Sprout Taller with Platelet-Derived Growth Factor

In our analysis of F-spondin, we found platelet-derived growth factor was one of the compounds affected by F-spondin.  Inhibiting F-spondin increased height by 30%.  So is inhibiting Platelet-derived growth factor the method by which inihibiting F-spondin increases height?  The most likely mechanism so far is that F-spondin acts by inhibiting FGF(specifically FGF-3).  You need a little bit of FGF but not too much and inhibiting F-spondin may provide a limiting factor on FGF growth.  Still, can augmenting your platelet-derived growth factor levels make you sprout taller?

Regulation of chicken ccn2 gene by interaction between RNA cis-element and putative trans-factor during differentiation of chondrocytes.

"CCN2/CTGF[Connective Tissue Growth Factor] is a multifunctional growth factor. CCN2 plays important roles in both growth and differentiation of chondrocytes and that the 3'-untranslated region (3'-UTR) of ccn2 mRNA contains a cis-repressive element of gene expression.  The stability of chicken ccn2 mRNA is regulated in a differentiation stage-dependent manner in chondrocytes. Stimulation by bone morphogenetic protein 2, platelet-derived growth factor, and CCN2 stabilized ccn2 mRNA in proliferating chondrocytes but that it destabilized the mRNA in prehypertrophic-hypertrophic chondrocytes. The minimal repressive cis-element[a DNA regulatory element] of the 3'-UTR of chicken ccn2 mRNA was located within the area between 100 and 150 bases from the polyadenylation tail. The stability of ccn2 mRNA was correlated with the interaction between this cis-element and a putative 40-kDa trans-factor in nuclei and cytoplasm. The binding between them was prominent in proliferating chondrocytes and attenuated in (pre)hypertrophic chondrocytes. Stimulation by the growth factors repressed the binding in proliferating chondrocytes; however, it enhanced it in (pre)hypertrophic chondrocytes. Gene expression of ccn2 mRNA during endochondral ossification is properly regulated, at least in part, by changing the stability of the mRNA, which arises from the interaction between the RNA cis-element and putative trans-factor."

"ccn2-overexpressing transgenic mice presented a dwarfism phenotype and decreased bone density, whereas ccn2-null mice showed skeletal dysmorphisms as a result of impaired chondrocyte proliferation "

So platelet-derived growth factor(and BMP-2) has the potential to decrease height by destablizing DNA in hypertrophic chondrocytes but it's also needed to stimulate chondrocyte proliferation.  So you need an optimal amount of platelet-derived growth factor to achieve your maximum height.

Impaired vascular invasion of Cbfa1-deficient cartilage engrafted in the spleen.

"Cbfal-deficient (Cbfa1-/-)[Cbfa1 is part of the RUNX2 family] mice displayed a complete absence of osteoblast and osteoclast maturation as well as severely inhibited chondrocyte maturation in most parts of the skeleton. Although chondrocyte maturation and mineralization were observed in restricted areas of Cbfa1-/- mouse skeleton, vascular invasion of calcified cartilage was never noted. To investigate the possibility of chondrocyte maturation and vascular invasion in Cbfal-/- cartilage and the role of the hematopoietic system in the process of vascular invasion, we transplanted embryonic day 18.5 (E18.5) Cbfa1-/- femurs, which are composed of immature chondrocytes, into spleens of normal mice. One week later, the transplanted femurs contained terminally differentiated chondrocytes expressing osteopontin, bone sialoprotein (BSP), and matrix metalloproteinase (MMP) 13. In the diaphyses of the transplants, the cartilage matrix was mineralized and the cartilage was invaded by vascular vessels and osteoclasts. However, chondrocyte maturation and vascular invasion were severely retarded in comparison with transplants of E14.5 wild-type femurs, in which the cartilage was rapidly replaced by bone, and neither mature osteoblasts nor bone formation were observed. In primary culture of Cbfa1-/- chondrocytes, transforming growth factor (TGF) beta1, platelet-derived growth factor (PDGF), interleukin (IL)-1beta, and thyroid hormone (T3) induced osteopontin and MMP-13 expression.  The hematopoietic system are able to support vascular invasion of cartilage independent of Cbfal but are less effective without it, suggesting that Cbfal functions in cooperation with factors from bone marrow in the process of growth plate vascularization."

