressively larger lesions showing enchondral ossification were seen distally.</b> The periosteum and the perichondrium were intact with normal physis. Our observations give support to the fact that <b>precursor cells in the periosteum adjacent to the physis (also called the 'groove of Ranvier') gives rise to the chondrocytes that clonally expands and develops into exostosis</b>."</div>
<div>
<br /></div>
<div>
"the cause of exostoses was a ‘fault of the epiphyseal plate, nests of cartilage being misplaced’. He indicated that ‘fragments of cartilage around the epiphyseal line become isolated on the surface of the metaphysis, proliferate, and form exostosis’. ‘The periosteum, which is incomplete at the sites of these cartilaginous nests, fails to model the metaphysis in a normal manner’."</div>
<div>
<br /></div>
<div>
"Multiple noncontiguous clusters of cartilage cells of increasing size were found on the surface of the bone. The chondromas increased in size as the distance from the physis increases."<br />
<br />
<b>In vivo generation of cartilage from periosteum.</b><br />
<div>
<br /></div>
<div>
"Damaging the periosteum may be a way to generate ectopic cartilage or bone, which may be useful for the repair of articular cartilage and bone defects. Periosteum was bilaterally dissected from the proximal medial tibia of New Zealand White rabbits. Reactive periosteal tissue was harvested 10, 20, and 40 days postsurgery and analyzed for expression of collagen types I, II, and X, aggrecan, osteopontin, and osteonectin and collagen types I and II. Reactive tissue was present in 93% of cases. Histologically, this tissue consisted of hyaline cartilage at follow-up days 10 and 20. Expression of collagen type II and aggrecan was present at 10 and 20 days postsurgery. Highest expression was at 10 days. Expression of collagen type X increased up to 20 days. No significant changes in the mRNA expression of osteopontin or osteonectin were observed. Cartilage [was present], which was positive for collagen types I and II at 10 days and only for collagen type II at 20 days. At 20 days postsurgery the onset of bone formation was also observed. At 40 days postsurgery, the reactive tissue had almost completely turned into bone."</div>
<div>
<br /></div>
<div>
"cells in the cambial layer of the periosteum have chondrogenic potential in vitro and in vivo"</div>
<div>
<br /></div>
<div>
The ectopic cartilage is at the longitudinal ends of the bones so maybe it can increase height.<br />
<br />
<b>Regulation of endochondral cartilage growth in the developing avian limb: cooperative involvement of perichondrium and periosteum. </b><br />
<br />
"To determine if the perichondrium and periosteum regulate growth through the production of diffusible factors, we have tested various conditioned media from these tissues for the ability to modify cartilage growth in tibiotarsal organ cultures from which these tissues have been removed. Both negative and positive regulatory activities were detected.<b> Negative regulation was observed with conditioned medium from (1) cell cultures of the region bordering both the perichondrium and the periosteum, (2) co-cultures of perichondrial and periosteal cells, and (3) a mixture of conditioned media from perichondrial cell cultures and periosteal cell cultures</b>. Positive regulation was observed with conditioned media from several cell types, with the most potent activity being from articular perichondrial cells and hypertrophic chondrocytes."<br />
<br />
"At the point where the boney shaft borders the cartilage, the perichondrium (PC) differentiates into the periosteum (PO), whose cells have osteoblastic potential"<br />
<br />
"PC/PO-free long bones [had an] increase in overall length of the cartilage [resulting from] increases in the sizes of both the proliferative and hypertrophic zones"<br />
<br />
<a href="http://onlinelibrary.wiley.com/doi/10.1002/dvdy.10160/full"><b>Multiple mechanisms of perichondrial regulation of cartilage growth. </b></a><br />
<br />
"he perichondrium (PC) and the periosteum (PO) negatively regulate endochondral cartilage growth through secreted factors. Conditioned medium from cultures of PC and PO cells when mixed (PC/PO-conditioned medium) and tested on organ cultures of embryonic chicken tibiotarsi from which the PC and PO have been removed (PC/PO-free cultures) effect negative regulation of growth. Of potential importance, this regulation compensates precisely for removal of the PC and PO, thus mimicking the regulation effected by these tissues in vivo. We have now examined whether two known negative regulators of cartilage growth (retinoic acid [RA] and transforming growth factor-beta1 [TGF-beta1]) act in a manner consistent with this PC/PO-mediated regulation. The results suggest that <b>RA and TGF-beta1, per se, are not the regulators in the PC/PO-conditioned medium</b>. Instead, they show that these two factors each act in regulating cartilage growth through an additional, previously undescribed, negative regulatory mechanism(s) involving the perichondrium. <b>When cultures of perichondrial cells (but not periosteal cells) are treated with either agent, they secrete secondary regulatory factors into their conditioned medium, the action of which is to effect precise negative regulation of cartilage growth when tested on the PC/PO-free organ cultures. This negative regulation through the perichondrium is the only activity detected with TGF-beta1. </b>Whereas, RA shows additional regulation on the cartilage itself. However, this regulation by RA is not "precise" in that it produces abnormally shortened cartilages. Overall, the precise regulation of cartilage growth effected by the action of the perichondrial-derived factor(s) elicited from the perichondrial cells by treatment with either RA or TGF-beta1, when combined with our previous results showing similar--yet clearly different--"precise" regulation by the PC/PO-conditioned medium suggests the existence of multiple mechanisms involving the perichondrium, possibly interrelated or redundant, to ensure the proper growth of endochondral skeletal elements."<br />
<br />
"RA has been reported to be both an inhibitor and promoter of cartilage development. In developing embryos of various species, both hypervitaminosis A and hypovitaminosis A greatly disturb the organization of the growth plate. In cell cultures, low doses (50 nM) of RA promote cartilage differentiation. However, in organ cultures, the addition of RA produces the opposite effect: a dose-dependent inhibition of longitudinal bone growth. This finding is due to decreases in both chondrocyte proliferation and hypertrophy"<-one difference between an organ culture and cell culture is the presence of the periosteum.<br />
<br />
"RA treatment of the intact cultures produced a reduction in cartilage length from 3.77 mm for the controls to 2.96 mm for the RA-treated. This reduction of 0.81 mm is an even greater overcompensation than for the PC/PO-free cultures, suggesting that RA must have another mechanism of action in addition to that which acts directly on cartilage"<br />
<br />
"TGF-β1 showed negative regulation only with the intact organ cultures—not with the PC/PO-free ones. When 10 ng/ml TGF-β1 was added to the intact cultures, the lengths of the cartilage was reduced to 3.48 mm for the treated vs. 3.81 mm for the controls. However, the PC/PO-free organ cultures showed no response to TGF-β1 treatment, with both treated and untreated cultures growing to 4.0 mm"<br />
<br />
"FGF-2 acts solely on the cartilage, resulting in identical cartilage lengths between intact and PC/PO-free cultures when treated with FGF-2."<br />
<br />
"one of the three nuclear RARs (RARβ) has been shown to be expressed at high levels in the perichondrium, as is RA itself; the remaining two RARs (RARα and RARγ) are expressed in cartilage."<br />
<br />
<b>Intracellular tension in periosteum/perichondrium cells regulates long bone growth. </b><br />
<br />
"erichondrium/periosteum cells were cultured on substrates with different stiffness. The medium produced by these cultures was added to embryonic chick tibiotarsi from which perichondrium/periosteum was either stripped or left intact. After 3 culture days, <b>long bone growth was proportionally related to the stiffness of the substrate on which perichondrium/periosteum cells were grown while they produced conditioned medium</b>. A second set of experiments demonstrated that the effect occurred through expression of a growth-inhibiting factor, rather than through the reduction of a stimulatory factor. Finally, evidence for the importance of intracellular tension was obtained by showing that the inhibitory effect was abolished when perichondrium/periosteum cells were treated with cytochalasin D, which disrupts the actin microfilaments. Modulation of long bone growth occurs through release of soluble inhibitors by perichondrium/periosteum cells, and that the ability of cells to develop intracellular tension through their actin microfilaments is at the base of this mechano-regulated control pathway."<br />
<br />
"periosteum [may regulate] growth via a direct mechanical feedback mechanism where pressure in growing cartilage, balanced by tension in the periosteum, [modulating] growth processes of chondrocytes. "<br />
<br />
" after 3 days of culture, distal cartilage length was significantly longer in stripped versus intact tibiotarsi in non-conditioned medium and in conditioned medium obtained from periosteum/perichondrium cell cultures on 3, 14, 21, and 48 kPa stiff substrates. The difference in distal length between stripped and intact tibiotarsus decreased with increasing stiffness and was no longer significant on 80 kPa gels and on glass"<-Thus the stiffness of the periosteum may affect the height reduction.<br />
<br />
"Both the variations in substrate stiffness and applying cytochalasin D in culture modulated the ability of periosteum cells to actively develop intracellular tension via their actin microfilament network."<br />
<br />
Stripped periosteum cartilage was about 33% higher than intact periosteum.<br />
<br />
