Ischemia is reduced blood supply to an organ(in our case we would be interested in cartilage and bone).

“Ischemic osteonecrosis is a process that involves impaired outflow of blood from the marrow space, increased intramedullary blood pressure, and reduced blood flow circulation in the bone marrow. This results in the death of osteocytes and other marrow tissues.” from Ischemic Osteonecrosis.  Now obviously osteonecrosis is not what we want but there’s a difference between doing cardio to induce an oxygen debt and choking yourself to death.  It’s a matter of severity.  If we can induce healthy, moderate ischemia(“Ischemia is a restriction in blood supply to tissues”) then that may be enough for neo chondrogenesis.  Maybe via something like occlusion bands?  It looks like intramedullar pressure is not what can induce possible chondrogenic adaptation but likely enhanced blood flow as a result of transient ischemia.

They’ve already kind of studied the effects of knee loading on osteonecrosis and found that it protects against it in “Knee loading protects against osteonecrosis of the femoral head by enhancing vessel remodeling and bone healing“

But we know that osteonecrosis increases intramedullary pressure so we can study this to see if it can prove that theory that increase intramedullary pressure can induce neo-chondrogenesis.

“Intramedullary pressures in osteonecrosis can be 5 times greater than normal because of backup pressure.”

“Shock wave therapy is based on the principles of ultrasonic lithotripsy and success in treating orthopedic neuralgias. Inducing micro-trauma by treatment of ischemic jawbones with an extra-oral ultrasonic wand can induce new circulation and bone regrowth”

“Where there is more bleeding, more bone will follow.” <-it’s probably not the ischemia that can induce anabolic effects but the overcompensation that occurs when blood flow returns to normal.  Sort of like the oxygen debt and exercise.  It may be the changes in blood flow that have the beneficial effects rather than the restriction itself.

Femoral Head Deformation and Repair Following Induction of Ischemic Necrosis

“Ischemic necrosis of the femoral head can be induced surgically in the piglet. We used this model to assess femoral head deformation and repair in vivo by sequential magnetic resonance imaging and by correlating end-stage findings with histologic assessments.

Ischemic necrosis of the femoral head was induced in ten three-week-old piglets by tying a silk ligature around the base of the femoral neck (intracapsular) and cutting the ligamentum teres. We used magnetic resonance imaging with the piglets under general anesthesia to study the hips at forty-eight hours and at one, two, four, and eight weeks. Measurements on magnetic resonance images in the midcoronal plane of the involved and control sides at each time documented the femoral head height, femoral head width, superior surface cartilage height, and femoral neck-shaft angle. Histologic assessments were done at the time of killing.

Complete ischemia of the femoral head was identified in all involved femora by magnetic resonance imaging at forty-eight hours. Revascularization began at the periphery of the femoral head as early as one week and was underway in all by two weeks. At eight weeks, magnetic resonance imaging and histologic analysis showed deformation of the femoral head and variable tissue deposition. Tissue responses included (1) vascularized fibroblastic ingrowth with tissue resorption and cartilage, intramembranous bone, and mixed fibro-osseous or fibro-cartilaginous tissue synthesis and (2) resumption of endochondral bone growth{Obviously resumption of endochondral bone growth in adults would be what we want}. At eight weeks, the mean femoral head measurements (and standard error of the mean) for the control compared with the ligated femora were 10.4 ± 0.4 and 4.8 ± 0.4 mm, respectively, for height; 26.7 ± 0.8 and 31.2 ± 0.8 mm for diameter; 1.1 ± 0.1 and 2.3 ± 0.1 mm for cartilage thickness; and 151° ± 2° and 135° ± 2° for the femoral neck-shaft angle. Repeated-measures mixed-model analysis of variance revealed highly significant effects of ligation in each parameter (p < 0.0001).

Magnetic resonance imaging allows for the assessment of individual hips at sequential time periods to follow deformation and repair. There was a variable tissue response, and histologic assessment at the time of killing was shown to correlate with the evolving and varying magnetic resonance imaging signal intensities. Femoral head height on the ischemic side from one week onward was always less than the initial control value and continually decreased with time, indicating collapse as well as slowed growth. Increased femoral head width occurred relatively late (four to eight weeks), indicating cartilage model overgrowth concentrated at the periphery.”