Platelet-derived growth factor enhances MMP-13 expression and growth plate vascularization thus potentially helping form cartilage canals.

Transforming growth factor-beta 1: induction of bone morphogenetic protein genes expression during endochondral bone formation in the baboon, and synergistic interaction with osteogenic protein-1 (BMP-7).

"TGF-betas do not initiate bone formation when implanted in heterotopic (extraskeletal) sites of rodents. Platelet-derived porcine TGF-beta 1 (pTGF-beta 1) induces endochondral bone in heterotopic sites of the baboon (Papio ursinus) at doses of 5 microgram per 100 mg of guanidinium-inactivated collagenous bone matrix as carrier, with an inductive efficiency comparable to 5 and 25 micrograms of recombinant osteogenic protein-1 (hOP-1, BMP-7), a well characterized inducer of bone formation. pTGF-beta 1 and hOP-1 interact synergistically to induce large ossicles in the rectus abdominis of the primate as evaluated by key parameters of bone formation on day 14 and 30. Tissue generated on day 30 by 5 microgram pTGF-beta 1 or 25 micrograms hOP-1 induced comparable expression levels of OP-1, BMP-3 and type IV collagen mRNA transcripts, whereas TGF-beta 1 and type II collagen expression was 2 to 3 fold higher in pTGF-beta 1-treated implants. In ossicles generated by 25 micrograms hOP-1 in combination with relatively low doses of pTGF-beta 1 (0.5, 1.5 and 5 micrograms), type II collagen expression increased in a pTGF-beta 1 dose-dependent manner, whilst type IV collagen was synergistically upregulated with a 3 to 4 fold increase compared to ossicles generated by a single application of 5 micrograms pTGF-beta 1 or 25 micrograms hOP-1. Morphogen combinations (5 micrograms pTGF-beta 1 with 20 micrograms hOP-1, and 5 and 15 micrograms pTGF-beta 1 with 100 micrograms hOP-1 per g of collagenous matrix as carrier) induced exuberant tissue formation and greater amounts of osteoid than hOP-1 alone when implanted in calvarial defects of the baboon as evaluated. on day 30 and 90, with displacement of the temporalis muscle above the defects. Since a single application of TGF-beta 1 in the primate did not induce bone formation in calvarial defects, whilst it induces endochondral bone differentiation in heterotopic sites, the bone inductive activity of TGF-beta 1 is site and tissue specific. mRNA expression of multiple members of the TGF-beta superfamily suggests complex autocrine and paracrine activities of the ligands and different signalling pathways on responding cells during the cascade of endochondral bone formation in the primate."

"specimens of collagenous matrix combined with 1.5 and 5 pg pTGFB1 showed islands of endochondral bone formation as early as day 14, and almost complete ossicles were generated by 5 pg pTGF-Bl on day 30"

"a. bone induction by 1.5 pg pTGF-BI. b, endochondral bone formation by 125 pg hOP-I. c and d, synergistic bone induction by combinations of 25 pg hOP-1 with 1.5 (c) and 5 pg pTGF-fiI (d). Extensive induction of mineralized bone and osteoid, and areas of chondrogenic tissue when using 5 pg pTGF-p1 (d)."

"Tissue morphogenesis and synergistic activity of hOP-l and pTGF-fi1 implanted singly or in combination in the rectus abdominis of the baboon and harvested on day 30. a and b, bone induction by a single administration of 25 bg hOP-l (a) and 5 pg pTGF-BI (b) delivered by 100 pg of guanidinium-inactivated collagenous matrix. c and d, large ossicles generated by 25 pg hOP-l combined with 1.5 (c) and 5 pg pTGF-Bl (d). Areas of chondrogenesis (arrows in c) at the periphery of the newly generated tissue and corticalization of the ossicles"

Platelet derived Transforming Growth Factor Beta has the potential to grow bone anywhere!  This means you can grow new limbs and longer ones at that.  TGF-Beta should be able to grow new cartilage in existing bone as that is not extraskeletal and I think we can see that by LSJL.