You can see here that<a href="http://www.heightquest.com/2011/07/huge-news-finally-another-lateral.html"> axial loading increases periosteal thickness</a>(From <b>Cortical and trabecular bone adaptation to incremental load magnitudes using the mouse tibial axial compression loading model</b>). This serves to <a href="http://www.heightquest.com/2010/05/grow-taller-with-epiphyseal.html">contrast LSJL images here </a>where there is less visible periosteal thickness in the without drilling mice. One reason for this difference could be that LSJL involves less force as in the axial loading study periosteal thickness increased with increasing force. So less increase of periosteal thickness could be one possibility in why LSJL can increase height but why axial loading does not. Which leads to the question of whether axial loading can increase height with periosteal stripping.</div><div><span style="color: #505050; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif;"><br /></span></div><div><span style="color: #505050; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif;"><b>Periosteal topology creates an osteo-friendly microenvironment for progenitor cells</b></span></div><div><span style="color: #2e2e2e; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif; font-size: 18px;"><br /></span></div><div><span style="color: #2e2e2e; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif;">"The periosteum on the skeletal surface creates a unique micro-environment for cortical bone homeostasis. In our study, we observed <b>the cells in the periosteum presented elongated spindle-like morphology within the aligned collagen fibers</b>, which is in accordance with the differentiated osteoblasts lining on the cortical surface. We planted the bone marrow stromal cells(BMSCs), the regular shaped progenitor cells, on collagen-coated aligned fibers, presenting similar cell morphology as observed in the natural periosteum. The aligned collagen topology induced the elongation of BMSCs, which facilitated the osteogenic process. Transcriptome analysis suggested the aligned collagen induced the regular shaped cells to present part of the periosteum derived stromal cells(PDSCs) characteristics by showing close correlation of the two cell populations. In addition, the elevated expression of PDSCs markers in the cells grown on the aligned collagen-coated fibers further indicated the function of periosteal topology in manipulating cells’ behavior. Enrichment analysis revealed <b>cell-extracellular matrix interaction was the major pathway initiating this process, which created an osteo-friendly micro-environment as well. </b>At last, we found the aligned topology of collagen induced mechano-growth factor expression as the result of Igf1 alternative splicing, guiding the progenitor cells behavior and osteogenic process in the periosteum. This study uncovers the key role of the aligned topology of collagen in the periosteum and explains the mechanism in creating the periosteal micro-environment, which gives the inspiration for artificial periosteum design."</span></div><div><span style="color: #2e2e2e; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif;"><br /></span></div><div><span style="color: #2e2e2e; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif;">"</span><span style="color: #2e2e2e; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif; font-size: 18px;">The natural periosteum is a thin layer of connective tissue covers the outer surface of bone and connects to bone by strong collagenous fibers. The periosteum extends to the outer circumferential and interstitial lamellae of bone"</span></div><div><span style="color: #2e2e2e; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif; font-size: 18px;"><br /></span></div><div><span style="color: #2e2e2e; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif; font-size: 18px;">"</span><span style="color: #2e2e2e; font-family: NexusSerif, Georgia, "Times New Roman", Times, STIXGeneral, "Cambria Math", "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", "Arial Unicode MS", serif; font-size: 18px;">collagen orientation in periosteum is aligned with preferential directions of tissue growth"</span></div><div><br /></div><div><div><span class="title-text" style="box-sizing: border-box; margin: 0px; padding: 0px; scroll-behavior: auto !important;"><br /></span></div><div class="Banner" id="banner" style="box-sizing: border-box; color: #2e2e2e; font-family: NexusSans, Arial, Helvetica, "Lucida Sans Unicode", "Microsoft Sans Serif", "Segoe UI Symbol", STIXGeneral, "Cambria Math", "Arial Unicode MS", sans-serif; font-size: 14px; margin: 0px 0px 8px; padding: 0px; scroll-behavior: auto !important;"><div class="wrapper truncated" style="box-sizing: border-box; margin: 0px; padding: 0px; scroll-behavior: auto !important;"><div class="AuthorGroups text-xs" style="box-sizing: border-box; font-size: 0.7rem; line-height: 1.57; margin: 0px; padding: 0px; scroll-behavior: auto !important;"><div class="author-group" id="author-group" style="box-sizing: border-box; margin: 0px; padding: 0px; scroll-behavior: auto !important;"></div></div></div></div></div>
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Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com3tag:blogger.com,1999:blog-1013552121036660524.post-88761275173784460852013-03-07T15:19:00.000-08:002013-04-04T15:20:09.595-07:00The Resting Zone of the Growth PlateWithin the resting zone of the growth plate are stem-like cells which means they are like stem cells but only have limited proliferative capacity. If we can characterize these resting zone cells we can know more about how to initiate the first stage of the growth plate.<br />
<b><br /></b>
<b><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912264/">Identification of target genes for wild type and truncated HMGA2 in mesenchymal stem-like cells.</a></b><br />
<div>
<br /></div>
"The HMGA2{up in LSJL} gene [codes] for an architectural transcription factor involved in mesenchymal embryogenesis.<br />
We have over-expressed wild type and truncated HMGA2 protein in an immortalized mesenchymal stem-like cell (MSC) line, and investigated the localisation of these proteins and their effects on differentiation and gene expression patterns.<br />
<b>Over-expression of both transgenes blocked adipogenic differentiation of these cells</b>, and microarray analysis revealed clear changes in gene expression patterns, more pronounced for the truncated protein. Most of the genes that showed altered expression in the HMGA2-overexpressing cells fell into the group of NF-kappaB-target genes, suggesting a central role for HMGA2 in this pathway. Of particular interest was the pronounced up-regulation of SSX1, already implicated in mesenchymal oncogenesis and stem cell functions, only in cells expressing the truncated protein. Furthermore, over-expression of both HMGA2 forms was associated with a strong repression of the epithelial marker CD24, consistent with the reported low level of CD24 in cancer stem cells.:<br />
We conclude that the c-terminal part of HMGA2 has important functions at least in mesenchymal cells, and the changes in gene expression resulting from overexpressing a protein lacking this domain may add to the malignant potential of sarcomas."<br />
<br />
"There were several genes up-regulated by HMGA2WT and down- regulated in cells expressing the truncated form, such as FGF13, EHF, HCLS1, MEST, G0S2 and PTPRN2."<-Since the truncated form of HMGA2 can increase height these genes may be important.<br />
<br />
Genes downregulated in HMGA2WT-transgenic also downregulated in LSJL:<br />
IL6{up}<br />
Ces1<br />
Thbs2{up}<br />
S100a4{up}<br />
JunB{up}<br />
Has1{up}<br />
Ptgs2{up}<br />
Kynu{up}<br />
Oasl<br />
<br />
Upregulated:<br />
<br />
Genes downregulated in HMGA2Ttruncated also downregulated in LSJL:<br />
LAMA4{up}<br />
Thbs2{up}<br />
S100a4{up}<br />
JunB{up}<br />
Has1{up}<br />
Ptgs2{up}<br />
Kynu{up}<br />
Oasl<br />
<br />
Upregulated:<br />
MMP3<br />
Edn1<br />
Hapln1<br />
<br />
"over-expression of truncated HMGA2 induces a more mesenchymal (stem-like) phenotype, characterized by resistance toward differentiation, over-expression of SSX1, lost expression of certain epithelial markers and strengthened expression of mesenchymal markers."<br />
<br />
<b>Differential expression of phenotype by resting zone and growth region costochondral chondrocytes in vitro.</b><br />
<div>
<br /></div>
<div>
"Chondrocytes derived from the resting cell zone and adjacent growth zone of rat costochondral cartilage were compared for retention of phenotype in culture. At third passage confluence, two cell populations differ morphologically and biochemically. <b>Resting zone cells are fibroblast-like, with smooth cell membranes and little rough endoplasmic reticulum</b>. Growth zone cells are more polygonal, smaller in diameter, with numerous cytoplasmic extensions of the plasma membranes and abundant rough endoplasmic reticulum. Both cell populations produce matrix vesicles that are comparable morphologically to matrix vesicles isolated enzymatically from epiphyseal cartilage. While membrane vesicles are released into the media by cells derived from the resting zone as well as from the growth cartilage, alkaline phosphatase activity is enriched in media vesicles produced by growth cartilage cells. Alkaline phosphatase enriched vesicles appear to be preferentially incorporated into the extracellular matrix. Both the plasma membrane marker enzyme activity and the membrane phospholipid composition are differentially expressed in matrix vesicles and plasma membranes and are cell specific. <b>Matrix vesicles produced by resting zone cells are enriched in alkaline phosphatase, 5'-nucleotidase, ouabain sensitive Na+/K+ ATPase and cardiolipin when compared to the cell membrane. </b>In addition, the plasma membranes of these cells contain more phosphatidylcholine plus sphingomyelin than do growth cartilage plasma membranes. Resting zone cell matrix vesicles have less phosphatidylethanolamine than do vesicles from growth cartilage cultures. Matrix vesicles produced by growth cartilage cells contain one proteolipid at 43,000 Mr which comigrates with plasma membrane proteolipid and an additional proteolipid at approximately 3,000 Mr. These data indicate that both cells retain differential expression of phenotype in culture and that one expression of this phenotype is production of specific extracellular matrix vesicles."</div>
<div>
<br /></div>
<div>
"Growth cartilage chondrocyte plasma membranes exhibit higher 5'-nucleotidase activity than do resting cell membranes"</div>
<div>
<br /></div>
<div>
"The resting zone cells membranes contain more phosphatidylcholinc plus sphingomyelin than do the growth zone chondrocyte membranes"</div>
<div>
<br /></div>
<div>
<div>
<b>Transforming growth factor-beta1 regulation of resting zone chondrocytes is mediated by two separate but interacting pathways.</b></div>
</div>
<div>
<br /></div>
<div>