“At higher magnification, the tissue was vascularized fibrocartilage.”<-this is good because fibrocartilage indicates possibly new cartilage(neo growth plates).

“Increased vessels within the lateral epiphyseal cartilage were frequently seen, many of which eventually became associated with ectopic foci of endochondral ossification.”<-ectopic means abnormal which could mean new growth plates.

“Greater cartilage height was observed in the ligated group compared with contralateral, control femoral heads at two weeks (F = 9.6, p = 0.003), four weeks (F = 33.4, p < 0.0001), and eight weeks (F = 55.7, p < 0.0001).”

Quantification of Angiogenesis in Otosclerosis

“The determinants of clinical versus histologic otosclerosis{“Otosclerosis is a condition where one or more foci of irregularly laid spongy bone replace part of normally dense enchondral layer of bony otic capsule in the bony labyrinth.”} are unknown, but angiogenesis is associated with active disease. We hypothesized that quantification of angiogenesis in otosclerotic human temporal bones could reveal significant differences between clinical and histologic cases.

Study Design: We reviewed all otosclerosis specimens meeting criteria from the temporal bone collection of the Massachusetts Eye and Ear Infirmary and 10 normal controls.

Methods: Digital images were taken at predilection sites, followed by computer‐assisted analysis. Canalicular area (CA), the aggregate of vascular spaces within bone, microvessel density (MVD), area, and depth were the main measures. Evidence of a direct connection between local vessels and the vasculature of the otosclerotic focus was also recorded for each specimen.

Results: The average area (mm²) and depth (number of sections containing otosclerosis) of clinical lesions was significantly greater than histologic lesions. Total microvessel counts were significantly greater in clinical versus histologic lesions, and both clinical and histologic lesions contained significantly greater numbers of microvessels than the normal otic capsule. CA was also significantly higher in clinical lesions. MVD was slightly but not significantly higher in clinical lesions. Importantly, a direct connection between named vessels and the otosclerotic vasculature was significantly more frequent in clinical lesions.

Conclusions: Computer‐assisted quantification revealed significantly greater measures of angiogenesis in clinical versus histologic otosclerosis. Direct connection to adjacent vessels may support angiogenesis in this disease. Sustained angiogenesis may be an important determinant of clinical otosclerosis.”

“otosclerosis resulted from instability in embryonic cartilage rests called “globuli interossei.” Because these rests are remnants of incomplete endochondral ossification, one possibility is that otosclerotic bone represents resumption of arrested endochondral ossification in the globuli interossei.”

“Indirect evidence for resumed endochondral ossification within the globuli interossei exists in otosclerotic temporal bones: otosclerotic bone demonstrates a woven pattern on polarized light microscopy identical to immature woven bone formed at sites of endochondral ossification“

“Angiogenesis is critical for the conversion of cartilage to bone to the extent that animal models of endochondral ossification are used to assess candidate angiogenesis inhibitors”

“The development of otosclerosis requires angiogenesis, which may reflect resumed endochondral ossification of the globuli interossei.”

Quantifying the effect of ischemia on epiphyseal growth in an extremity replant model

“Warm ischemia (21°C) of 0, 2, 4, 6, or 8 hours was produced in a modified hindlimb preparation of 35 10-week-old Lewis rats by amputation. Subsequent microvascular anastomoses of each hindlimb to a syngeneic animal was done after which fluorochrome bone labels were administered 5 minutes after operation and on day 14 after operation. Epiphyseal plate growth (that between bone labels) was analyzed histomorphometrically and statistically. Epiphyseal plate growth was found to have a linear inverse relationship to ischemia time. Overgrowth occurred at all ischemic periods except 8 hours, and vascular pedicle patency decreased as ischemia time progressed.”