Characteristics and regulation of Pi transport in osteogenic cells for bone metabolism.

"Inorganic phosphate (Pi)[Organic Phosphate can be produced by inorganic phosphate and vice versa] is an essential element in the development of osteogenic cells. The translocation of Pi from the systemic to the skeletal extracellular compartment appears to be an important function of osteoblastic cells. The plasma membrane of osteogenic cells is endowed with a sodium-dependent Pi transport system that is regulated by osteotropic factors such as parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP), insulin-like growth factor-1 (IGF-1), platelet-derived growth factor (PDGF) and fluoride. A similar Pi transport system has been recently identified in matrix vesicles derived from the plasma membrane of osteogenic cells, such as epiphyseal chondrocytes or osteoblastic cells. Matrix vesicles are extracellular structures which are considered to play an important role in endochondral and membranous calcification. Pi transport appears to be the driving force responsible for the accumulation of mineral inside the matrix vesicles and thereby can be considered as a pivotal determinant in the induction of the calcification process. Furthermore, modulation of the activity of the Pi transport at the level of the plasma membrane of osteogenic cells by osteotropic factors is transferred to the matrix vesicles derived from these cells. This notion implies that hormonal and other environmental factors, such as Pi itself and calcium, which have a direct impact on the Pi transport activity of osteogenic cells can also influence the capacity of the matrix vesicles to initiate the mineralization of the bone matrix. The cellular mechanisms involved in the regulation of Pi transport by osteotropic factors have been recently investigated. For the PTH/PTHrP regulatory effect, cAMP appears to be the main mediator and the response does not require the de novo synthesis of proteins. For the effects of IGF-1, PDGF and fluoride, tyrosine phosphorylation processes are involved and responses are dependent upon the de novo synthesis of proteins. The molecules responsible for activation of these signaling pathways are currently under investigation. Such an investigation may improve our understanding of the mechanisms underlying the differentiation processes of osteogenesis such as the calcification of the extracellular matrix."

Remember Calcium Phosphate is pretty indistinguishable from Calcium Carbonate aside from that Phosphate group.  Platelet-Derived Growth Factor affects phosphate transport.  Phosphate transport can be the indection of mineralization of the growth plate by mineralizing hypertrophic chondrocytes.  This doesn't have to be a bad thing as more minerals in hypertrophic chondrocytes could determine their final size.  Remember that IGF-1 increases inorganic phosphate transport too...

So platelet-derived factor does help you sprout taller but possibly only in the minimum amounts and inhibition by inhiting F-spondin may increase height as long as you don't inhibit too much.  This is validated by the dwarfism expressed by ccn2 mice.

Thrombopoietic-mesenchymal interaction that may facilitate both endochondral ossification and platelet maturation via CCN2.

"CCN2 plays a central role in the development and growth of mesenchymal tissue and promotes the regeneration of bone and cartilage in vivo. Abundant CCN2 is contained in platelets[More PDGF, more platelets, more CCN2]. In this study, we initially pursued the possible origin of the CCN2 in platelets. First, we examined if the CCN2 in platelets was produced by megakaryocyte progenitors during differentiation. Unexpectedly, neither megakaryocytic CMK cells nor megakaryocytes that had differentiated from human haemopoietic stem cells in culture showed any detectable CCN2 gene expression or protein production. Together with the fact that no appreciable CCN2 was detected in megakaryocytes in vivo, these results suggest that megakaryocytes themselves do not produce CCN2. Next, we suspected that mesenchymal cells situated around megakaryocytes in the bone marrow were stimulated by the latter to produce CCN2, which was then taken up by platelets. To evaluate this hypothesis, we cultured human chondrocytic HCS-2/8 cells with medium conditioned by differentiating megakaryocyte cultures, and then monitored the production of CCN2 by the cells. As suspected, CCN2 production by HCS-2/8 was significantly enhanced by the conditioned medium. We further confirmed that human platelets were able to absorb/uptake exogenous CCN2 in vitro. These findings indicate that megakaryocytes secrete some unknown soluble factor(s) during differentiation, which factor stimulates the mesenchymal cells to produce CCN2 for uptake by the platelets. During bone growth, such thrombopoietic-mesenchymal interaction may contribute to the hypertrophic chondrocyte-specific accumulation of CCN2 that conducts endochondral ossification."

