Tuesday, October 18, 2011

Gain in Height by decreasing bone marrow fat content

It was once speculated that bone marrow turned to fat post epiphyseal fusion.  Later it was learned that that is based on nutrition and that if the bone marrow turns to fat then bone marrow can be restored with proper nutrition again.  Stem cell count decreases with age.  Since our goal with Lateral Synovial Joint Loading is to get stem cells to differentiate into chondrocytes(via hydrostatic pressure, which we induce by compression by a table clamp or dumbell) it behooves us to try to increase our stem cell count as much as possible.  How do we increase our stem cell count so we have more stem cells available for differentiation?  We already know that mechanical stimulation increases mesenchymal stem cell count.  One way is to discourage stem cells from differentiating into fat leaving more to differentiate into chondrocytes and osteoblasts. 

Human blood and marrow side population stem cell and Stro-1 positive bone marrow stromal cell numbers decline with age, with an increase in quality of surviving stem cells: Correlation with cytokines. 

"Hematological deficiencies increase with aging leading to anemias, reduced hematopoietic stress responses and myelodysplasias. This study tested the hypothesis that side population hematopoietic stem cells (SP-HSC) would decrease with aging, correlating with IGF-1 and IL-6 levels and increases in bone marrow fat. Marrow was obtained from the femoral head and trochanteric region of the femur at surgery for total hip replacement (N=100). Whole trabecular marrow samples were ground in a sterile mortar and pestle and cellularity and fat content determined. Marrow and blood mononuclear cells were stained with Hoechst dye and the SP-HSC profiles acquired. Marrow stromal cells (MSC) were enumerated flow cytometrically employing the Stro-1 antibody, and clonally in the colony forming unit fibroblast (CFU-F) assay. Plasma levels of IGF-1 (ng/ml) and IL-6 (pg/ml) were measured by ELISA. SP-HSC in blood and bone marrow decreased with age but the quality of the surviving stem cells increased. MSC decreased non-significantly. IGF-1 levels (mean=30.7, SEM=2) decreased and IL-6 levels (mean=4.4, SEM=1) increased with age as did marrow fat (mean=1.2mmfat/g, SEM=0.04). There were no significant correlations between cytokine levels or fat and SP-HSC numbers. Stem cells appear to be progressively lost with aging and only the highest quality stem cells survive." 

So increasing IGF-1 levels and decreasing IL-6 levels may increase stem cell count.  IL-6 is an inflammatory cytokine so it likely "kills" stem cells.  However, the last sentence of the study indicates that there is no correlation between IL-6 and IGF-1 and stem cell count and rather that it's some other process related to aging.  This could be something like Methylation Status or Telomere length[although the effectiveness of both is in question].  Supplementing with B-6, B-12, or Folic Acid will work for the former unless for some reason you are non responsive and then it would be best to take S-Adenosyl Methionine.  Telomere length involves supplements like Astragalus and you may increase telomere length with weight lifting also.  None of those will work unless your body is deficient as you can't make your body methylate cells it doesn't want to by supplementing with SAM-e[and SAM-e is an expensive experiment]. 

It's very likely that increased IL-6 and decreased IGF-1 levels are just the by-product of some pathway that happens to decrease MSC number rather than increased IL-6 reducing MSCs.

The pathophysiology of the aging skeleton. 

"In recent decades the population of both elderly men and women has grown substantially worldwide. Aging is associated with a number of pathologies involving various organs including the skeleton. Age-related bone loss and resultant osteoporosis put the elderly population at an increased risk for fractures and morbidity. Fortunately, in parallel our understanding of this malady has also grown substantially in recent years. A number of clinical as well as translational studies have been pivotal in providing us with an understanding of the pathophysiology of this condition. This article discusses the current concepts of age-related modulation of the skeleton involving intrinsic factors such as genetics, hormonal changes, levels of oxidative stress[IL-6, TNF-alpha], and changes in telomere length, as well as extrinsic factors such as nutritional and lifestyle choices. It also briefly outlines recent studies on the relationship between bone and fat in the marrow as well as the periphery." 