“Early clinical reports suggested that epiphyseal growth after replantation might be an all-or-none phenomenon, with overgrowth not uncommon”

“warm ischemia in a young rat hindlimb replant model. In general, at time periods of total warm ischemia between 0 and 4 hours, epiphyseal overgrowth (up to three times that of control hindlimbs) and excellent vascular pedicle patency may be expected. At 6 hours of total warm ischemia some minor epiphyseal overgrowth and good to fair vascular patency can be expected. At 8 hours of total warm ischemia and later, normal or retarded epiphyseal growth and poor vascular patency rates are expected.”

That 8 hours did not induce overgrowth likely means that the growth stimulation is not due to the ischemia itself but due to the compensation afterwards.

Ischemia’s effects may be due to hypoxia.

Effect of Hypoxia on Gene Expression of Bone Marrow‐Derived Mesenchymal Stem Cells and Mononuclear Cells

“MSC have self‐renewal and multilineage differentiation potential, including differentiation into endothelial cells and vascular smooth muscle cells. Although bone marrow‐derived mononuclear cells (MNC) have been applied for therapeutic angiogenesis in ischemic tissue, little information is available regarding comparison of the molecular foundation between MNC and their MSC subpopulation, as well as their response to ischemic conditions. Thus, we investigated the gene expression profiles between MSC and MNC of rat bone marrow under normoxia and hypoxia using a microarray containing 31,099 genes. In normoxia, 2,232 (7.2%) and 2,193 genes (7.1%) were preferentially expressed more than threefold in MSC and MNC, respectively, and MSC expressed a number of genes involved in development, morphogenesis, cell adhesion, and proliferation, whereas various genes highly expressed in MNC were involved in inflammatory response and chemotaxis. Under hypoxia, 135 (0.44%) and 49 (0.16%) genes were upregulated (>threefold) in MSC and MNC, respectively, and a large number of those upregulated genes were involved in glycolysis and metabolism. Focusing on genes encoding secretory proteins, the upregulated genes in MSC under hypoxia included several molecules involved in cell proliferation and survival, such as vascular endothelial growth factor‐D, placenta growth factor, pre‐B‐cell colony‐enhancing factor 1, heparin‐binding epidermal growth factor‐like growth factor, and matrix metalloproteinase‐9[extracellular matrix remodeling], whereas the upregulated genes in MNC under hypoxia included proinflammatory cytokines such as chemokine (C‐X‐C motif) ligand 2 and interleukin‐1α. Our results may provide information on the differential molecular mechanisms regulating the properties of MSC and MNC under ischemic conditions.”

There are some anabolic genes in here(table 2).

Anabolic Pathways(table 4).

Spontaneous regeneration can occur after osteonecrosis

Spontaneous regeneration of the mandible following hemimandibulectomy for medication-related osteonecrosis of the jaw

“oral function including mobility of the tongue and buccal mucosa may influence spontaneous regeneration of the mandible”

GIRK3 deletion facilitates kappa opioid signaling in chondrocytes, delays vascularization and promotes bone lengthening in mice

“Activation of G protein-coupled receptor (GPCR) signaling pathways is crucial for skeletal development and long bone growth.  protein-gated inwardly-rectifying K⁺ (GIRK) channel genes are key functional components and effectors of GPCR signaling pathways in excitable cells of the heart and brain, but their roles in non-excitable cells that directly contribute to endochondral bone formation have not been studied. In this study, we analyzed skeletal phenotypes of Girk2^−/−, Girk3^−/− and Girk2/3^−/− mice. Bones from 12-week-old Girk2^−/− mice were normal in length, but femurs and tibiae from Girk3^−/− and Girk2/3^−/− mice were longer than age-matched controls at 12-weeks-old. Epiphyseal chondrocytes from 5-day-old Girk3^−/− mice expressed higher levels of genes involved in collagen chain trimerization and collagen fibril assembly, lower levels of genes encoding VEGF receptors, and produced larger micromasses than wildtype chondrocytes in vitro. Girk3^−/− chondrocytes were also more responsive to the kappa opioid receptor (KOR) ligand dynorphin, as evidenced by greater pCREB expression, greater cAMP and GAG production, and upregulation of Col2a1 and Sox9 transcripts. Imaging studies showed that Kdr (Vegfr2) and endomucin expression was dramatically reduced in bones from young Girk3^−/− mice, supporting a role for delayed vasculogenesis and extended postnatal endochondral bone growth. Together these data indicate that GIRK3 controls several processes involved in bone lengthening.”

