Flurbiprofen(Grow Taller by manipulating Lymphocyte count)

 This is a compliment to the analysis by Natural Height Growth on Flurbiprofen.

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.

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.

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.

Flurbiprofen-induced stimulation of periosteal bone formation and inhibition of bone resorption in older rats.

"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. 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. However, these changes were insufficient to increase cortical bone mass. In the proximal tibial metaphysis, 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{osteoclasts may be good for height during development and may allow for the formation of cartilage canals to form new growth plates}. 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."

"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.

"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 ."

In older rats, there was an increase in the size of the calcified cartilage core.

Flurbiprofen enhances growth and cancellous and cortical bone accumulation in rapidly growing long bones.

"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. 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}. 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."

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.

Here's a drug that's sort of the inverse to Flubiprofen:

Effects of phytohemagglutinin-P (PHA-P) on bone of the growing rat.

"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."

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.

According to Flurbiprofen and immunosuppression of Trypanosoma brucei infection in the goat., Flurbiprofen inhibits T-lymphocytes.

This study provides a possibly model for how lymphocytes may affect longitudinal bone growth:

Growth plate compressions and altered hematopoiesis in collagen X null mice.

"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, 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}."

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).

Inflammatory cytokines may have effects like lymphocytes.

Interleukin-6 modulates trabecular and endochondral bone turnover in the nude mouse by stimulating osteoclast differentiation.

"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. Both 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. 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 IL-6 replaces other factors that are supplied by T lymphocytes directly or indirectly. 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."

"hematopoietic cells and lymphocytes residing in the bone marrow may have effects on bone, especially in the pathological state."

On lymphocytes affecting height:

Growth patterns in pubertal HIV-infected adolescents and their correlation with cytokines, IGF-1, IGFBP-1, and IGFBP-3.

"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. 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}. There was a positive correlation between CD4 count and FAH{But this correlation occur indefinately}. 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."

Adult Height Achieved was linearly correlated to CD4+ lymphocyte count to 2000.

Osteoclasts Increase Height?

Intuitively, one would think that osteoclasts(bone breakers) would be bad for height increase.  Osteoblasts build up bone and osteoclasts tear down bone.  But, do osteoclasts play a vital role in the height increase process and if so how can we use this in our own grow taller methodology? 

Alendronate affects long bone length and growth plate morphology in the oim mouse model for Osteogenesis Imperfecta. 

"Alendronate, a bisphosphonate drug, has shown promise in reducing remodeling and bone loss in postmenopausal osteoporosis. Alendronate acts directly on the osteoclast, inhibiting its resorption capability. This inhibition of osteoclast activity has led to the use of bisphosphonates in the treatment of the osteogenesis imperfecta condition. Treatment of osteogenesis imperfecta[Osteogenesis imperfecta is a disease where there are brittle bones that fracture easily] with bisphosphonates[which inhibit osteoclasts] enhances bone strength, but the consequences on linear bone growth are not well defined. Using the oim mouse model for type III osteogenesis imperfecta, two doses of alendronate, low (0.125 mg/kg/wk) and high (2.5 mg/kg/wk) were administered weekly via intraperitoneal injection starting at 4 weeks of age and ending at 12 weeks of age to assess the effects of alendronate on humerus and ulna length. The higher dose of alendronate reduced humerus and ulna length in the oim/wt and wt/wt genotypes for both sexes (P < 0.05). The oim/oim humerus and ulna were not significantly affected by the higher dose of alendronate in females, but reduced bone length in males (P < 0.0085). Proximal humerus growth plate area was affected by both genotype and alendronate dose and growth plate diameter was increased at the chondro-osseous junction by both alendronate doses (P < 0.011). Genotype and alendronate dose affected growth plate height. The oim/oim genotype displayed taller growth plates. The high dosage of alendronate increased overall growth plate height, particularly within the hypertrophic zone, which suggests a failure of vascular invasion-induced apoptosis in the hypertrophic cells. In conclusion, these results indicate that high doses of alendronate (>2.5 mg/kg/wk) inhibit long bone length in mice through alteration of the growth plate and possibly reduced resorption at the chondro-osseous junction." 