" transforming growth factor-beta1 (TGF-beta1) stimulates protein kinase C (PKC) via a mechanism that is independent of phospholipase C or tyrosine kinase, but involves a pertussis toxin-sensitive G-protein. Maximal activation occurs at 12 h and requires new gene expression. To understand the signaling pathways involved, resting zone chondrocytes were incubated with TGF-beta1 and PKC activity was inhibited with chelerythrine, staurosporine or H-7. [(35)S]Sulfate incorporation was inhibited, indicating that PKC mediates the effects of TGF-beta1 on matrix production. However, there was little, if any, effect on TGF-beta1-dependent increases in [(3)H]thymidine incorporation, and TGF-beta1-stimulated alkaline phosphatase was unaffected, indicating that these responses to the growth factor are not regulated via PKC. <b>TGF-beta1 caused a dose-dependent increase in prostaglandin E(2) (PGE(2)) production which was further increased by PKC inhibition</b>. The increase was regulated by TGF-beta1-dependent effects on phospholipase A(2) (PLA(2)). Activation of PLA(2) inhibited TGF-beta1 effects on PKC, and inhibition of PLA(2) activated TGF-beta1-dependent PKC. Exogenous arachidonic acid also inhibited TGF-beta1-dependent increases in PKC. The effects of TGF-beta1 on PKC involve genomic mechanisms, but not regulation of existing membrane-associated enzyme, since no direct effect of the growth factor on plasma membrane or matrix vesicle PKC was observed. TGF-beta1 modulates its effects on matrix production through PKC, but its effects on alkaline phosphatase are mediated by production of PGE(2) and protein kinase A (PKA). Inhibition of PKA also decreases TGF-beta1-dependent proliferation. We have previously shown that PGE(2) stimulates alkaline phosphatase through its EP2 receptor, whereas EP1 signaling causes a decrease in PKC. Thus, there is cross-talk between the two pathways."</div>
<div>
<br /></div>
<div>
"Resting zone chondrocytes synthesize TGF-β1 in latent form and store it in their extracellular matrix as a 290 kDa complex consisting of latent TGF-β1, latent TGF-β1 binding protein-1 and the latency-associated peptide. Extracellular matrix vesicles produced by these cells can activate latent TGF-β1 when they are exposed to 1,25-(OH)2D3. The interrelationship of TGF-β1 action and vitamin D metabolites is also demonstrated by the fact that TGF-β1 causes resting zone cells to produce increased 1,25-(OH)2D3 within 1 h and increased 24,25-(OH)2D3 at 24 h, which is correlated with TGF-β1-dependent downregulation of the 1α-hydroxylase and upregulation of the 24-hydroxylase in these cells"</div>
<div>
<br /></div>
<div>
"PGE2 has multiple effects on the chondrocytes, promoting differentiation and anabolic responses via cAMP production and PKC activity"</div>
<div>
<br /></div>
<div>
" Resting zone cells have both EP1 and EP2 receptors, as well as an EP1 variant, EP1v. The increase in cAMP leads to increased PKA activity. The importance of this pathway in the response to TGF-β1 is evident in the decrease in proliferation following treatment of the cells with TGF-β1 and the PKA inhibitor, H-8."</div>
<div>
<br /></div>
<div>
<div>
<b>Direct effects of 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 on growth zone and resting zone chondrocyte membrane alkaline phosphatase and phospholipase-A2 specific activities.</b></div>
</div>
<div>
<b><br /></b></div>
<div>
"1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] and 24,25-(OH)2D3 differentially affect the specific activity of alkaline phosphatase (ALPase) and phospholipase-A2 (PLA2) of plasma membranes and extracellular matrix vesicles produced by costochondral reserve zone and growth zone cartilage chondrocytes in culture. In the present study, growth zone and cartilage and reserve zone matrix vesicles and plasma membranes were isolated from confluent chondrocyte cultures and incubated with hormone for 3 and 24 h in vitro. <b>Addition of 1,25-(OH)2D3 to GC matrix vesicles and plasma membranes resulted in dose-dependent increases in ALPase and PLA2 specific activities in both membrane fractions.</b> Addition of 24,25-(OH)2D3 to RC membrane fractions stimulated matrix vesicle ALPase at 10(-7) and 10(-8) M and plasma membrane ALPase at 10(-8) M only. However, 24,25-(OH)2D3 inhibited matrix vesicle and plasma membrane PLA2 activity. The effects of the vitamin D metabolites were noticed after both 3 and 24 h. Neither hormone metabolite had any effect on these enzymes in membrane fractions from cultures of neonatal rat muscle mesenchymal cells, which do not calcify their matrix in vivo. 1,25-(OH)2D3 and 24,25-(OH)2D3 can directly affect chondrocyte membrane enzymes without genomic influence or protein synthesis and that membrane response depends on the stage of chondrocyte differentiation. Changes in PLA2 activity may change membrane fluidity and may be a mechanism by which the hormones affect cell membranes."</div>
<div>
<br /></div>
<div>
"Enzymes present in membranes isolated from the less differentiated mesenchymal cells do not respond to either vitamin D3 metabolite tested, although both metabolites stimulate ALPase gene expression in cultures of these cells"</div>
<div>
<br /></div>
<div>
<div>
<b>Treatment of resting zone chondrocytes with bone morphogenetic protein-2 induces maturation into a phenotype characteristic of growth zone chondrocytes by downregulating responsiveness to 24,25(OH)2D3 and upregulating responsiveness to 1,25-(OH)2D3.</b></div>
</div>
<div>
<br /></div>
<div>
"To determine if bone morphogenetic protein-2 (BMP-2) can induce the endochondral maturation of resting zone (RC) chondrocytes, confluent fourth-passage cultures of these cells were pretreated for 24, 36, 48, 72, or 120 h with recombinant human BMP-2. At the end of pretreatment, the media were replaced with new media containing 10(-10)-10(-8) M 1,25-(OH)2D3 or 10(-9)-10(-7) M 24,25-(OH2)D3 and the cells incubated for an additional 24 h. This second treatment was chosen, because prior studies had shown that the more mature growth zone (GC) chondrocytes and RC cells respond to 1,25-(OH)2D3 and 24,25-(OH)2D3 in distinctly different ways with respect to the parameters examined. The effect of BMP-2 pretreatment on cell maturation was assessed by measuring alkaline phosphatase specific activity (ALPase). In addition, changes in matrix protein production were assessed by measuring collagen synthesis, as well as [35S]-sulfate incorporation into proteoglycans. When RC cells were pretreated for 72 or 120 h with BMP-2, treatment with 1,25-(OH)2D3 caused a dose-dependent increase in ALPase specific activity and collagen synthesis, with no effect on proteoglycan sulfation. RC cells pretreated with 1,25-(OH)2D3 responded like RC cells that had not received any pretreatment. <b>RC cells normally respond to 24,25-(OH)2D3; however, RC cultures pretreated for 72 or 120 h with BMP-2 lost their responsiveness to 24,25-(OH)2D3.</b> These results indicate that <b>BMP-2 directly regulates the differentiation and maturation of RC chondrocytes into GC chondrocytes</b>. These observations support the hypothesis that BMP-2 plays a significant role in regulating chondrocyte maturation during endochondral ossification."</div>
<div>
<br /></div>
<div>
"Resting zone cells exhibit greater sensitivity to BMP-2 than do cells derived from the prehypertrophic and upper hypertrophic zones"</div>
<div>
<br /></div>
<div>
<div>
<b>Treatment of resting zone chondrocytes with 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3] induces differentiation into a 1,25-(OH)2D3-responsive phenotype characteristic of growth zone chondrocytes.</b></div>
</div>
<div>
<b><br /></b></div>
<div>
"rat costochondral cartilage chondrocytes isolated from the growth zone (GC) respond to 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3], whereas those from the resting zone (RC) respond to 24,25-(OH)2D3[the inactive form of Vitamin D]. The aim of the present study was to determine whether 24,25-(OH)2D3 induces differentiation of RC cells into a 1,25-(OH)2D3-responsive GC phenotype. To do this, confluent, fourth passage RC chondrocytes were pretreated for 24, 36, 48, 72, and 120 h with 10(-7) M 24,25-(OH)2D3. The medium was then replaced with new medium containing 10(-10) to 10(-8) M 1,25-(OH)2D3, and the cells were incubated for an additional 24 h. At harvest, DNA synthesis was measured as a function of [3H]thymidine incorporation; cell maturation was assessed by measuring alkaline phosphatase (ALPase) specific activity. Incorporation of [3H]uridine was used as a general indicator of RNA synthesis. Matrix protein synthesis was assessed by measuring incorporation of [3H]proline into collagenase-digestible protein (CDP) and collagenase-nondigestible protein (NCP) as well as 35SO4 incorporation into proteoglycans. When RC cells were pretreated for 24 h with 24,25-(OH)2D3, they responded like RC cells that had received no pretreatment; further treatment of these cells with 1,25-(OH)2D3 had no effect on ALPase, proteoglycan, or NCP production, but CDP production was inhibited. However, when RC cells were pretreated for 36-120 h with 24,25-(OH)2D3, treatment with 1,25-(OH)2D3 caused a dose-dependent increase in ALPase, CDP, and proteoglycan synthesis, with no effect on NCP production. RC cells pretreated with 1,25-(OH)2D3 responded like RC cells that had not received any pretreatment. To determine whether these responses were specific to chondrocytes in the endochondral pathway, cells were isolated from the xiphoid process, a hyaline cartilage. In these cells, 1,25-(OH)2D3 inhibited ALPase, whereas 36 h of pretreatment with 24,25-(OH)2D3 caused these cells to lose their response to 1,25-(OH)2D3. 24,25-(OH)2D3 can directly regulate the differentiation and maturation of RC chondrocytes into GC chondrocytes, as evidenced by increased responsiveness to 1,25-(OH)2D3. 24,25-(OH)2D3 also promotes differentiation of cells derived from xiphoid cartilage, resulting in the loss of 1,25-(OH)2D3 responsiveness."</div>
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<br /></div>
<div>
The 24,25-form tends to correlate with chondrogenesis whereas the 1,25 form tends to correlate with osteogenesis. The 24,25-form downregulates it's own production in resting zone chondrocytes but upregulates the active form by growth chondrocytes.</div>
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<br /></div>
<div>
<div>
<b>Monocarboxylate transporter 10 functions as a thyroid hormone transporter in chondrocytes.</b></div>
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<br /></div>
<div>
"untreated congenital hypothyroidism is marked by severe short stature. The monocarboxylate transporter 8 (MCT8) is a highly specific transporter for thyroid hormone. The hallmarks of Allan-Herndon-Dudley syndrome, caused by MCT8 mutations, are severe psychomotor retardation and elevated T(3) levels. However, growth is mostly normal. We therefore hypothesized that growth plate chondrocytes use transporters other than MCT8 for thyroid hormone uptake. Extensive analysis of thyroid hormone transporter mRNA expression in mouse chondrogenic ATDC5 cells revealed that monocarboxylate transporter 10 (Mct10) was most abundantly expressed among the transporters known to be highly specific for thyroid hormone, namely Mct8, Mct10, and organic anion transporter 1c1. <b>Expression levels of Mct10 mRNA diminished with chondrocyte differentiation in these cells.</b> Accordingly, <b>Mct10 mRNA was expressed most abundantly in the growth plate resting zone chondrocytes in vivo</b>. Small interfering RNA-mediated knockdown of Mct10 mRNA in ATDC5 cells decreased [(125)I]T(3) uptake up to 44% compared with negative control. Moreover, silencing Mct10 mRNA expression abolished the known effects of T(3), i.e. suppression of proliferation and enhancement of differentiation, in ATDC5 cells. Mct10 functions as a thyroid hormone transporter in chondrocytes and can explain at least in part why Allan-Herndon-Dudley syndrome patients do not exhibit significant growth impairment."</div>