“GIRK channels are homo- and hetero-tetramers formed by four mammalian GIRK subunits (GIRK1/Kcnj3, GIRK2/Kcnj6, GIRK3/Kcnj9, and GIRK4/Kcnj5). GIRK channels are activated when GPCR ligands stimulate pertussis toxin-sensitive G_i/o-G proteins; the liberated Gβγ subunit then binds to GIRK channels and increases their gating. The resultant efflux of K⁺ reduces the excitability of neuronsand cardiomyocytes. Knockout studies in mice have shown that GIRK2-containing GIRK channels mediate pain relief evoked by opioids and other analgesics. In chondrocytes, K⁺ efflux reduces swelling during unloading and can affect proteoglycan secretion”<-so maybe GIRK2 and GIRK3 knockouts have more chondrocyte hypertrophy and are more responsive to mechanical loading.

“GIRK2 mutations in patients with Keppen Lubinsky syndrome, which is characterized by growth above the 50th to 75th percentile at birth with subsequent developmental delays and other phenotypes “

“Girk3 deletion increases femur and tibia lengths and augments kappa opioid signaling in chondrocytes. Thus, these data identify GIRK3 as a suppressor of bone lengthening and kappa opioid activity in developing skeletons.”

“Numerous GPCR-signaling pathways, including kappa opioids, influence growth.”

Need to get the full paper and research more on GIRK3.

I’m still working on height increase.  Just doing more independent research and learning more about anatomy and physiology and actions of cells as the research I’m looking at is a lot of the same old, same old.  Maybe the key is to look at older studies before things were set in their ways.  It seems in the old days they were willing to try new risks to get people to grow taller.

Essentially the study found that heat did not increase bone length however there was some promise in that decalcification could be caused by the heat and that could enable longitudinal bone growth.  And the study shows islands of cartilage which could be the creation of new growth plates which is quite promising.  But the heat itself actually didn’t stimulate the growth plate itself.  It was only the heat degeneration the calcified bone matrix and stimulating the creation of growth plate islands that incurred new growth.

The effect of heat upon the growth of bone

“GROWTH in length of long bones consists of two mutually independent processes, the division and palisade arrangement of cartilage cells, and the subsequent calcification of the matrix between these cells and its replacement by bone. It is generally agreed that growth is dominated by the activities of the cells of the reserve zone and those in the adjacent apex of the cartilage columns. The subsequent enmeshment, of hypertrophic cartilage cells within a calcified matrix must prevent elongation at other sites. Recent attempts to stimulate the growth of bone have been based upon the production of an irritative lesion within the metaphysis, stimulating ossification rather than cartilage-cell division. ”

“Chapchal and Zeltienrust (1947-48) reported an inconstant increase in the rate OF growth in the rabbit after the insertion of metal or ivory pins within the metaphysis. Wilson (1952) using copper and constantan wire in the dog produced similar results. The application of these methods to limb inequality in children has been reported by Pease (1962). Metal or ivory screws WPI’P inserted transversely into the metaphysis of the femur and tibia. Each of the seven children subjected to this procedure showed an increase in the rate of growth of the shorter limb, but equalization of length was not attained. ”

“The overgrowth of bone which is constantly seen after fractures, in the presence of arteriovenous aneurysms, and in association with bone and joint infections”

arteriovenous aneurysm an abnormal communication between an artery and a vein in which the blood flows directly into a neighboring vein or is carried into the vein by a connecting sac.<-Lateral loading can increase blood flow.  Though this probably won’t work without existing growth plates.