"Although the mechanism of long bone growth relies upon clonal expansion and subsequent hypertrophy of chondrocytes, endochondral bone growth absolutely requires that chondroclasts resorb the septa of calcified cartilage at the chondro-osseous junction of the growth plate, permitting vascular invasion of the hypertrophic cell lacunae. Inhibition of the resorption impedes the elongation process8. C.E. Farnum and N.J. Wilsman, Cellular turnover at the chondro-osseous junction of the growth plate cartilage: analysis by serial sections at the light microscopical level. J Orthop Res 7 (1989), pp. 654–666. Full Text via CrossRef | View Record in Scopus | Cited By in Scopus. In addition, osteoclasts must participate in the ultimate replacement of calcified cartilage by remodeling the metaphyseal primary spongiosa to create a mechanically sound metaphyseal architecture. If a bisphosphonate used to treat OI in children inhibits the function of osteoclasts and chondroclasts, the result could significantly exacerbate the tendency of OI to interfere with the patient’s normal growth and bone development."

"The low dose of alendronate did have a significant effect on the length of the humerus in males"

So it's not a matter of that total inhibition of osteoclasts is bad for height growth.  An incomplete inhibition of osteoclasts can be bad for height growth.  

"Alendronate interferes with osteoclast action by interrupting the prenylation of small guanidine triphosphate-associated proteins involved in the intracellular signaling pathway that modulates osteoclast structural proteins. The osteoclast then becomes unable to attach to bone matrix and loses its resorbing ability. The septoclast (chondroclast) operates in the same manner as the osteoclast, and only differs in the types of hydrolytic enzymes secreted and its location within the growing bone. Thus, it is reasonable to believe that alendronate acts via a similar antiprenylation pathway in this cell. Inhibition of septoclastic resorption would obstruct vascular invasion and reduce chondrocyte apoptosis at the base of the growth plate, leading to an increase in growth plate area and height and diminished bone length. This mechanism would be consistent with the qualitative observation in this study that alendronate treatment diminished removal of cartilagenous cores in the primary spongiosa; persistent calcified cartilage within primary spongiosa as a consequence of alendronate treatment."

Alternatively, Alendronate may inhibit height by a non-osteoclast related mechanism...

"Furthermore, prenylation of guanidine triphosphate-associated proteins (such as Ras, Rac, and Rho) is involved in the intracellular regulation of growth factors controlling growth plate function and alendronate may affect growth via this pathway17. S.P. Luckman, D.E. Hughes, F.P. Coxon, R. Graham, G. Russell and M.J. Rogers, Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 13 (1998), pp. 581–589. Full Text via CrossRef | View Record in Scopus | Cited By in Sco. For example, inhibition of prenylation may disrupt cell progression within the growth plate by disrupting the ability of terminal hypertrophic chondrocytes to respond to hormones and signaling molecules. This too would be consistent with the experimental observations of reduced bone length, increased overall growth plate height, increased height of the hypertrophic zone, and obvious derangement of the growth plate and adjacent metaphyseal bone."

The apoptosis of hypertrophic cells is a critical part of endochondral ossification(long bone growth).  In the zone of calcification in the growth plate dead cartilage cells are consumed by bone-forming cells.  Alendronate, a biophosphate actually increased the growth plate height, but did not result in an increase in the length of the bone.  Osteoclasts are a critical part of growth plate remodeling which is vital for height growth.  Epiphyseal distraction was a method tried by scientists to increase height and reduce limb length discrepancies which although increased growth rate ultimately failed to improve final adult stature.  Showing that longer growth plates does not necessarily lead to increased final adult height.

A single nucleotide polymorphism on exon-4 of the gene encoding PPARdelta is associated with reduced height in adults and children. 