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<br /></div>
<div>
"TH inhibits proliferation and promotes differentiation of chondrocytes and is indispensable for normal growth"</div>
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<br /></div>
<div>
"The SLC16A10 gene, which encodes MCT10, localizes to 6q21-q22 [and is associated with height growth]"</div>
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<br /></div>
<div>
"in RZ chondrocytes, TH exerts its actions via TRα1."</div>
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<br /></div>
<div>
<div>
<b><a href="http://www.j-smu.com/pdf2/201102/201102353.pdf">[Histology and proliferative capability of thoracic vertebral body growth plates of rats at different ages].</a></b></div>
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<b><br /></b></div>
<div>
"The thoracic VBGPs obtained from rats aged 1 day and 1, 4, 8, 16 and 28 weeks were identified using safranin O-fast green staining, and the height of the hypertrophic zone, proliferative zone, and resting zone were measured. The chondrocytes were isolated from these VBGPs with a modified trypsin-collagenase type II digestion method for primary culture in vitro. The expressions of proliferating cell nuclear antigen (PCNA) mRNA and protein was detected by real time-PCR and Western blotting, respectively.</div>
<div>
The 1-day- and 1-week-old rats showed significantly greater hypertrophic zone and proliferative zone in the VBGPs than older rats; the proliferative zone was significantly greater in rats aged 4 weeks than in those aged 28 weeks. <b>The resting zone was obviously greater in rats aged 1 day and 1 week than in older rats</b>, <b>and also greater in rats aged 4 weeks than in those aged 16 and 28 weeks</b>. <b>Obvious ossification in the resting zone occurred at 16 weeks, and most of the resting zone became ossified at 28 weeks</b>. The expression of PCNA decreased at both the mRNA and protein levels as the rats grew.</div>
<div>
The 3 zones of VBGPs are greater in rats aged 1 day and 1 week than in older ones. Ossification in the resting zone begins at 16 weeks, and till 28 weeks, most of the resting zone is ossified. The proliferation ability of VBGP chondrocytes decreases with the increase of age of the rats."</div>
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<br /></div>
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Study is in a foreign language unfortunately.</div>
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<br /></div>
<div>
<div>
<b>Distribution of type I and type II collagen gene expression during the development of human long bones.</b></div>
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<br /></div>
<div>
"The temporal and spatial gene expression of collagen type I and type II during the development of the human long bones was studied by the technique of in situ hybridization covering the period from the cartilagenous bone anlage to the formation of a regular growth plate in the newborn. Analysis of the early stages around the seventh week of gestation revealed for type II collagen a strong hybridization signal limited to the chondrogenic tissue. The surrounding connective tissue and the perichondrium showed weak type I collagen expression, while the zones of desmal ossification like the clavicle gave a strong signal. Beginning with the eighth week of gestation, type I collagen mRNA was detectable in newly formed osteoblasts at the diaphysis and appeared along with the formation bone marrow, in the areas of enchondral ossification. Parallel to the development of the different zones of cartilage differentiation, a specific pattern of type II expression could be observed: type II was mainly found in the chondrocytes of the hypertrophic zone and to a lesser degree in the zone of proliferation, while the resting zone and the zone of provisional calcification showed little activity. This segregation of type II expression was most pronounced in the early stages of cartilage calcification and in the growth plate of the newborn."</div>
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<br /></div>
<div>
"As prechondrogenic mesenchyme cells develop to chondrocytes, a dramatic increase in the cytoplasmatic volume, the rough endoplasmatic reticulum and the Golgi apparatus takes place. This is</div>
<div>
paralleled by the switch from collagen type I, the predominant collagen of fibroblasts, to collagen type II, the major collagen found in cartilage"</div>
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<br /></div>
<div>
"Limbs of human fetuses between the 7th and 15th menstrual weeks" Mature chondrocytes never displayed Type I Collagen activity. Type II collagen negative cells occur at the osteochondral junction.</div>
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<br /></div>
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<div>
<b><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3092148/">Mesenchymal chondroprogenitor cell origin and therapeutic potential.</a></b></div>
</div>
<div>
<br /></div>
<div>
"In embryonic limb development, FGF-4 stimulates Sonic hedgehog (Shh) expression in a positive feedback loop that coordinates proximal-distal and anterior-posterior patterning of the cartilaginous anlagen"</div>
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<br /></div>
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According to the paper 20-50% of cells in the bone marrow have the ability to differentiate into chondrocytes.</div>
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<br /></div>
<div>
"progenitor cells with chondrogenic capacity have been isolated from the superficial zone of articular cartilage"</div>
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<br /></div>
<div>
"chondroprogenitors have been identified in arthritic cartilage after their migration from the bone marrow through breaks in the tidemark and into the diseased cartilage"<-meaning chondroprogenitors exist in the bone marrow.</div>
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<br /></div>
<div>
<div>
<b><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2817664/">Morphogenetic and regulatory mechanisms during developmental chondrogenesis: new paradigms for cartilage tissue engineering.</a></b></div>
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<div>
<br /></div>
<div>
Some great diagrams in this paper.</div>
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<br /></div>
<div>
"When the cells aggregate, MCs[mesenchymal cells] begin to produce collagen I, fibronectin, and proteoglycans. The result of the strong interactions that cells establish with their environment is the formation of a dense mass of MCs that immediately begins to differentiate into chondroblasts. Condensed MCs start expressing mainly the transcription factor Sox9 that controls downstream genes involved in chondrogenesis, promoting these progenitor cells to secrete cartilage-specific ECM molecules"</div>
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<br /></div>
<div>
"MMP1 and MMP2 have the capacity to degrade cartilage matrix, and they are characterized as the MMPs that are involved in earlier chondrogenesis. Specifically, blockage of MMP2 function supports precartilage condensation and chondrogenesis, and MMP1 knockout mice show decreased chondrocyte proliferation in the proliferative zone of the growth plates of long bones." MMP2 is increased in LSJL so perhaps we should find a way to decrease it's expression.</div>
<div>
<br /></div>
<div>
"overexpression of human Sox9 in murine ESCs (mESCs) leads to upregulated expression of the cartilage markers collagen IIA, aggrecan, and pax1 even in undifferentiated ESCs"</div>
<div>
<br /></div>
<div>
"fibroblasts can undergo spontaneous chondrogenesis in simple three-dimensional culture conditions"</div>
Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com2tag:blogger.com,1999:blog-1013552121036660524.post-34109935948012373852013-03-07T11:16:00.000-08:002013-03-07T12:48:09.279-08:00LSJL progress update 2-23-13<div class="separator" style="clear: both; text-align: center;">
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<b>Unfortunately on one has been able to explain how I can retrieve x-rays from Sharp-Reese Steeley Online and the internet has been no luck either. The threshold required for growth to show up via x-ray is pretty high. No micro-growth plates are going to show up. So until someone can explain how I can access my x-ray records via the Sharp Reese Steeley medical system there can be no X-rays for now. I've been using an allen wrench and a hammer to test out <a href="http://www.naturalheightgrowth.com/2013/03/06/the-chisel-and-hammer-supplement-technique-explained-through-video/">Natural Height Grow's Pick Axe method</a> in addition to LSJL: <a href="http://www.amazon.com/gp/product/B001HW8YYO/ref=as_li_ss_tl?ie=UTF8&camp=1789&creative=390957&creativeASIN=B001HW8YYO&linkCode=as2&tag=thequ01-20">Bondhus 12116 1/2-Inch Long Hex L-Wrench</a><img alt="" border="0" height="1" src="http://www.assoc-amazon.com/e/ir?t=thequ01-20&l=as2&o=1&a=B001HW8YYO" style="border: none !important; margin: 0px !important;" width="1" />. Since Michael is now performing the LSJL method maybe that is the solution to proving the LSJL method. My tests so far show that the allen wrench + hammer has been effective in creating sensations in the bone. In fact, I was worried that doing this may actually fracture the bone but I think it would take tons of hard taps to create enough residual strain to fracture the bone. And it may be necessary to fracture the bone as there is a different microenvironment involved in a microfracture versus a macrofracture. A microenvironment that is more chondrogenic. It's unclear whether this method has synergy with LSJL as drilling the bone in LSJL has been shown to reduce LSJL effectiveness. However this method may be a way to induce (-micro)fractures without penetrating the skin. There might be a region between micro- and macro-fracture that can generate a pro-chondrogenic microenvironment without the disability caused by a full blown macro-fracture.