“increase in the length of a limb following the production of an arteriovenous fistula in the dog”

“One of the clinical features of most cases of limb elongation with an increase in the temperature of the skin, and in the arteriovenous aneurysm this is associated with an increase in the temperature of bone”

“The rate of growth of the ulna was in some animals slightly depressed, in rabbit 480 markedly SO. In this animal there was considerable formation of new bone around tJie resistor, although the epiphyseal cartilage appeared normal. The overgrowth of the ulna noted in rabbit 465 was not associated with any abnormal histological appearance of the epiphyseal cartilage and the radiographs suggest that the discrepancy may have been due to a disturbance of growth in the control limb. The radiographs also show a relative decalcification of the the whole of the treated forelimb and this may have been associated with a generalized hyperemia{excess of blood in the vessels} of this limb.”

“Where the heating level was high, the epiphyseal cartilage is affected. The earliest changes in this region are an irregularity of the cartilage columns and a granularity of the matrix. When cellular destruction occurs it is at first confined to the region of the apex of the cartilage columns and is associated with fibrillation of the cartilage matrix. ”

“In only one animal (465) did an increase in bone length occur. This animal was heated for two days and, the wires having broken, the resistor was left unheated for a further 36 days. Although the increase in length of the limb was considerable, aid was associated with a generalized decalcification of the forelimb, suggesting an increase in the vascularity of this member, the difference in length of the limbs may have been due to some abnormality of growth on the control side. “<-So decalcification is key to growing taller.  High levels of heat can was found to cause necrosis which reduced growth but if decalcification can enhance growth.  Then maybe heat could enhance growth by decalcifying bones.

“heat has been shown to stimulate the production of cartilage around the resistor and to produce islands of endochondral ossification within the bony epiphysis and along the shaft of the radius.”<-islands of endochondral ossification is promising because it shows new induction of bone growth.

“Islands of cartilage were produced within the bony epiphysis close to the resistor, and along the ulnar border of the radial shaft. Some of them islands showed endochondral ossification, but there was no increase of cellular activity in the epiphyseal cartilage. A large cartilaginous mass developed in the region where the resistor was buried, and, in many animals, the transverse diameter of the metaphysis was greatly increased. ”

Figure 8 is an image near the resistor so there should be islands of cartilage visible.  I can’t tell If there are cartilage islands or not and if there are cartilage islands we can’t say for sure whether they are not just broken off cartilage from the growth plate.  Cartilage islands within the diaphysis would be key to seeing if heat can induce new growth plates.

Here’s mentioned overgrowth.

I’m still working on my own device.   I’m not sure if the device listed here is stimulatory enough to induce longitudinal bone growth.  The device may be useful if you have existing growth plates.  But to grow taller you’d need bone breakdown to occur faster than bone buildup{so that cartilage has room to grow} and the device is optimized for bone buildup.

Development of an Artificial Finger-Like Knee Loading Device to Promote Bone Health.

“This study presents the development of an innovative artificial finger-like device that provides position specific mechanical loads at the end of the long bone and induces mechanotransduction in bone{So you could theoretically use your own fingers to see what such an a device would do; use your own fingers to press on the epiphysis of bone}. Bone cells such as osteoblasts are the mechanosensitive cells that regulate bone remodeling{in order to induce height growth you’d need a lot more than bone remodeling, you need to degrade cortical bone and induce MSC differentiation into chondrogenic cells}. When they receive gentle, periodic mechanical loads, new bone formation is promoted{how this bone formation is promoted is of importance of whether such a method can induce height growth}. The proposed device is an under-actuated multi-fingered artificial hand with 4 fingers, each having two phalanges. These fingers are connected by mechanical linkages and operated by a worm gearing mechanism. With the help of 3D printing technology, a prototype device was built mostly using plastic materials. The experimental validation results show that the device is capable of generating necessary forces at the desired frequencies, which are suitable for the stimulation of bone cells and the promotion of bone formation. It is recommended that the device be tested in a clinical study for confirming its safety and efficacy with patients.”

Cortical bone is highly inhibitory towards longitudinal bone growth.  You need to generate sufficient fluid flow to induce degradation of the cortical bone or you likely will not be able to grow taller.  I think it would take a lot of fluid flow for that to happen.  Maybe with very high frequency and duration with this device it would be possible.