"CONTEXT: Peroxisome proliferator-activated receptor (PPAR)-delta is a nuclear transcription factor that plays a key role in many metabolic processes, including energy metabolism, and lipid and glucose metabolism. Candidate gene studies have identified a putative functional variant, rs2016520, in the gene encoding PPARdelta (PPARD), which is associated in some studies with metabolic traits. In addition, this single-nucleotide polymorphism was associated with adult height in several whole-genome scans, but this association did not achieve whole genome significance. OBJECTIVE: This study sought to determine whether PPARD variation influenced height. DESIGN: Haplotype tagging analysis across PPARD was performed in about 11,000 individuals from the Wellcome Trust U.K. Type 2 Diabetes Case Control Collection (Go-DARTS2). RESULTS: There was an association between rs2016520 and height in both patients with type 2 diabetes and controls without diabetes (combined P = 5 x 10(-5)). In a metaanalysis using published data from Caucasian cohorts totaling more than 38,000 participants, compelling evidence was found for this locus and its association with height (P = 10(-8)) with an overall effect size of about 0.5 cm per allele. A similar analysis in a group of 2700 prepubescent children also displayed a similar effect size to that seen in the adults. CONCLUSION: PPARD variation is clearly associated with a phenotype of reduced stature in both adults and children. Because height is an important indicator of metabolic and nutritional status, this provides additional support for a key role for PPARdelta in critical metabolic functions. PPARdelta may affect height through a variety of mechanisms including altered metabolic efficiency or effects on osteoclast function." 

Proper osteoclast function seems to be necessary for achieving maximum adult stature but it doesn't seem like improving osteoclast function would take you past that stature. 

"With this in mind, it has been shown that PPAR activation modulates cholesterol uptake from the gut[cholesterol is important for height growth so lack of cholesterol uptake may stunt growth]. Other evidence suggests that PPARdelta may exert a direct effect on the control of bone growth in the early rapid growth phase shown by young children because it has been demonstrated that activation of PPARdelta by agonists promotes bone remodeling by osteoclasts" 

PPAR delta stimulates osteoclasts without that stimulation height growth is reduced.

"height is inversely associated with glucose intolerance and type 2 diabetes"

Deficiency of insulin receptor substrate-1 impairs skeletal growth through early closure of epiphyseal cartilage. 

"Morphological analyses in and around the epiphyseal cartilage of mice deficient in insulin receptor substrate-1 (IRS-1) showed IRS-1 signaling to be important for skeletal growth by preventing early closure of the epiphyseal cartilage and maintaining the subsequent bone turnover at the primary spongiosa[Bone Turnover including osteoclasts is important]. Introduction: IRS-1 is an essential molecule for intracellular signaling by IGF-I and insulin, both of which are potent anabolic regulators of cartilage and bone metabolism. To clarify the role of IRS-1 signaling in the skeletal growth, morphological analyses were performed in and around the epiphyseal cartilage of mice deficient in IRS-1 (IRS-1(-/-)), whose limbs and trunk were 20-30% shorter than wildtype (WT) mice. MATERIALS AND METHODS: The epiphyseal cartilage and the primary spongiosa at proximal tibias of homozygous IRS-1(-/-) and WT male littermates were compared using histological, immunohistochemical, enzyme cytohistochemical, ultrastructural, and bone histomorphometrical analyses. RESULTS: In and around the WT epiphyseal cartilage, IRS-1 and insulin-like growth factor (IGF)-1 receptors were widely expressed, whereas IRS-2 was weakly localized in bone cells. Chronological observation revealed that height of the proliferative zone and the size of hypertrophic chondrocytes were decreased in WT mice as a function of age, and these decreases were accelerated in the IRS-1 (-/-) cartilage, whose findings at 12 weeks were similar to those of WT at 24 weeks. In the IRS-1(-/-) cartilage, proliferating chondrocytes with positive proliferating cell nuclear antigen (PCNA) or parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor immunostaining had almost disappeared by 12 weeks. Contrarily, TUNEL+ apoptotic cells were increased in the hypertrophic zone, at the bottom of which most of the chondrocytes were surrounded by the calcified matrix, suggesting the closure of the cartilage. In the primary spongiosa, bone volume, alkaline phosphatase (ALP)+ osteoblasts, TRACP+ osteoclasts[IRS-1 interacts with osteoclasts], and the osteopontin-positive cement line were markedly decreased. Bone histomorphometrical parameters for both bone formation and resorption were significantly lower in IRS-1(-/-) mice, indicating the suppression of bone turnover. CONCLUSION: The IRS-1(-/-) epiphyseal cartilage exhibited insufficient proliferation of chondrocytes, calcification of hypertrophic chondrocytes, acceleration of apoptosis, and early closure of the growth plate. Thus, the data strongly suggest that IRS-1 signaling is important for the skeletal growth by preventing early closure of the epiphyseal cartilage and by maintaining the subsequent bone turnover at the primary spongiosa." 