"growth plate chondrocytes facing the bone marrow are known to produce a vast amount of CCN2 in vivo"<-hypertrophic zone.

Natural Height Increase with Creatine

Previously, we read about how inhibiting F-spondin can increase height.  F-spondin increases MMP levels, TGF-Beta levels, FGF, platelet-derived growth factor levels, and hepatic growth factor levels.  One of the members of the TGF-Beta super family is Myostatin(or GDF-8).  TGF-Beta is used to promote differentiation into chondrocytes and osteoblasts(although sometimes Bone Morphogenic Proteins can be used) so it is absolutely needed.  But there are several cellular proliferation inhibiting mechanisms of TGF-Beta including Myostatin.  But since TGF-Beta promotes cellular differentiation so effectively it is superior for us to target the catabolic genes or counteract the catabolic effects(such as taking Astragalus due to effect TGF-Beta has on shortening telomeres).  Creatine may inhibit Myostatin and therefore may be a potent way for natural height increase.  Creatine is readily available: Optimum Nutrition Creatine Powder, 600g

First, let's discuss GASP-1:

Regulation of myostatin in vivo by GASP-1: a novel protein with protease inhibitor and follistatin domains

"Myostatin, a member of the TGF\- superfamily, is a potent and specific negative regulator of skeletal muscle mass. In serum, myostatin circulates as part of a latent complex containing myostatin propeptide and/or follistatin-related gene (FLRG).  GDF-associated serum protein-1 (GASP-1), contains multiple domains associated with protease inhibitory proteins, including a WAP domain, a Kazal domain, two Kunitz domains, and a netrin domain [is associated with endogenous myostatin in normal mouse and human serum]. GASP-1 also contains a domain homologous to the 10-cysteine repeat found in follistatin, a protein that binds and inhibits activin, another member of the TGF\- superfamily. We have cloned mouse GASP-1 and shown that it inhibits the biological activity of mature myostatin, but not activin. Recombinant GASP-1 binds directly not only to mature myostatin, but also to the myostatin propeptide."

Note that Netrin is involved in axonal guidance providing a link between it and F-spondin which modifies axons.  GASP-1 may inhibit Netrin and thereby inhibit commissural axon outgrowth.  Now by inhibiting F-spondin you are also inhibiting commisural axon outgrowth.  Perhaps, commisural outgrowth of motor axons results in growth reduction.

The other effect of GASP-1 is that it inhibits protease.  Protease breaks down peptide bonds that link amino acids together which means that it can break down compounds like Human Growth Hormone(growth hormone is peptide based)!

"Myostatin RNA is produced nearly exclusively in skeletal muscle[so muscular exercise may help bone growth by inhibiting myostatin]. To determine the tissue distribution of GASP-1 mRNA, a 551-bp fragment of GASP-1 was amplified from first-strand cDNA produced from a variety of mouse tissues and staged embryos. GASP-1 appears to be fairly widely expressed, with particularly high expression in skeletal muscle and heart. Significant expression is also seen in brain, lung, and testis. In contrast, liver and kidney express relatively low levels of GASP-1 mRNA. Developmentally, the level of GASP-1 mRNA remains fairly constant, perhaps increasing slightly between d 7 and d 11 of mouse embryogenesis[GASP-1 doesn't seem to be expressed(or at least not as much to mention) in bone, thus again muscular exercise may be needed to stimulate the effects of GASP-1, and the muscular production of GASP-1 may be stimulatory on bone]."