"There has been much recent interest in the relationship between fat and the aging skeleton. This is very important because both bone-forming osteoblastic cells and fat-forming adipocytic cells arise from a common progenitor in the marrow. Another exciting and recent area of investigation is the central regulation of bone mass and how this might be affected by age. Finally, a number of recent studies point to telomere shortening and its association with age-related bone loss."<-So osteoblastic cells compete with adipocytic cells for progenitors more than chondrogenic cells although adipocytic cells may still leave a smaller pool of progenitors for potential chondrocytes.

"With aging, hematopoietic tissue is replaced by fatty bone marrow, with consequent reduction in osteoblast number and function. Further, there appears to be a predominant differentiation of MSCs into adipocytes at the expense of osteoblasts"<-Again this likely applies to chondrocytes as well but the effect is not being reported.

"More recent studies found that a higher percentage of body fat was associated with a higher risk for osteoporosis, osteopenia, and non-spine fractures, as well as an inverse relationship between fat mass and bone mass after adjusting for the mechanical loading effects of body weight has been reported"<-so overall fat mass does reduce the available pool of bone marrow progenitors for chondrogenic and osteoblastic activities.  This can be reversed by mechanical loading somewhat but it's better to maximize mechanical loading and ensure that the amount of fat is not so great as to strikingly inhibit osteoblastic and chondrogenic stem cell differentiation.

PPARγ: a circadian transcription factor in adipogenesis and osteogenesis. 

"Peroxisome proliferator-activated receptor γ (PPARγ) is a critical factor for adipogenesis and glucose metabolism, but accumulating evidence demonstrates the involvement of PPARγ in skeletal metabolism as well. PPARγ agonists[agonist means that it activates], the thiazolidinediones, have been widely used for the treatment of type 2 diabetes mellitus owing to their effectiveness in lowering blood glucose levels. However, the use of thiazolidinediones has been associated with bone loss and fractures. Thiazolidinedione-induced alterations in the bone marrow milieu-that is, increased bone marrow adiposity with suppression of osteogenesis-could partially explain the pathogenesis of drug-induced bone loss. Furthermore, several lines of evidence place PPARγ at the center of a regulatory loop between circadian networks and metabolic output. PPARγ exhibits a circadian expression pattern that is magnified by consumption of a high-fat diet. One gene with circadian regulation in peripheral tissues, nocturnin, has been shown to enhance PPARγ activity. Importantly, mice deficient in nocturnin are protected from diet-induced obesity, exhibit impaired circadian expression of PPARγ and have increased bone mass. This Review focuses on new findings regarding the role of PPARγ in adipose tissue and skeletal metabolism and summarizes the emerging role of PPARγ as an integral part of a complex circadian regulatory system that modulates food storage, energy consumption and skeletal metabolism." 

PPAR-lambda may be what's involved in "turning" bone marrow into fat.  PPAR-lambda's effects are augmented by a high-fat diet and a gene called nocturnin.  So, you can inhibit PPAR-lambda by not eating a high fat diet.  Also, ways of decreasing the expression of nocturnin will decrease the number of MSC's turning into fat. 

The Effects of Native and Synthetic Estrogenic Compounds as well as Vitamin D Less-Calcemic Analogs on Adipocytes Content in Rat Bone Marrow. 

"We demonstrated previously that phytoestrogens and vitamin D analogs like estradiol-17betaf0 (E2) modulate bone morphology in rat female model. Aim: We now analyze the effects of phytoestrogens, E2, SERMs and the lesscalcemic analogs of vitamin D: JKF1624F2-2 (JKF) or QW1624F2-2 (QW) on fat content in bone marrow (BM) from long bones in ovariectomized female rats (OVX). Materials and Methods: OVX rats were injected with treatments known to affect bone formation, 5 days per week for 2.5 month for analysis of fat content in BM. Results: In OVX young adults there is a decreased bone formation and a 10 folds increase in fat cells content in BM. Treatment with E2, raloxifene (Ral) or Femarelle (DT56a) resulted in almost completely abolishment of fat cells content. Daidzein (D) decreased fat cells content by 80%, genistein (G) or biochainin A (BA) did not change fat cells content and carboxy BA (cBA) had a small but significant effect. JKF or QW did not affect fat cells content, whereas combined treatment of JKF or QW with E2 resulted in complete abolishment of fat cells content. These changes in fat cells content are inversely correlated with changes in bone formation." 