IRS-1 deficiency decreases height growth.  IRS-1 interacts with Osteoclasts.

"Regarding osteoclastic cells, because we previously reported that IRS-1 is not expressed in these cells, the downregulation of bone resorption markers is likely to be caused by the decrease in the supporting ability of osteoclastogenesis by osteoblasts through RANKL induction"

Role of tartrate-resistant acid phosphatase (TRAP) in long bone development.

"Tartrate resistant acid phosphatase (TRAP)[TRAP expression is connected to osteoclasts] was shown to be critical for skeleton development, and TRAP deficiency leads to a reduced resorptive activity during endochondral ossification resulting in an osteopetrotic phenotype and shortened long bones in adult mice. A proper longitudinal growth depends on a timely, well-coordinated vascularization and formation of the secondary ossification centre (SOC) of the long bones epiphysis. Our results demonstrate that TRAP is not essential for the formation of the epiphyseal vascular network. Therefore, in wild type (Wt) controls as well as TRAP deficient (TRAP-/-) mutants vascularised cartilage canals are present from postnatal day (P) five[so perhaps osteoclasts are not necessary for the formation of cartilage canals]. However, in the epiphysis of the TRAP-/- mice cartilage mineralization, formation of the marrow cavity and the SOC occur prematurely compared with the controls[so osteoclasts keep "growth plates" open longer]. In the mutant mice the entire growth plate is widened due to an expansion of the hypertrophic zone. This is not seen in younger animals but first detected at week (W) three and during further development. Moreover, an enhanced number of thickened trabeculae, indicative of the osteopetrotic phenotype, are observed in the metaphysis beginning with W three. Epiphyseal excavation was proposed as an important function of TRAP, and we examined whether TRAP deficiency affects this process. We therefore evaluated the marrow cavity volume (MCV) and the epiphyseal volume (EV) and computed the MCV to EV ratio (MCV/EV). We investigated developmental stages until W 12. Our results indicate that both epiphyseal excavation and establishment of the SOC are hardly impaired in the knockouts. Furthermore, no differences in the morphology of the epiphyseal bone trabeculae and remodelling of the articular cartilage layers are noted between Wt and TRAP-/- mice. We conclude that in long bones, TRAP is critical for the development of the growth plate and the metaphysis but apparently not for the epiphyseal vascularization, excavation, and establishment of the SOC. "

So osteoclasts may play a role in height growth other than cartilage canal formation.

"The canals erode the non-mineralized cartilage matrix and thus give blood vessels and bone-forming cells access to the epiphysis for the subsequent development of the SOC. Canal formation is governed by several matrix metalloproteinases (MMPs) and, most notably, membrane-bound type-1 matrix metalloproteinase (MT1-MMP = MMP 14) is critical for this process. As a result, MT1-MMP−/−mice reveal a vascular defect accompanied by delayed ossification"<-so MT1-MMP may help you grow taller.

"In mice lacking both MMP 9 and MMP 13 epiphyseal development is affected"<-So MMP9 and 13 help with height as well.

As does VEGF...