So, muscular exercise has stimulatory effects on height increase by inhibiting myostatin and stimulatory effects on GASP-1 which could be a negative feedback mechanism on HGH by degrading peptide bonds.

"GASP-1 inhibited the activity of BMP-11"<-BMP-11 is very similar to Myostatin genetically but BMP-11 seems to be more necessary than Myostatin.  In the study, they managed to inhibit Myostatin exclusively with the IC50 domain but it's unclear whether collateral inhibition of BMP-11 by GASP-1 will be detrimental and whether development will be fine with reduced but not inhibited levels of BMP-11.

Effects of oral creatine and resistance training on serum myostatin and GASP-1

"[We] determine the effect of resistance training for 8 weeks in conjunction with creatine supplementation on muscle strength, lean body mass, and serum levels of myostatin and growth and differentiation factor-associated serum protein-1 (GASP-1). In a double-blinded design 27 healthy male subjects (23.42 ± 2.2 years) were assigned to control (CON), resistance training + placebo (RT + PL) and resistance training + creatine supplementation (RT + CR) groups. The protocol consisted of 3 days per week of training for 8 weeks, each session including three sets of 8–10 repetitions at 60–70% of 1 RM for whole-body exercise. Blood sampling, muscular strength testing and body composition analysis (full body DEXA) were performed at 0, 4th and 8th weeks. Myostatin and GASP-1 was measured. Resistance training caused significant decrease in serum levels of myostatin and increase in that of GASP-1. Creatine supplementation in conjunction with resistance training lead to greater decreases in serum myostatin, but had no additional effect on GASP-1. The effects of resistance training on serum levels of myostatin and GASP-1, may explain the increased muscle mass that is amplified by creatine supplementation."

Creatine can make you taller by inhibiting myostatin.  Exercise can make you taller by inhibiting myostatin and increasing serum levels of GASP-1 which in turn inhibits Myostatin further.  GASP-1 can also prevent the breakdown of anabolic hormones like HGH.  Lower serum levels of myostatin means lower levels of myostatin for the growth plate.  Creatine also may be superior to exercise as GASP-1 additionally inhibits BMP-11 which is needed for proper development.

Activin IIRB is expressed in chondrocytes and the periosteum. "Myostatin mediates its actions through binding to activin IIb receptors"<-So again myostatin has an effect on bone but the main inhibitory factors on myostatin occur with muscle.

"Subjects assigned to the RT + CR group received creatine monohydrate in capsule form (Gensan Abiogen Pharama; Italy) at a dose 0.3 g kg−1 day−1 (divided into three equal doses) for the 1st week (loading period) and 0.05 g kg−1 day−1 (once daily) for the remaining 7 weeks. This supplementation protocol was anticipated to increase muscle creatine levels by 14–28%"<-The dosages used.  Creatine inhibits myostatin production of the muscle which has effects on all cell types.

Creatine and Resistance training combined decreased serum levels of Myostatin by about 1/6th(120ng/ml to 100 ng/ml) over 8 weeks.  Resistance Training on it's own increased levels of GASP-1 more than Resistance Training plus creatine.  Thus, Creatine helped selectively inhibit Myostatin while avoiding GASP-1 induced inhibition of BMP-11.

Creatine would seem to be optimized for height increase during development and during a height increase program like LSJL.

Child Height Increase by inhibiting F-spondin

Previously, in the article on Alkaline Phosphatase we found that F-spondin antibodies increased height of rats by about 30%.  Now it's important to note that this was in organ cultures and not in a body where negative feedback mechanisms are present.  But 30% is huge.  A 30% increase on 69 inches(5'9") results in a height of about 90(7'6") inches.  What are the mechanisms in which F-spondin works and how can he inhibit F-spondin?

Plasmin-mediated release of the guidance molecule F-spondin from the extracellular matrix.