” if a small magnitude of mechanical stimuli is applied at a high frequency, an osteogenic response can be stimulated via mechanotransduction in bone cells.”<-we don’t care about stimulating bone cells EXCEPT for osteoclasts.  We need to simulate stem cells to differentiate into chondrocytes.

“Osteocytes are the most abundant type of cells in bone tissue, and they constitute more than 90% of the cells in bone matrix. They are rooted in the calcified bone medium, and communicate with each other and with bone-forming osteoblasts through slender processes and gap junctions. Osteocytes are highly mechanosensitive. Haversian system or osteon, one of the key components of a porous bone matrix, encloses a blood vessel in its center and sets up the canals known as Haversian canals or Volkmann’s canals. Osteogenesis is induced by the process of osteoinduction in which premature cells are recruited, stimulated and developed into pre-osteoblasts{we just need to induce a microenvironment where premature cells are induced into pre-chondrocytes instead and one way to do that is via a high hydrostatic pressure environment which could be induced by manipulating fluid flow}. Osteogenesis can also result from osteoconduction which is the passive process of bone growth on surfaces such as bone-implant surfaces”

“When rapid mechanical loading is applied at the end of long bone (e.g., knee), it is proposed that the interstitial fluid present around the osteocytes in the lacuna-canalicular network induces a pressure gradient and elevates nutrient transport throughout the porous network. “<-interstitial fluid flow could do more than this.  If you have a lot of fluid flow it could induce shear that degrades the cortical bone that prevents longitudinal bone growth.

Update:  I’m still hard at work for a methodology to grow taller.  It’s just mostly a lot of self experimentation.  Most scientific studies seem to be a lot of more of the same stuff like IGF2 is key.

Cartilage degeneration and excessive subchondral bone formation in spontaneous osteoarthritis involves altered TGF-β signaling.

The question is:  Can excessive subchondral bone formation make you taller?

Judging from this picture here yes it should.

“Transforming growth factor-β (TGF-β) has been demonstrated as a potential therapeutic target in osteoarthritis. However, beneficial effects of TGF-β supplement and inhibition have both been reported, suggesting characterization of the spatiotemporal distribution of TGF-β during the whole time course of osteoarthritis is important. To investigate the activity of TGF-β in osteoarthritis progression, we collected knee joints from Dunkin-Hartley (DH) guinea pigs at 3, 6, 9, and 12-month old (n = 8), which develop spontaneous osteoarthritis in a manner extraordinarily similar to humans. Via histology and micro-computed tomography (CT) analysis, we found that the joints exhibited gradual cartilage degeneration, subchondral plate sclerosis[a thickening of the subchondral bone where it begins to develop cysts, hardens, and thickens], and elevated bone remodeling during aging. The degenerating cartilage showed a progressive switch of the expression of phosphorylated Smad2/3 to Smad1/5/8, suggesting dual roles of TGF-β/Smad signaling during chondrocyte terminal differentiation in osteoarthritis progression. In subchondral bone, we found that the locations and age-related changes of osterix(+) osteoprogenitors were in parallel with active TGF-β, which implied the excessive osteogenesis may link to the activity of TGF-β. Our study, therefore, suggests an association of cartilage degeneration and excessive bone remodeling with altered TGF-β signaling in osteoarthritis progression of DH guinea pigs.”

“knee osteoarthritis is a disease of the entire joint, including synovitis, meniscal degeneration and malposition, periarticular bone overgrowth{periarticular bone is bone that surrounds the joint overgrowth of this bone should be good for height growth}, and articular cartilage destruction”

” In response to the altered mechanical environment, the bone–cartilage functional unit adjusts the architecture via cells’ adaptations. However, a discrepancy of repair capacity between the chondrocytes and other skeletal cells is thought to further accelerate the progression of osteoarthritis. Furthermore, it is widely appreciated that the subchondral plate and trabecular bone show different responses, where thickening of the plate can be identified along with osteopenic trabeculae at the advanced stage of osteoarthritis”

“ALK5/Smad2/3 route restrains terminal differentiation of chondrocytes, whereas the ALK1/Smad1/5/8 route induces the differentiation. The increase in ALK1/ALK5 ratio in chondrocytes may contribute to the cartilage degeneration.On the other hand, TGF‐β acts as a coupling factor to induce the migration of mesenchymal stem cells (MSCs) to bone resorption sites, implying its potential function in rebalancing bone resorption and formation.  Inhibition of TGF‐β signaling in subchondral bone resulted in higher bone quality and less cartilage degeneration in an induced‐osteoarthritis model”

If you look at figure 3 you can see increased subchondral bone height although it should be noted that these pigs were still growing.