"the establishment of the epiphyseal vascular network is triggered by the vascular endothelial growth factor (VEGF), and VEGF deficiency causes a delayed vascularization and formation of the SOC"

"Tartrate-resistant acid phosphatase activity type 5 (TRAP or Acp5) is an iron-containing enzyme that is found in humans and murine species. It occurs in diverse tissues including bone and cartilage . TRAP is, at first, synthesized as a latent proenzyme with low activity, and proteolytic processing generates two subunits of about 16 and 20–23 kDa with enhanced enzymatic activity. The cysteine proteinase cathepsin K has been suggested to be responsible for the proteolytic activation of TRAP. TRAP is highly expressed in chondroclasts as well as osteoclasts"

"chondroclasts attack the mineralized cartilage matrix whereas osteoclasts participate in the resorption of the mineralized bone matrix. TRAP prompts the dephosphorylation of bone matrix phosphoproteins like osteopontin and bone sialoprotein and was originally shown to be important for a normal endochondral bone formation"

"In long bones, the excavation of the epiphysis is mainly achieved by chondro/osteoclasts that bind to the substrate via their ruffled border. They create a highly acidic milieu, enabling disintegration and finally resorption of the mineralized cartilage and bone matrix. We could show that in Wt controls and TRAP−/− mice chondro/osteoclasts were formed to the same extent throughout development, hence the absence of TRAP did not impair their genesis. Moreover, their differentiation is normal, even though several ultrastructural subdomains are altered, resulting in a moderately reduced lysosomal degradation of the mineral crystallites compared to Wt littermates. Apart from TRAP, chondro/osteoclasts secrete tartrate-sensitive lysosomal acid phosphatase (LAP) during the resorptive process[so osteoclasts secrete LAP to compensate for the loss of TRAP but LAP is less effective at increasing height]. LAP mutants show almost no bone abnormalities but in LAP/TRAP doubly deficient mice, bone malformations are severe, and long bones are distinctly shorter compared to the TRAP knockouts. Furthermore, in the double knockout mice a distinct enlargement of the liver and spleen has been observed whereas hepatosplenomegaly has never been noted in LAP- and TRAP single knockout mice. This suggests that in distinct tissues the two phosphatases are capable to complement for each other thereby maintaining lysosomal function. We could demonstrate that after examination of a long postnatal period, epiphyseal excavation and bone formation was hardly impaired in the femur of mice lacking TRAP. Furthermore, trabeculation and reorganization of the articular cartilage layers was not altered in the knockouts. Thus, our data collectively indicate that the absence of TRAP does not affect marrow cavity formation, bone morphology and formation of the articular cartilage, and we suggest that LAP largely compensates for the loss of TRAP."

So if there are instances where LAP is being used over TRAP it may cause a loss of height.

So, it's likely that the proper paired activity of osteoblasts and osteoclasts are needed for proper height growth.  Things like Alendronate disrupt that homeostasis reduce height growth.  Similar disruption of that homeostasis with excessive osteoclasts is not likely to increase height either.  An increase in both osteoblasts/osteoclasts simultaneously may increase height.


Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow.

"Formation of the hematopoietic stem cell (HSC) niche in bone marrow (BM) is tightly associated with endochondral ossification[endochondral ossification is required to form stem cell niches within the bone marrow]. We used the oc/oc mouse, a mouse model with impaired endochondral ossification caused by a loss of osteoclast (OCL) activity, to investigate the role of osteoblasts (OBLs) and OCLs in the HSC niche formation. The absence of OCL activity resulted in a defective HSC niche associated with an increased proportion of mesenchymal progenitors but reduced osteoblastic differentiation, leading to impaired HSC homing to the BM[so without osteoclasts there are more MSCs but they don't go to bone marrow]. Restoration of OCL activity reversed the defect in HSC niche formation. Our data demonstrate that OBLs are required for establishing HSC niches and that osteoblastic development is induced by OCLs."

"Signaling through Jagged 1 (Jag-1) on OBLs and its receptor Notch on HSCs is involved in the expansion of the HSC pool, and signaling through stromal Angiopoietin 1 (Ang-1) and its receptor Tie-2 on HSCs is involved in maintaining HSC quiescence in the niche"

"OBLs and mesenchymal cells also express osteopontin (OPN), which is a negative regulator of HSC pool size that inhibits HSC proliferation, promotes HSC apoptosis, and affects the expression of Jag-1 and Ang-1 by stromal cells"<-Maybe inhibiting osteopontin will help you grow taller?