So, Vitamin D will help prevent bone marrow from turning into fat. 

One way to increase stem cell count is to reduce bone marrow fat content.  To do that you can lower the amount of fat in your diet and make sure you have enough Vitamin D.  You can also increase stem cell count by mechanical stimulation and various supplements.

Bone marrow fat content may not be the only thing that changes but also the sub-populations of the bone marrow itself.

The composition of the mesenchymal stromal cell compartment in human bone marrow changes during development and aging.

"Life-long hematopoiesis depends on the support by mesenchymal stromal cells within the bone marrow. Therefore, changes in the hematopoietic compartment that occur during development and aging probably correlate with variation in the composition of the stromal cell microenvironment[if we can alter the composition of the stromal cell microenvironment than we can reverse some of the changes that occur during development and aging]. Mesenchymal stromal cells are a heterogeneous cell population and various subtypes may have different functions. In accordance with others, we show that CD271 and CD146 define distinct colony-forming-unit-fibroblast containing mesenchymal stromal cell subpopulations. In addition, analysis of 86 bone marrow samples revealed that the distribution of CD271brightCD146- and CD271brightCD146+ subsets correlates with donor age. The main subset in adults was CD271brightCD146-, whereas the CD271brightCD146+ population was dominant in pediatric and fetal bone marrow[increasing the amount of CD271brightCD146+ population may help increase the differentiative potential of stem cells into chondrocytes]. A third subpopulation of CD271-CD146+ cells contained colony-forming-unit-fibroblasts in fetal samples only[Thus fetal marrow has even better differentiation potential with CFUFs in the subpopulation of CD271-CD146+ cells]. These changes in composition of the mesenchymal stromal cell compartment during development and aging suggest a dynamic system, in which the subpopulations may have different functions."

"Mesenchymal stromal cells (MSC) cultured from adult and fetal tissues constitute a heterogeneous cell population. Although a panel of markers, including CD105 (Endoglin) and CD90 (Thy-1), was introduced to define cultured MSC, the cells initiating the culture remain unidentified. Recently, the low-affinity nerve growth factor receptor CD271 and melanoma cell adhesion molecule CD146 were described for prospective isolation of MSC with colony forming unit-fibroblast capacity."<-The presence of CD271 and CD146 means that the MSC population has good differentiation capabilities.

"These subsets had a similar capacity to differentiate and to support hematopoiesis, but their localization in human BM was different. CD271+/CD146-lo cells were bone-lining, while CD271+CD146+ had a perivascular localization."<-perivascular means surrounding a blood vessel.  Adults have more of the bone-lining stem cells which would explain why there's more apopsitional growth.  Whereas youthful individuals have perivascular stem cells which will enable more interstitial(height gaining) growth.

"CD271+CD146-/lo and CD271+CD146+ respectively localize to endosteal or perivascular niches in vivo"<-Thus even if there's growth stimulation for a perivascular region a bone lining cell will still localize to a bone-lining(appositional thereby non-height gaining region).  Thus, perivascular localizating bone marrow may be essential for height growth.

Alternatively, the number of subpopulations may be a function of need.  There is far perivascular growth without growth plates thus it makes sense that there are less mesenchymal stem cells localized to perform perivascular growth.

Microarchitectural Changes in the Aging Skeleton

"The main cortical age-related change is increased porosity due to negatively balanced osteonal remodeling and expansion of Haversian canals, which occasionally merge with endosteal and periosteal resorption bays, thus leading to rapid cortical thinning and cortical weakening."

"Periosteal porosity contributes to age-related weakening of the skeleton. It results from negatively balanced osteonal remodeling, which leads to a progressive increase in the volume fraction of osteonal (Haversian) canals (cortical porosity) and thus to significant deficits in cortical mineralized matrix and decreased resistance to fracturing, as intracortical porosity accounts for about 70% of elastic modulus and 55% of yield stress . Neighboring canals progressively increase in size and merge to become super-osteons."

Note the large amount of adipose tissue.

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