“The tidemark advancement is a result of the pathological endochondral ossification at the calcified zone of cartilage”

“Smad2/3 signaling is essential to repress the hypertrophy of chondrocyte, whereas Smad1/5/8 route, namely bone morphogenetic protein (BMP) pathway, is required for chondrocyte terminal differentiation. Inhibition of the Smad1/5/8 signaling pathway led to reduced or delayed chondrocyte hypertrophy. Increase in ALK1/ALK5 ratio was associated with age and osteoarthritis and dominant ALK1/Smad1/5/8 pathway was found in advanced stage of induced osteoarthritis”

Here’s an interesting Jeffrey Baron paper who’s done a lot of growth research.  Essentially, smaller bones undergo senescence earlier so the chondrocytes undergo less proliferation cycles.

Differential aging of growth plate cartilage underlies differences in bone length and thus helps determine skeletal proportions.

“Bones at different anatomical locations vary dramatically in size. For example, human femurs are 20-fold longer than the phalanges in the fingers and toes. The mechanisms responsible for these size differences are poorly understood. Bone elongation occurs at the growth plates and advances rapidly in early life but then progressively slows due to a developmental program termed “growth plate senescence.”{estrogen may be responsible for this senescence} This developmental program includes declines in cell proliferation and hypertrophy, depletion of cells in all growth plate zones, and extensive underlying changes in the expression of growth-regulating genes. Here, we show evidence that these functional, structural, and molecular senescent changes occur earlier in the growth plates of smaller bones (metacarpals, phalanges) than in the growth plates of larger bones (femurs, tibias) and that this differential aging contributes to the disparities in bone length. We also show evidence that the molecular mechanisms that underlie the differential aging between different bones involve modulation of critical paracrine regulatory pathways, including insulin-like growth factor (Igf), bone morphogenetic protein (Bmp), and Wingless and Int-1 (Wnt) signaling. Taken together, the findings reveal that the striking disparities in the lengths of different bones, which characterize normal mammalian skeletal proportions, is achieved in part by modulating the progression of growth plate senescence.”

<-So if the change in body proportions is a result of senescence shouldn’t the body proportions be different in someone with different senescence such as someone with no estrogen receptors.  We know that body proportions are different in dwarfism.

“. The rate of long bone elongation (length/time) is primarily determined by the rate of chondrocyte proliferation (cells/time) per column multiplied by the cell height (length/cell) achieved after chondrocyte hypertrophy”

“During mammalian embryonic development, all long bones form from mesenchymal condensations of similar size. However, different long bones diverge in growth rate, ultimately leading to dramatic differences in bone length. ”

“the rates of bone elongation at the proximal tibia and the distal femur, measured by calcein labeling, were greater than those of the metacarpal bones and proximal phalanges. Some previous studies have attributed these differences in growth rate between bones to differences in the size attained by the hypertrophic chondrocytes of the growth plate. However, the rate of bone elongation is also dependent on chondrocyte proliferation and is approximated by the height of the terminal hypertrophic chondrocyte in the column multiplied by the chondrocyte proliferation rate per cell column ”

” a chondrocyte near the top of the growth plate in the larger bones would go through more rounds of cell division before slowing and ceasing proliferation compared with the smaller bones.”<-So how do we get chondrocytes to undergo more rounds of cell division?  There are number of factors.    A number of senescence related genes are mentioned in the study itself.  IGF2 is a key one.

“Growth plate senescence is characterized not only by a decline in proliferation rates but also by a gradual structural involution of the growth plate, including declines in the overall height of each growth plate zone and the number of chondrocytes in each zone.”