"Stromal-derived factor-1 (SDF-1), which is produced by mesenchymal cells and OBLs, is the major chemoattractant for many hematopoietic progenitors, including HSCs"<-maybe we can induce expression of SDF-1 to where we want the growth plate to be to grow taller in that specific area?

"Coupling factors such as insulin-like growth factor, basic fibroblast growth factor, TGF-β, bone morphogenetic proteins, and platelet-derived growth factor are released from the bone matrix during bone resorption and are known to induce bone formation, thereby coupling bone resorption and formation "<-Many of these factors are pro-chondrogenic.

Therapeutic implications of suppressing osteoclast formation versus function

"osteoclasts recruit osteoblasts to sites of bone remodelling by mobilizing chemotactic proteins from matrix and direct secretion of such proteins that attract osteoblast precursors. Thus, anti-resorptive agents, such as the cathepsin K inhibitor odanacatib, that dampen osteoclast function but not number may also preserve osteoblast recruitment by preserving the bone resorptive cell."

"Evidence exists that osteoclasts recruit osteoblasts to sites of bone remodelling by two distinct mechanisms. The first is mobilization and activation of bone-residing growth factors such as TGFβ and IGF-I. These proteins, in turn, target mesenchymal stem cells that are osteoblast precursors and recruit them to sites of remodelling where they undergo differentiation into mature bone-forming cells. The other mechanism whereby osteoclasts recruit osteoblasts is by direct secretion of chemotactic molecules independent of bone degradation. CTHRC1 has recently been identified as one such molecule. Thus osteoclasts promote bone formation by mobilizing matrix-residing growth factors and by direct secretion of molecules such as CTHCR1, both of which recruit osteoblast precursors."

Osteoclasts: more than ‘bone eaters’

"Osteoclasts (OC) differentiate from OC precursors (OCP) under the influence of MCSF and RANKL produced by osteoblast (OB) lineage cells including osteocytes. As OCs create a resorption pit, growth factors, including TGFβ and IGF1, are released from the bone matrix. These growth factors may recruit mesenchymal osteoblast progenitors and promote their differentiation into mature cells that secrete osteoid to fill the area of resorbed bone. Some OBs differentiate further into matrix embedded osteocytes."

"Osteoclasts degrade bone by the polarized secretion of proteolytic enzymes (e.g. cathepsin K) and acid, which hydrolyze and solubilize the organic and inorganic components of bone, respectively. Proton and enzyme secretion is directed into a resorption lacunae, which is partitioned from rest of the bone microenvironment by a sealing zone of densely packed podosomes that surrounds the apical membrane of the osteoclast"

"Transforming growth factor β 1 (TGFβ1) released during osteoclast culture on bone induces the migration of mesenchymal stem cells (MSC) in vitro and MSC migration to bone surfaces is reduced in Tgfb1−/− mice"

The application of nanogenerators and piezoelectricity in osteogenesis

"Piezoelectricity is one of several mechanical responses of the bone matrix that allows osteocytes, osteoblasts, osteoclasts, and osteoprogenitors to react to changes in their environment."

"Mechanical force can push some atoms closer together or further apart in piezoelectric materials, upsetting the balance of positive and negative forces, and causing net electrical charges to appear outside."

"The extracellular matrix consists of 65% mineral matrix and 35% organic matrix. Type I collagen makes up about 90% of the organic matrix and possesses a triple helical structure that contributes tensile strength to the extracellular matrix. Inorganic minerals, which are responsible for the compressive strength of bone, are incorporated with the collagen fibrils in the form of calcium hydroxyapatite. Osteoblasts arise from mesenchymal stem cells and are responsible for bone formation. On the other hand, osteoclasts are multinucleated cells deriving from hematopoietic progenitors in the bone marrow and are responsible for bone resorption. Osteocytes are thought to be mechanosensor cells that control the activity of osteoblasts and osteoclasts. They are embedded in lacunae with long processes located in small channels called canaliculi. Canaliculi are considered the lifelines that permit nutrients, oxygen, and waste products to be exchanged with the blood vessels within the Haversian canal, Volkmann canal, and osteocytes. When a bone is loaded, the interstitial fluid within the lacuna and canaliculi is squeezed through a thin layer of non-mineralized matrix surrounding the cell bodies and cell processes toward the Haversian or Volkmann channels. This flow of fluid mobilizes the cell surface glycocalyx and initiates biochemical processes promoting osteogenesis"