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<img border="0" height="180" src="http://3.bp.blogspot.com/-75QthUpl7SY/USe8OPff5dI/AAAAAAAAA90/DUWy7CSvaY8/s320/22213leg+pic.jpg" width="320" /></div>
The current progress pic is above.<br />
Here's the <a href="http://www.heightquest.com/2011/06/lsjl-update-bone-length-increase.html">last set of pictures</a>.<br />
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I know it's grainy but if you look at these <a href="http://www.heightquest.com/2010/04/results-for-lateral-synovial-joint.html">pics</a> from 2010:<br />
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<a href="http://1.bp.blogspot.com/-41zs3nB4Cy0/USe-wCP-zYI/AAAAAAAAA98/oNVkH-SaXg4/s1600/oldlegpic.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="http://1.bp.blogspot.com/-41zs3nB4Cy0/USe-wCP-zYI/AAAAAAAAA98/oNVkH-SaXg4/s1600/oldlegpic.jpg" /></a></div>
So here's me trying to match that measurement today at 13 1/4 inches:<br />
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<a href="http://1.bp.blogspot.com/-lFnd2kJQJmI/USfAT4CBxzI/AAAAAAAAA-E/ZkRQi7bm0HU/s1600/22213legmatch.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="320" src="http://1.bp.blogspot.com/-lFnd2kJQJmI/USfAT4CBxzI/AAAAAAAAA-E/ZkRQi7bm0HU/s320/22213legmatch.jpg" width="240" /></a></div>
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The ruler was too far to the side so I tried to move it in:</div>
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<a href="http://2.bp.blogspot.com/-hmy576VM69Q/USfBUFuGsZI/AAAAAAAAA-M/TKYTddbm1V0/s1600/22213legmatch2.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="320" src="http://2.bp.blogspot.com/-hmy576VM69Q/USfBUFuGsZI/AAAAAAAAA-M/TKYTddbm1V0/s320/22213legmatch2.jpg" width="240" /></a></div>
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You can see that 13 1/4 no longer quite covers end of the ankle to where the calf stops sloping in and where the next muscle slopes out. And I think this is true even if you account for the account that the tibia is rotated slightly outward in the present pics.</div>
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You can also see an increase in ankle width even if the foot in the before pic is rotated slightly inward. So I definitely gained some height with LSJL.</div>
<br />Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com85tag:blogger.com,1999:blog-1013552121036660524.post-26211015758228434062013-03-06T13:44:00.000-08:002013-04-15T13:46:40.116-07:00How much does frequency matter for LSJL?In the <a href="http://www.heightquest.com/2010/03/best-proof-so-far-of-non-surgical-ways.html">LSJL lengthening studies a frequency of 5 Hz is used</a>. Frequency is the hardest thing to mimic in our home made clamping method. Even though this is an axial loading study it is still by the LSJL scientist Hiroki Yokota and it'll provide insights on how important frequency is for LSJL results.<br />
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<b>Resonance in the mouse tibia as a predictor of frequencies and locations of loading-induced bone formation</b><br />
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"we conducted axial tibia loading using low, medium, or high frequency to the mouse tibia. The experimental data demonstrated dependence of the maximum bone formation on location and frequency of loading{But does frequency influence chondrogenic differentiation?}. Samples loaded with the low-frequency waveform exhibited peak enhancement of bone formation in the proximal tibia, while the high-frequency waveform offered the greatest enhancement in the midshaft and distal sections. Furthermore, the observed dependence on loading frequencies was correlated to the principal strains in the first five resonance modes at 8.0–42.9 Hz. Collectively, the results suggest that resonance is a contributor to the frequencies and locations of maximum bone formation."<br />
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"When loading is applied to such a material at or near its resonant frequencies, additional energy is absorbed and the material tends to vibrate at greater amplitude than when loading is applied at other frequencies. These vibrations propagate through the material in specific ways, or modes, based on the geometry and characteristics of the material."<br />
<br />
"he tibia is composed of a shell of dense, stiff cortical bone that is thinnest on the outside of each epiphysis and thickest throughout the diaphysis. Inside the epiphysis a matrix of less dense, weaker trabecular bone is present. An epiphyseal plate is found at the border between the each epiphysis and diaphysis, which consists of hyaline cartilage. Each type of tissue likely contributes to the frequency response of the tibia."<-So when the epiphyseal plate is absent that affects the optimal frequency for chondroinduction.<br />
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"(C57BL/6 male, ∼13 weeks old) were used in this study."<-So these mice were definitely growing.<br />
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7N were used versus 0.5N in LSJL.<br />
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Low Frequency: 1-17Hz<-So LSJL is in this range<br />
Medium Frequency: 18-34Hz<br />
High Frequency: 35-51Hz<br />
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The animals experienced all 200 repetitions at each of the frequencies within the range.<br />
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<img alt="/static-content/0.6380/images/428/art%253A10.1007%252Fs10237-013-0491-2/MediaObjects/10237_2013_491_Fig2_HTML.gif" src="http://link.springer.com/static-content/0.6380/images/428/art%253A10.1007%252Fs10237-013-0491-2/MediaObjects/10237_2013_491_Fig2_HTML.gif" /><br />
So 8% region would be the region closest to the growth plate range and that was the range the responded most to low frequency.<br />
<img alt="/static-content/0.6380/images/428/art%253A10.1007%252Fs10237-013-0491-2/MediaObjects/10237_2013_491_Fig3_HTML.gif" src="http://link.springer.com/static-content/0.6380/images/428/art%253A10.1007%252Fs10237-013-0491-2/MediaObjects/10237_2013_491_Fig3_HTML.gif" /><br />
It's hard to tell how chondrogenesis was affected in the 8% region.<br />
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"When a periodic load is applied at or near one of an object’s resonant frequencies, it tends to absorb more energy and oscillate at greater amplitudes than at other loading frequencies. In the case of the tibia, loading at frequencies near the resonant frequencies of the bone may be causing more energy to be dissipated and larger displacements in certain areas of the bone than loading at other frequencies with equal amounts of force. This may lead to increased strain rates, amplified intramedullary fluid flow, increased fluid shear stresses on bone cells, and enhanced cellular response in areas that absorb the most energy"<-So the correct frequency is a bonus but is not required. Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com0tag:blogger.com,1999:blog-1013552121036660524.post-54575546463800593632013-03-04T12:39:00.000-08:002013-03-04T12:41:17.177-08:00LSJL Prototype Device designed by Yokota/ZhangThis study was actually published in 2005 but it's in an obscure space journal so I didn't find it until now.<br />
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<a href="https://www.jstage.jst.go.jp/article/bss/19/4/19_4_245/_pdf"><b>Development of a Knee-Loading Joint Supporter for Potential Use in Preventing Bone Loss during Spaceflight/Aging</b></a><br />
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14 week old female C57/BL6 mice were used. Knee loading was applied for 3 minutes for 3 consecutive days. Peak force of 0.5N was used. Groups were 5, 10, 15Hz. 5Hz was the one used to generate the most bone formation which doesn't mean it will translate into the most length but 5 Hz was used in the lengthening study.<br />
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Fig1 provides a diagram with a loaded mouse.<br />
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In Figure 3 they give the knee prototype. In this study they blocked copy and pasting so you'll have to read the full study.<br />
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In the device there is a pad to avoid a local stress concentration on the knee. Perhaps for LSJL foam could be placed in between the clamp and the knee. Although the study above did not study any lengthening effects of LSJL.<br />
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Yokota/Zhang mention 10N being what is required for humans but again this was before they noted any LSJL lengthening effects.<br />
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Usage mentioned being approx. 30 min daily...per knee. In this study the the outer part of the knee was the one loaded.
Here's how a gear/cam mechanism works:
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<iframe allowfullscreen="" frameborder="0" height="315" src="http://www.youtube.com/embed/dGmX_Blsfr8" width="420"></iframe><br />
This ratcheting motion is very similar to a clamp.Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com2tag:blogger.com,1999:blog-1013552121036660524.post-19401433300326320942013-02-21T11:49:00.000-08:002013-08-22T13:52:08.440-07:00Grow taller by eating deer antlers?Deer antler extract is available for sale: <a alt="" border="0" height="1" href="http://www.amazon.com/gp/product/B007K9WCPA/ref=as_li_ss_tl?ie=UTF8&camp=1789&creative=390957&creativeASIN=B007K9WCPA&linkCode=as2&tag=thequ01-20&l=as2&o=1&a=B007K9WCPA" style="border: none !important; margin: 0px !important;" width="1">3 Pack Deer Antler Velvet 2 oz. Liquid Extract.</a><br />
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Deer antler has been reported to have anecdotal uses on dogs. I'm bumping this study due to this topic being a possible field of interest for an upcoming Natural Height Growth Podcast. Deer Antler has had positive effects on chondrogenesis but only in vitro(in cell cultures). So it's unknown whether digestion ruins the pro-chondrogenic stimulatory effects. Only few in vivo(in live animals) studies have been done on bones and deer antler but found that bone and deer antler did have a stimulatory effect on bone formation. So deer antler can affect the bone but it's still unclear whether the chondrogenic effects can remain unmolested.<br />
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So Deer Antler could possibly play a role in inducing ectopic chondrogenesis or enhancing the growth plate in the developing. But it may not do anything at all but it shouldn't hurt or inhibit any pro-chondrogenic actiions.<br />
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<b></b><b><a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3226629/?tool=pubmed">Pilose antler polypeptides promote chondrocyte proliferation via the tyrosine kinase signaling pathway.</a></b><br />
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"<span style="background-color: white;"><b>Pilose antler polypeptides (PAP) have been reported to promote chondrocyte proliferation. </b> [We] investigate the effects of PAP on the proliferation of chondrocytes.</span><br />
Chondrocytes isolated from the knee of Zealand white rabbits were cultured. The second generation chondrocytes were collected. The chondrocytes were divided into the following 4 groups including serum-free, PAP, genistein (an inhibitor of tyrosine kinases), and PAP plus genistein group. Cell viability was analyzed. The cell cycle distribution of the chondrocytes was analyzed. The expression levels of cyclin A was detected.<br />
No significant difference was observed between serum-free and genistein group.<b> Treatment of the cultures with PAP produced a significant dose-dependent increase in cell viability, the percentage proportion of chondrocytes in the S phase and Cyclin A expression as well</b>. However, the promoting effect of PAP on chondrocyte proliferation were dose-dependently inhibited by genistein, whereas genistein alone had no effect on proliferation of isolated chondrocytes.<br />
<b>PAP promotes chondrocyte proliferation with the increased cell number, percentage proportion of chondrocytes in S phase and expression of protein cyclin A via the TK signaling pathway</b>."<br />