"Serine proteases are implicated in a variety of processes during neurogenesis, including cell migration, axon outgrowth, and synapse elimination. Tissue-type plasminogen activator and urokinase-type activator are expressed in the floor plate during embryonic development. F-spondin, a gene also expressed in the floor plate, encodes a secreted, extracellular matrix-attached protein that promotes outgrowth of commissural axons and inhibits outgrowth of motor axons[inhibit outgrowh of commissural axon and promote outgrowth of motor axons to grow taller?]. F-spondin is processed in vivo to yield an amino half protein that contains regions of homology to reelin and mindin, and a carboxyl half protein that contains either six or four thrombospondin type I repeats (TSRs). Plasmin cleaves F-spondin at its carboxyl terminus[inhibit plasmin to grow taller?]. By using nested deletion proteins and mutating potential plasmin cleavage sites, we have identified two cleavage sites, the first between the fifth and sixth TSRs, and the second at the fifth TSR. Analysis of the extracellular matrix (ECM) attachment properties of the TSRs revealed that the fifth and sixth TSRs bind to the ECM, but repeats 1-4 do not. Two basic motives are required to elicit binding of TSR module to the ECM. Plasmin releases the ECM-bound F-spondin protein."

Inhibiting motor axon growth and inhibiting plasmin may be a way to increase height in children.

"Metalloproteases, transforming growth factor-β, vascular endothelial growth factor, fibroblast growth factor, platelet-derived growth factor, and hepatic growth factor/scatter factor are produced as matrix-attached latent proteins, subjected to cleavage and subsequently to activation by plasmin" 

This us a clue that one of these factors inhibit growth.  We have metalloproteases, TGF-Beta(which is needed), VEGF(Released by Estrogen which gives the estrogen theory some weight), FGF, platelet-derived growth factor, and hepatic growth factor.  We also have plasmin inhibition as a way to increase height.

Here's a patent related to F-spondin by Steven B. Abramson. 

REGULATION OF CHONDROCYTES BY EXTRACELLULAR MATRIX PROTEIN.

"F-spondin is a member of a family of proteins that collectively belong to a subgroup of TSR (thrombospondin) type I class molecules. F-spondin expression is significantly increased in osteoarthritic cartilage as well as in rodent meniscectomy models of OA. F-spondin has significant effects on human chondrocyte metabolism and is also expressed in the hypertrophic regions of embryonic growth plates where it acts to regulate mineralization and endochondral bone formation. F-spondin [may modulate] collagen degradation via unrecognized pathways that include activation of TGF-Beta and induction of MMPs and F-spondin [may induce] hypertrophic differentiation of articular chondrocytes and plays an essential role in the regulation of mineralization and endochondral bone formation. [We will] identify MMPs induced by F- spondin and examine their role in F-spondin-mediated collagen degradation[thus we can find which MMPs inhibit height growth], establish the role of TGF-Beta in modulation of F-spondin functions and compare functional activity of the full length F-spondin molecule relative to its proteolytic fragments. We will identify and characterize the interacting proteins of F-spondin:  investigate the interaction of F-spondin with the Latency-associated peptide (LAP) of the latent TGF-Beta complex and identify novel F- spondin binding proteins (proteases, receptors, matrix molecules) that may regulate its activity in articular cartilage. We will investigate F-spondin expression in cartilage in vivo iduring endochondral bone development. We will generate an F-spondin knockout mouse and characterize the changes in cartilage phenotype during endochondral bone development."

Cure Dwarfism with Alkaline Phosphatase Research

Previously, we discussed some methods that may govern cellular senescence and in turn growth plate senescence including DNA Methylation and telomere length.  Endochondral ossification stops as a result of cellular senescence in the growth plate.  DNA Methylation and telomere length may regulate senescence in the stem cells but alkaline phosphatase may determine the terminal chondrogenic differentiation in growth plate chondrocytes.  Studying growth plate alkaline phosphatase activity may be a key in curing dwarfism and in increasing height in normal individuals.