"here are two major effects of calcium hydroxyapatite that contribute to collagen piezoelectricity. One is that the mineral crystal structure of calcium hydroxyapatite displays a high elastic modulus compared to other biological molecules and bone. This allows the collagen fibers to respond mechanically to loads onto the bone locally and bear the greatest strain of all the molecules within the solid matrix, thus generating the needed deformation required for a piezoelectric effect. The other is water resistance and restriction of hydroxyapatite to collagen. A number of physical observations support the dehydrating effect of calcium hydroxyapatite, including the result that collagen in calcified bone does not shrink and there exists a higher rate of water resorption in decalcified bone than that measured in calcified bone"

"The re-organization of a dipole moment is triggered by the compressive force on collagen, thus generating negative charges on the surface. The negative charges can open the voltage-gated calcium channels on osteocytes. After the opening of voltage-gated calcium channels, cascades of signaling pathways are triggered. The active channels promote the influx of extracellular calcium and further activate calmodulin, which subsequently stimulates the activation of calcineurin. This could ultimately lead to the activation of Ras and the extracellular signal-related protein kinase (ERK) signaling pathway that is critical for Runx2 activation and induction of several growth factors, including transforming growth factor β and bone morphogenetic protein. Growth factors can promote osteoblast activation, proliferation, differentiation, extracellular matrix deposition, and subsequent bone formation. However, the deformation of bone tissue during normal locomotion does not exceed 0.1%, and in vitro studies have shown that at least 1 to 10% deformation of bone tissue is necessary for osteocytes to respond to a mechanical strain. Mechanical strains resulting in such deformations would cause the bone to fracture"

"Primary bone healing involves a direct attempt by the cortex to reestablish itself in circumstances of strains less than 5% with compressive or tensile pressures of 0.15 MPa or less. Primary bone healing is driven by remodeling osteoclasts and osteoblasts bridging the fracture gap and rejoining the fractured fragments"

"Without grossly visible callus formation, osteoclasts cut across the fracture line, and osteoblasts then follow the osteoclasts to deposit new bone, and this occurs along with angiogenesis. If the fracture gaps prevent direct extension of osteons across the fracture site, osteoblasts fill the defects with woven bone. New lamellar bone is thus formed, and the fracture is bridged. Haversian remodeling starts reestablishing a normal cortical bone structure after the gaps are filled with woven bone."

"primary bone healing is rare, and the majority of fracture healing proceeds via secondary bone healing, or endochondral ossification, which occurs via a cartilage callus. There are four major phases of secondary bone healing, which include the inflammatory phase, early callus phase, mature callus phase, and remodeling phase. The inflammatory phase is characterized by an acute bone marrow response, post-damaged inflammation, and hematoma formation immediately following the fracture and up to 3–4 days after. The damaged tissue releases proinflammatory mediators, such as interleukin 1 (IL-1), IL-6, and tumor necrosis factor alpha (TNF-α), to initiate the repair process. The second stage is the early callus phase. This phase is predominated by soft cartilage callus formation, angiogenesis, and chondrogenesis at the fracture gap. Subsequently, the cartilaginous matrix is mineralized to begin the third phase, the mature callus phase. At this point, the chondrocytes undergo apoptosis and osteoblasts infiltrate the callus. The primary bone is laid down on these surfaces. In the last phase or remodeling phase, the newly formed woven bone is progressively replaced by mature lamellar bone, ultimately restoring the original cortical structure"

"The piezoelectricity induced by mechanical deformation of bone generates a negative electrical charge in areas of bone compression and a positive charge in the areas of traction"

Conclusion:  Height Increase Methods that involve suppressing osteoclast activity will not increase height.  Osteoclasts are an important part of the process of growing taller.  Ensuring proper function of insulin receptor substrate-1 and peroxisome profilerator-activated receptor in children can increase final adult stature.