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"Genistein (4,7,4'-trihydroxyisoflavone), a major isoflavone from soybean, has been proven as a specific inhibitor of TK. Genistein, which block kinase ATP-binding sites, specifically inhibit phosphorylation of tyrosine residues, thereby inhibiting cells growth"<br />
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"The higher concentration of PAP added the [higher the] number of cultured chondrocytes". Genistein inhibited this increase in proliferation.<br />
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"Compared to control group, the mean proportion of cells in S phase increased sharply from 6.4% to 35.2% after adding PAP."<-The S phase is the DNA replication phase of the cell cycle.<br />
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"cyclin A expression increased to 50% after adding PAP"<br />
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"level of cyclin A correlates directly with the proliferative state of cells"<br />
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It should be noted that this may only increase growth rate in growth plates and may not increase adult height. It should also be noted that the PAP was added directly to the cartilage so it doesn't show whether or not deer antler supplemenation can bypass digestion.<br />
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<b>[Role of pilose antler polypeptides on replicative senescence of rat chondrocyte].</b><br />
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"3rd generation chondrocytes were divided into blank group, and PAP groups with three different concentration of PAP which were passaged to the 4th generation. Meanwhile, the 2nd generation of chontrocytes were used as control group. The chondrocytes in different groups were detected with the method of histochemistry for S-A-beta-gal, flow cytometry for cell life cycle and proliferation index, alcian blue test for the content and structure of GAG of ECM, and RT-PCR for type II collagen and Aggrecan. Then PAP's function was observed regarding the appearance and functional status in the process of chondrocyte's senescence.<br />
<b>PAP significantly inhibited chondrocyte's express of S-A-beta-gal, promoted chondrocyte's proliferation, reduced cell content on G1 phase, enhanced the content of GAG, type II collagen and Aggrecan of ECM</b>."<br />
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So deer antlers are pro chondrogenic but the study was not done on live rats so no idea whether it gets past digestion. This was a chinese study so couldn't get access to the full version.<br />
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<b>Effect of Pilose Antler Polypeptides on Cataplasia and Senescence of Rat Chondrocyte in Vitro</b><br />
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" 1. The rat articularchondrocytes were isolated with the method of enzyme digestion.The 3rdpassage chondrocytes were divided into blank group, different concentration PAP groups,different concentration glucosaminsalfate groups and were sequently passaged to 4thgeneration. The 2nd passage chondrocytes was contrasted as young cells group. Thechondrocytes of different groups were detected with the methods of histochemistry forS-A-β-gal, and with alcian blue test for the content and constructure of GAG of ECM,immuocytochemistry for typeⅡcollagen and PCNA, MTT assay for proliferation, RT-PCRfor typeⅡcollagen and Aggrecan, flow cytometry for cell life cycle and proliferationindex,by which to observe PAP’s function regarding to the appearance and functional status inthe process of chondrocyte’s cataplasia and senescence. 4. The successive tert-generation (2ndpassage, 3rd passage, 4th passage) chondrocytes and the 4th passage cells intervented by PAPwere studied for senenscence mechanism. In this course, immuocytochemistry was applied for p16, pRb, E2F, CyclinD, CDK4 and TRAP-ELISA was applied for telomerase activation toobserve targets’ changing regarding to cataplasia and senescence. The function of PAP wasdetected too. Results: 1. The method of enzyme digestion is practicable for harvesting considerable and better activity cells, which were identified that had good phenotype anddifferentiation. 2. <b>From 4th passage, the chondrocytes emerging some cataplasia-senescence changes such as the expression of S-A-β-gal raising to large extent, cell life cycle being detented on G1 phase, dedifferentiation and so on. 3. PAP has better anti-senenscence function than GS on several respect such as inhibiting express of S-A-β-gal, promoting chontrocyte proliferating, reducing cell content on G1 phase, promoting cell energy metabolism, makingcell growth active, enhancing chondrocyte differentiating and so on. 4. In the course ofchondrocyte’s cataplasia and senescence, factors controlling cell life cycle and cell growth changes as follow: p16↑—pRb↑—E2F↓—CyclinD↑—CDK4↓—telemorase"</b><br />
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<b>Effect of pilose antler polypeptides on chondrogenic phenotype differentiation of bone marrow-derived mesenchymal stem cells in vitro</b><br />
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"third passage BMSCs from [6-month old] rabbits were randomly divided into control group cultured in ordinary medium, induced group cultured in defined medium, and PAP group cultured in defined medium containing 10 mg/L PAP. An equal volume of articular chondrocytes were selected from rabbits as articular cartilage group. The cellular morphological and functional characteristics were observed after 1, 2, 3 weeks in centrifuge tubes by histological, biochemical and reverse transcription-polymerase chain reaction (RT-PCR) technique. Cell masses in the control group gradually crumbled after 2 weeks, and hematoxylin-eosin staining could not be done. Cell masses in the induced and PAP groups were semitransparent, but slightly contracted. A part of these cells were round or oval with a high density distribution at the surface. The content of GAG and mRNA expression of typeⅡ collagen in the induced and PAP groups were increased with culture time, and higher than those in the control group at different time points. The content of GAG and mRNA expression of type Ⅱ collagen in the PAP group were higher than those in the induced group, but lower than those in the articular cartilage group. BMSCs can differentiate into chondrogenic phenotype in the defined medium, and <b>PAP can significantly enhance chondrogenic phenotype differentiation of BMSCs</b>."<b> </b><br />
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TGFB1 was present in the serum.<br />
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<b>[The initial mechanism's investigation of pilose antler polypeptides resisting replicative senescence of rat chondrocyte].</b><br />
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"The successive tert-generation (2nd passage, 3rd passage, 4th passage) chondrocytes and the 4th passage cells intervented by PAP were studied for senenscence mechanism. In this course, immunocytochemistry was applied for pl6, pRb, E2F, CyclinD, CDK4 and TRAP-ELISA (telomerase repeat amplification protocol assay-enzyme linked immunosorbent assay) was applied for telomerase activation to observe targets' changing regarding to senescence and the function of PAP.<br />
<b>Along with cell's replicative senescence, pl6, pRb and Cyclin D express significantly rised, while E2F, CDK4 and telomerase express significantly lowerd</b>. Meanwhile,<b> in PAP interfered group compared with which in 4th passage group, pl6, pRb and Cyclin D express significantly lowered, while E2F, CDK4 and telomerase express significantly increased</b>.<br />
PAP postpones chondrocyte senenscence{thus it could possibly keep growth plates open longer}."<br />
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<b>[Comparison of protein composition and activities of pilose antler processed by different methods].</b><br />
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"To elucidate the influence of processing conditions on pilose antlerś therapic effects, the protein composition and activities were compared on three kinds of pilose antler processed by lyophilization, freezing and traditional short-time heating, respectively. The concentration of the water soluble protein in freeze-dried pilose antler was 126.54 mg/g (Folin-Phenol assay), which was 13.1 times higher than that of heating processed antler. These proteins distributed widely in SDS-PAGE electrophoresis and the protein band between 50.0 kDa approximately 60.0 kDa achieved the highest concentration. The water extract of freeze-dried antler promoted the proliferation and IGF-I secretion of rat osteogenic-like cell UMR-106 by 245.25% ( MTT assay) and 66.36 ng/ml, which was respectively 2.2 times and 1.2 times of those of heating processed antler. The same candidate inhibited the growth of human hepatic carcinoma cell BEL-7402 by the highest rate of 47.64% , which was 1.4 times of heating processed antler. The activities of frozen fresh pilose antler were lower than those of its freeze-dried counterpart, but were much higher than those of heating processed antler. The results indicated that lyophilization help to remain the activity of pilose antlerś proteins as much as possible and improve its efficacy."<b> </b><br />
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This study could be informative but can't get access.<br />
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<b>[Effect of pilose antler polypeptides on the apoptosis of rabbit marrow mesenchymal stem cells differentiated into chondrogenic phenotype in vitro].</b><br />
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"The MSCs were separated from the nucleated cells fraction of autologous bone marrow by density gradient centrifuge and cultured in vitro. The MSCs were induced into chondrogenic phenotype by transforming growth factor beta1 (TGF-beta1) and basic fibroblast growth factor (bFGF). According to different medias, the MSCs were randomly divided into four groups: group A as black control group, group B (100 ng IL-1beta),<b> group C (10 microg/ml PAP + 100 ng IL-1beta)</b> and group D (100 ng/ml TGF-beta1 + 100 ng IL-1beta). The samples were harvested at 24, 48 and 72 hours.<br />
The intranuclear chromatin agglutinated into lump and located under nuclear membranes which changed into irregular shape at 24 hours. The intranuclear chromatin agglutinated intensified at 48 hours. Then the nuclear fragments agglutinated into apoptosis corpuscles at 72 hours in group B. The structure change of cells in groups C and D was later than that in group B, and the number of cells changed shape was fewer than that in group B. The structure change of cells in group A was not significant. The apoptosis rate of cells, the mRNA expression of Caspase-3 and the enzymatic activity of Caspase-3 gradually increased in group B, and there were significant differences compared with groups A, C and D.<br />
<b>Caspase-3 is involved in apoptosis of the MSCs differentiated into chondrogenic phenotype cultured in vitro. PAP could prevent from or reverse apoptosis of these MSCs by decreasing the expression of Caspase-3 and inhibiting the activity of Caspase-3.</b>"<br />
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<b>Adult stem cells and mammalian epimorphic regeneration-insights from studying annual renewal of deer antlers. </b><br />
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"[Some] animals have the ability to reprogram phenotypically committed cells at the amputation plane toward an embryonic-like cell phenotype (dedifferentiation). <b>Deer antlers are the only mammalian appendages capable of full renewal</b>. <b>Following casting of old hard antlers, new antlers regenerate from permanent bony protuberances, known as pedicles</b>. Antler renewal is markedly different from that of amphibian limb regeneration (dedifferentiation-based), being a stem cell-based epimorphic process. <b>Antler stem cells reside in the pedicle periosteum</b>. <b>We envisage that epimorphic regeneration of mammalian appendages, other than antler, could be made possible by recreating comparable milieu to that which supports the elaboration of that structure from the pedicle </b>"<br />