F-spondin regulates chondrocyte terminal differentiation and endochondral bone formation. 

"F-spondin [is] an extracellular matrix protein of osteoarthritic cartilage [expressed] during chondrocyte maturation in embryonic growth plate cartilage. In chick tibia, F-spondin expression localized to the hypertrophic and calcified zones of the growth plate. F-spondin inhibited (∼35%), and antibodies to F-spondin increased (∼30%) longitudinal limb growth relative to untreated controls[inhibiting F-spondin will increase your height].  Induction of chondrocyte maturation, by retinoic acid (RA) or transforming growth factor (TGF)-β treatment led to a significant upregulation of F-spondin. F-spondin transfection increased mineral deposition, alkaline phosphatase (AP) and matrix metalloproteinase (MMP)-13 mRNA levels), and AP activity following RA stimulation, compared to mock transfected controls. Using AP as a differentiation marker we then investigated the mechanism of F-spondin promaturation effects. Blocking endogenous F-spondin via its thrombospondin[we've linked thrombospondin to height increase before] (TSR) domain inhibited RA induced AP activity 40% compared to controls. The stimulatory effect of F-spondin on AP expression was also inhibited following depletion of TGF-β from culture supernatants. Our findings indicate that F-spondin is expressed in embryonic cartilage, where it has the capacity to enhance chondrocyte terminal differentiation and mineralization via interactions in its TSR domain and TGF-β dependent pathways." 

F-spondin increases Alkaline Phosphatase activity in growth plate chondrocytes and encourages them to differentiate into bone cells.  Inhibiting F-spondin can make you taller. 

"F-spondin treatment was found to increase both type II collagen degradation and MMP-13 secretion"

"inhibition of F-spondin by antibody treatment caused a reduction in the number of hypertrophic chondrocytes"

"in the presence of RA, F-spondin enhances terminal differentiation and mineralization, but not induction of hypertrophy, of chick sternal chondrocytes"<-So F-spondin only has negative effects with Retonoic Acid?

"F-spondin [inhibitor] treated limbs revealed increased numbers of hypertrophic chondrocytes in the growth plate cartilage adjacent to the mineralized core"<-F-spondin reduces the number of hypertrophic chondrocytes.

"F-spondin mRNA levels, along with MMP13, were highest within the calcified region. "

"addition of F-spondin to cartilage explant cultures was found to increase active TGF-β levels in culture supernatants and regulate synthetic activity."<-This is something we'd expect to increase height not decrease height. However, "Late hypertrophic chondrocytes produce more TGF-β than early hypertrophic chondrocytes and the percentage of TGF-β that is activated increases as the chondrocyte nears terminal differentiation."  So the greater amount of TGF-Beta can be due to more terminal differentiating chondrocytes than F-spondin upregulating TGF-Beta.

"treatment of embryonic chick chondrocytes with TGF-β2 for 24 h in a serum-free alginate culture system led to dose dependent increases in expression of hypertrophic markers AP (~1.3- to 4.3-fold) and MMP-13 (~3.5- to 30-fold), as well as F-spondin (~2.4 to 5-fold)"

"Addition of exogenous recombinant TGF-β increases the expression of MMP-13 and AP as well as F-spondin. Thus, late-stage hypertrophic chondrocytes may respond to activated TGF-β by further progression toward terminal differentiation. F-spondin is part of a positive feedback loop that accelerates this process, ensuring terminal differentiation of hypertrophic chondrocytes and subsequent endochondral ossification via induction of MMP-13 and further activation of TGF-β"<-so inhibiting F-spondin will knock out the positive feedback loop that causes terminal differentiation.

Since only alkaline phosphatase and MMP13 were monitored it's possibly that other genes affected by F-spondin are the ones mediating the height decreasing effect.

The role of pyrophosphate/phosphate homeostasis in terminal differentiation and apoptosis of growth plate chondrocytes. 