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<b>Deer antler regeneration: a stem cell-based epimorphic process.</b><br />
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"Antler regeneration takes place in yearly cycles from its pedicle, a permanent protuberance on the frontal bone. Both growing antlers and pedicles consist of internal (cartilage and bone) and external components (skin, blood vessels, and nerves). The regeneration of both internal and external components relies on the presence of pedicle periosteum (PP){the properties of the pedicle periosteum can provide insight into how to grow taller}. <b>PP cells express key embryonic stem cell markers (Oct4, Nanog, and SOX2) and are multipotent, so are termed antler stem cells</b>. Now it is clear that proliferation and differentiation of PP cells directly forms internal antler components. <b>The full regenerative ability of external antler tissue components is achieved through PP-derived chemical induction and PP-derived mechanical stimulation: the former triggers the regeneration of these external components, whereas the latter drives their rapid elongation.</b>"<br />
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"Antlers, despite being called head pieces, do not regenerate directly from the head of a deer but instead from the permanent cranial bony outgrowths, known as pedicles. Deer are not born with pedicles; instead, these start to develop from frontal crests (behind and above the eye sockets) when deer approach puberty" <br />
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" Initially, the developing pedicles are covered by typical scalp skin. When they have grown to their species-specific height (around 5–6 cm in red deer), first antlers begin to generate spontaneously from the apices of these pedicles. This development can be seen externally by a change in the appearance of the skin from the typical scalp skin to a velvet-like soft pelage, called velvet skin or velvet. When the rutting season approaches, the antlers become fully calcified and the blood supply is occluded, which causes the demise of the velvet skin. The dead velvet is subsequently shed to expose the bare bone of the hard antlers. These are cast in the following spring, and regeneration of the second set antlers from their living pedicle stumps is immediately initiated. From then on, annual renewal of subsequent antlers enters a well-defined cycle: casting of previous hard antler and regeneration of a new soft antler in spring, with rapid antler growth (up to 2 cm/day) and maturation in summer, then full antler calcification and velvet shedding in autumn, followed by the bare bony antler phase in winter"<br />
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" Immediately after a hard antler falls off, the rim of pedicle skin surrounding the distal end of a pedicle stump encroaches upon the bone margin, the space that was formerly occupied by the periphery of the antler base. This rim of skin is shiny, only sparsely populated by hair, and it possesses the peculiar features of velvet skin, specifically a thicker epidermis and the de novo formation of hair follicles, which distinguishes it from the more proximal pedicle skin, typical of the scalp skin. Within days of hard antler casting, wound healing nears completion by centripetal growth of velvet skin over the cast plane of a pedicle. At the same time, the distal part of pedicle periosteum (PP) becomes thickened through the active division of cells resident within it. Toward the late wound healing stage, two crescent-shaped growth centers are formed directly from the thickening distal PP, one of which is located anteriorly and the other posteriorly. Each center is made up of cartilaginous clusters that are capped by a layer of hyperplastic PP/perichondrium. Further augmentation of each growth center pushes up the anterior and posterior portions of the pedicle stump and leaves the central region behind. These posterior and anterior growth centers are the centers for the formation of the antler “main beam” and “first tine”"<br />
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"both PP and antlerogenic periosteum, from which PP is derived, express the stem cell marker CD9 antigen [and have elevated telomerase and nucleostemin activity]"<br />
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"stretching the skin stimulates epidermal proliferation only sufficiently to relieve tension. "<-Maybe such a concept would work for the one if osteoblast proliferation was stimulated to relieve stretching tension in the bone.<br />
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"direct proliferation and differentiation of the PP cells cause the internal tissue components (cartilage and bone) of a regenerating antler to form, whereas close association with PP or PP-derived tissue is the prerequisite for regeneration of external pedicle components (including skin, blood vessels, and nerves) to take place."<br />
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Deer antler supplements could certainly be a source of embryonic-like stem cells.<br />
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<b>Histological studies of bone formation during pedicle restoration and early antler regeneration in roe deer and fallow deer </b><br />
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"Initially, [during antler regeneration], bone formation occurs by intramembranous ossification, but early during the regeneration process cartilage is formed at the tips of the cranial appendages, and is subsequently replaced by bone in a process of endochodral ossification"<br />
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"the periosteum serves as a cell source for the bone-forming tissue covering the exposed pedicle bone."<br />
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"The early onset of chondrogenesis in the regeneration process is regarded as an adaptation to the necessity of producing a huge volume of bone within a short period. This parallels the situation in other cases of chondrogenesis in membrane bones."<br />
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"antler casting can be postponed by administration of testosterone or estradiol to deer carrying hard antlers"<br />
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"administration of compounds that inhibit LH and thus testosterone release (medroxyprogesterone acetate), or interfere with both the release of testosterone and its action at the receptor level (cyproterone acetate) [can cause premature antler casting]"<br />
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<a href="http://onlinelibrary.wiley.com/store/10.1002/ar.a.10082/asset/image_n/nfig006.jpg?v=1&t=hdgb3edn&s=440ed70b524e32b214a33cb517b9606dff1c4eac" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="225" src="http://onlinelibrary.wiley.com/store/10.1002/ar.a.10082/asset/image_n/nfig006.jpg?v=1&t=hdgb3edn&s=440ed70b524e32b214a33cb517b9606dff1c4eac" style="margin-top: 10px;" width="400" /></a></div>
"Early regenerating antler of a roe buck. a: Middle portion of regenerated antler. The cartilage (asterisks) is lined by a perichondrium consisting of an inner cellular (C) and an outer fibrous layer (F). D, dermis; E, epidermis; H, hair follicle; S, sebaceous gland; arrows, vascular spaces. Specimen R4: Heidenhain's azan (×26, bar = 500 μm). b: Vertical columns of cartilage (C) separated by highly vascularized mesenchymal tissue. Arrowheads, vascular spaces. Specimen R4: Heidenhain's azan (×80, bar = 100 μm). c: Zone of cartilage resorption and replacement by bone. Asterisk, cartilage; arrows, newly formed bone; arrowheads, multinucleated chondro-/osteoclasts; I, intertrabecular tissue. Specimen R4: Heidenhain's azan (×160, bar = 50 μm)."<br />
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<img src="http://onlinelibrary.wiley.com/store/10.1002/ar.a.10082/asset/image_n/nfig005.jpg?v=1&t=hdgb3edh&s=ee993496a217a6ce6d9ffec82619810afb0bf833" style="margin: 10px;" /> <br />
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"Cells from the cellular condensations in the fibrous mesenchymal tissue of the fallow deer pedicle distal to the newly formed osseous trabeculae. The cells contain numerous mitochondria (M) and a prominent rough endoplasmic reticulum (ER). N, nucleus; asterisks, bundles of collagen fibers in the extracellular matrix cut at different angles (×4,800, bar = 2 μm)."<br />
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<img src="http://onlinelibrary.wiley.com/store/10.1002/ar.a.10082/asset/image_n/nfig003.jpg?v=1&t=hdgb3ed7&s=4a7de772ea2e008268f2774a4919e07a124ce05f" style="margin: 10px;" /><br />
"Advanced stage of pedicle restoration in a fallow buck. a: Overview of regenerated cranial appendage. Newly formed slender osseous trabeculae (T) distal to the pedicle stump (asterisk). The zone of the slender trabeculae is capped by mesenchymal tissue (M). D, dermis; E, epidermis. The rectangles indicate the regions shown in b, c, and e. Specimen F: Heidenhain's azan (×6.4, bar = 1.25 mm). b: Higher magnification of the transition zone between the pedicle stump (asterisk) and the newly formed osseous trabeculae (T). The mesenchymal tissue (M) overlying the trabecular bone is seen in the upper left corner of the figure. Specimen F, Heidenhain's azan (×13.2, bar = 600 μm). c: Newly formed, mostly vertically oriented osseous trabeculae (T) lined by osteoblasts (arrow). Note the presence of numerous capillaries (asterisk) in the intertrabecular mesenchymal tissue. Specimen F: Heidenhain's azan (×53, bar = 150 μm). d: Higher magnification of a newly formed osseous trabecula with some recently incorporated cells (osteocytes, black arrow). White arrows, osteoblasts; asterisk, mineralized bone matrix. Specimen F: semithin section, toluidine blue-borax (×211, bar = 38 μm). e: Cellular condensations and accompanying reticular bundles of collagen fibers (arrow) in the richly vascularized mesenchymal tissue overlying the zone of the newly formed osseous trabeculae. Asterisk, vascular space. Specimen F: Heidenhain's azan (×53, bar = 150 μm)."<br />
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<b>Evidence that the canonical Wnt signalling pathway regulates deer antler regeneration</b><br />
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"Immunocytochemistry was used to map the distribution of the activated form of β-catenin (aβCAT). <b>A low level of aβCAT staining was detected in chondrocytes and in osteoblasts at sites of endochondral bone formation</b>{Thus perhaps inhibiting Beta-Catenin activation can be a possible way to form ectopic growth plates]. However, aβCAT was localised in cellular periosteum and in osteoblasts in intramembranous bone, where it co-localised with osteocalcin. <b>The most intense aβCAT staining was in dividing undifferentiated cells in the mesenchymal growth zone. Antler progenitor cells (APCs) were cultured from this region and when the canonical Wnt pathway was inhibited at the level of Lef/TCF by epigallocatechin gallate (EGCG), the cell number decreased.</b> TUNEL staining revealed that this was as a result of increased apoptosis. <b>Activation of the pathway by lithium chloride (LiCl) had no effect on cell number but inhibited alkaline phosphate activity (ALP), a marker of APC differentiation, whereas EGCG increased ALP activity</b>."<br />
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"targeted deletion of β-catenin in head and limb mesenchyme prevents the trans-differentiation of osteoblasts into chondrocytes"<br />
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<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2312329/"><b>Localization and characterization of STRO-1 cells in the deer pedicle and regenerating antler. </b></a><br />
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"Cells positive for the mesenchymal stem cell marker STRO-1 [were present] in the chondrogenic growth zone and the perivascular tissue of the cartilaginous zone in primary and regenerating antlers as well as in the pedicle of fallow deer (Dama dama). In addition, <b>cells positive for the stem cell/progenitor cell markers STRO-1, CD133 and CD271 (LNGFR) were isolated from the growth zones of regenerating fallow deer antlers as well as the pedicle periosteum and cultivated for extended periods of time</b>. STRO-1(+) cells isolated from the different locations are able to differentiate in vitro along the osteogenic and adipogenic lineages."<br />
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"the growing tip of the deer antler contains proliferating perivascular cells and possible angioblastic precursors"<br />
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"In contrast to long bones, adipogenesis does not occur in regenerating antlers."<br />
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<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1693364/pdf/15293809.pdf"><b>Exploring the mechanisms regulating regeneration of deer antlers. </b></a><br />
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" Molecules that we have identified as having potentially important local roles in antlers include parathyroid hormone-related peptide and retinoic acid (RA). Both are present in the blastema and in the rapidly growing antler where they regulate the differentiation of chondrocytes, osteoblasts and osteoclasts in vitro. Blockade of RA signalling can alter cellular differentiation in the blastema in vivo. The trigger that regulates the expression of these local signals is likely to be changing levels of sex steroids because the process of antler regeneration is linked to the reproductive cycle. The natural assumption has been that the most important hormone is testosterone, however, at a cellular level oestrogen may be a more significant regulator. Exogenous oestrogen acts as a 'brake', inhibiting the proliferation of progenitor cells in the antler tip while stimulating their differentiation, thus inhibiting continued growth. Deciphering the mechanism(s) by which sex steroids regulate cell-cycle progression and cellular differentiation in antlers may help to address why regeneration is limited in other mammalian tissues."<br />
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"The first set of antlers are shed in the spring when testosterone levels fall, a process known as ‘casting’. A blastema then forms on the exposed surface of the pedicle bone and from this the first set of ‘mature’ branched antlers regenerate"<br />
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"RXRB expression increases as cells differentiate from chondroprogenitors into mature chondrocytes."<br />
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"significant amounts of vitamin A (retinol) are present in antler tissues at all stages of differentiation."<br />
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"IGF-I and IGF-II receptors [are present] in the antler tip" <br />
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"[regenerating antlers express] Wnt 3a and the active form of Beta-catenin, leptin, the beta isoform of the leptin receptor, Msx-1 and Msx-2, FGF-4, cbfa1 and osterix"<br />
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<a href="http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3467256/"><b>Lentiviral-mediated RNAi knockdown of Cbfa1 gene inhibits endochondral ossification of antler stem cells in micromass culture.</b></a><br />
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"we silenced expression of Cbfa1 [in antler cartilage] , a key factor regulating endochondral ossification, using RNAi, and showed that expression of the downstream genes type I collagen and osteocalcin were suppressed which, in turn, inhibited endochondral ossification process taking place in the antler stem cell-formed nodules."<br />
<b> </b><br />
Neither chondrogenesis or osteogenesis occured in the Runx2(Cbfa1) knock down culture.<br />
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<b>Gene expression dynamics in deer antler: mesenchymal differentiation toward chondrogenesis.</b><br />
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"To identify novel genes involved either in early events of mesenchymal cell specialization or in robust bone development, we have introduced a 3 K heterologous microarray set-up (deer cDNA versus mouse template). Fifteen genes were differentially expressed; genes for housekeeping, regulatory functions (components of different signaling pathways, including FGF, TGFbeta, Wnt), and genes encoding members of the Polycomb group were represented. Expression dynamics for genes are visualized by an expression logo. The expression profile of the gene C21orf70 of unknown function is described along with the effects when over-expressed; furthermore the nuclear localization of the cognate protein is shown. In this report, we demonstrate the particular advantage of the velvet antler model in bone research for: (1) identification of mesenchymal and precartilaginous genes and (2) targeting genes upregulated in robust cartilage development."<br />
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Skeletal development genes upregulated in gene antlers:<br />
Sprouty 1 homolog<br />
Gas2<br />
Bmpr2<br />
Glypican 3<br />
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Detailed comparison to LSJL genes to be done.<br />
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"unlike in the growth plate cartilage, the antler cartilage is densely vascularized. Expression of p311 may keep under control the proliferation of the myofibroblast-like cells surrounding the blood vessels "<br />
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<b>Identification of differentially expressed genes in the developing antler of red deer Cervus elaphus.</b><br />
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"we have identified the expression patterns for 36 genes that were characteristic or dominant in the consecutive cell differentiation zones (mesenchyme, precartilage, cartilage) of the tip section of the developing velvet antler of red deer Cervus elaphus. Two major functional groups of these genes clearly outlined: six genes linked to high metabolic demand and other five to tumor biology. Our study demonstrates the advantages of the antler as a source of mesenchymal markers, for distinguishing precartilage and cartilage by different gene expression patterns and for identifying genes involved in the robust bone development, a striking feature of the growing antler. Putative roles for "antler" genes that encode alpha-tropomyosine (tpm1), transgelin (tagln), annexin 2 (anxa2), phosphatidylethanolamine-binding protein (pebp) and apolipoprotein D (apoD) in intense but still controlled tissue proliferation are discussed."<br />
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"In the antler mesenchyme, α-tropomyosin (tpm1) and less profoundly, transgelin, (tagln) slow down the vigorous cell proliferation and make conditions favorable toward differentiation. Downstream of this pathway, annexin 2 (anxa2) acts by channeling the cells toward chondrogenesis."<br />
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Comparison to LSJL genes to be done.<br />
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<b>Deer antler base as a traditional Chinese medicine: A review of its traditional uses, chemistry and pharmacology.</b><br />
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"Both in vitro and in vivo pharmacological studies have demonstrated that deer antler base possess immunomodulatory, anti-cancer, anti-fatigue, anti-osteoporosis, anti-inflammatory, analgesic, anti-bacterial, anti-viral, anti-stress, anti-oxidant, hypoglycemic, hematopoietic modulatory activities and the therapeutic effect on mammary hyperplasia."<br />
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"Based on animal studies and clinical trials, deer antler base causes no severe side effects."<br />
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The Table summary of chemical constituients reveals no unusual compositions but those would not reveal things like the embryonic-like stem cells. And there may be some unique proteins.<br />
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"Deer antler base collagens (800 mg/kg/day, i.g., for 90 days)" had a stimulatory effect on bone formation parameters on rats in vivo(<b>Therapeutic effects of collagen of antler base on osteoporosis in ovariectomized rats</b>).<br />
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<b>Effects of Velvet Antler with Blood on Bone in Ovariectomized Rats</b><br />
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" In traditional Chinese medicine (TCM), both velvet antlers (VA) and VA blood can tonify qi, essence, and marrow, nourish the blood, and invigorate bones and tendons. In TCM, the combination of VA and VA blood is believed to have superior pharmacological effects. The effectiveness of the combination therapy of VA middle sections (VAMs) and VA blood (VAM-B) was first examined in promoting proliferation of mouse osteoblastic cells (MC3T3-E1). <b>The anti-osteoporotic activity of VAM-B (ratio of VAM:VA blood = 1:0.2) was evaluated with ovariectomized (OVX) rats at a dose of 0.2 g/kg.</b> In VAM-B-treated OVX rats, the body weight decreased 10.7%, and the strength of vertebrae and the femur respectively increased 18.1% and 15.4%, compared to the control. VAM-B treatment also recovered the estrogen-related loss of the right tibial trabecular bone microarchitecture. Alkaline phosphatase (ALP) significantly decreased, but estradiol did not significantly change in serum of VAM-B-treated OVX rats."<br />
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"[In another study], long-term antler administration (13 months) moderated decreased plasma phosphorus and calcitonin levels and femoral bone density and calcium content, and increased plasma parathyroid hormone (PTH) and alkaline phosphates (ALP) activity levels associated with an ovariectomy (OVX) in 2 month-old senescence-accelerated mouse (prone-8, SAMP8)"<br />
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"VAM-B contained testosterone, estradiol, and IGF-1. The top three amino acids in VAM-B were in the order glutamic acid, glycine, and aspartic acid."<br />
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<b>The effect of sambar velvet antler suplement on femur bone, body growth, and physical endurance in rat. </b><br />
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"Antlers are deer's bony organ that follows a cycle of growing, hardening, casting and regrouping within a certain period. The effect of consuming velvet antler from temperate origin has been known scientifically to have positive effect for rheumatism and metabolic disorder sickness therapy. However, the role of velvet antler originated from tropical deer has not yet been explored. This study aimed to assess the potential of the velvet antler of sambar deer (Rusa unicolor) which was experimentally fed to laboratory rats. The assessment was made based on the animals growth rate (i.e. femur length, weight of testicle, body eight) and physical endurance (i.e. swimming test). <b>Laboratory rats at 21 days old were allocated into four different groups and each group consisted of five rats were fed with powder of soft and hard parts of velvet antler at dose of 0, 1, 2, and 3 g/kg body weight, respectively.</b> Animals were examined for eight weeks the body weight was examined weekly and the dose at velvet antler supplement was adjusted accordingly. At the end of the study the rat were put on endurance swimming test and then euthanized, for measurement of femur bone length and weight of testis. The results showed that there were no differences in the body weight. However at dose of 2 g soft part/kg BW indicating a consistently higher live weight gains across the observation time. Testis weight showed no significant differences between the treatments, but t<b>he length of femur bone showed a significant effect (p<0.05) with the doses level, with the highest score being at 3 g hard part / kg BW. </b>Physical endurance showed a significant effect (p<0.05) with the doses level, with the level of 1 g soft part/kg BW gave the best performance."<br />
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Couldn't get full study.Tyler Christopher Davishttp://www.blogger.com/profile/07640336101527064906noreply@blogger.com14