"Extracellular inorganic phosphate (P(i)) concentrations are the highest in the growth plate just before the onset of mineralization. P(i) not only is required for hydroxyapatite mineral formation but also modulates terminal differentiation and apoptosis of growth plate chondrocytes. Extracellular P(i) stimulated terminal differentiation marker gene expression, including the progressive ankylosis gene (ank), alkaline phosphatase (APase), matrix metalloproteinase-13 (MMP-13), osteocalcin, and runx2, mineralization, and apoptosis of growth plate chondrocytes. The stimulatory effect of extracellular P(i) on terminal differentiation and apoptosis events of growth plate chondrocytes was dependent on the concentration, the expression levels of type III Na(+)/P(i) cotransporters, and ultimately P(i) uptake. A high extracellular P(i) concentration was required for the stimulation of apoptosis, whereas lower P(i) concentrations were required for the most effective stimulation of terminal differentiation events, including terminal differentiation marker gene expression and mineralization. Suppression of Pit-1 was sufficient to inhibit the stimulatory effects of extracellular P(i) on terminal differentiation events. On the other hand, increasing the local extracellular P(i) concentration by overexpressing ANK, a protein transporting intracellular PP(i) to the extracellular milieu where it is hydrolyzed to P(i) in the presence of APase, resulted in marked increases of hypertrophic and early terminal differentiation marker mRNA levels, including APase, runx2 and type X collagen, and slight increase of MMP-13 mRNA levels, but decreased osteocalcin mRNA level, a late terminal differentiation markers. In the presence of levamisole, a specific APase inhibitor to prevent hydrolysis of extracellular PP(i) to P(i), ANK overexpression of growth plate chondrocytes resulted in decreased mRNA levels of hypertrophic and terminal differentiation markers but increased MMP-13 mRNA levels. In conclusion, with extracellular PP(i) inhibiting and extracellular P(i) stimulating hypertrophic and terminal differentiation events, a precise regulation of PP(i)/P(i) homeostasis is required for the spatial and temporal control of terminal differentiation events of growth plate chondrocytes." 

"APase, hydrolyzes extracellular PPi into Pi. Extracellular PPi concentrations in the growth plate are mainly regulated by two proteins, the phosphodiesterase nucleotide pyrophosphatase family isoenzyme plasma cell membrane glycoprotein-1 (PC-1) and the progressive ankylosis protein (ANK). PC-1 is an enzyme that hydrolyzes extracellular adenosine triphosphate, thereby producing PPi. ANK is a transmembrane protein that transports intracellular PPi to the extracellular milieu. Extracellular Pi–induced effects on skeletal tissue cells and other cells are dependent on Pi entry into cells."

"The primary mechanism for extracellular Pi entry through the cell membrane is via a family of Na+-dependent Pi transporters."<-NPT3 for growth plate chondrocytes.  So this is another means to how sodium transporters can influence height.

"increasing concentrations of extracellular Pi resulted in further decreases in the mRNA levels of type II and X collagen with 8mM Pi being the most effective in decreasing mRNA levels of type II and X collagen"<-evidence shows that type II collagen is good for height so increasing concentrations of extracellular Pi may be bad for height.

"PFA treatment[a sodium-potassium co-transporter] resulted in decreased mRNA levels of APase, MMP-13, osteocalcin, and runx2 compared to the mRNA levels of these genes in growth plate chondrocytes treated with various concentrations of extracellular Pi in the absence of PFA, whereas mRNA levels of type II and X collagen increased"

"Extracellular Pi concentrations in the growth plate increase when growth plate chondrocytes undergo hypertrophic differentiation and reach the highest levels just before mineralization of the extracellular matrix starts"<-So lowering these levels by exogenous means may keep growth plate chondrocytes from terminal differentiation longer and thus keep you growing taller longer.

So reducing extracellular inorganic phosphate may be a means of growing taller in active growth plates.

24R,25-Dihydroxyvitamin D3, lysophosphatidic acid, and p53: a signaling axis in the inhibition of phosphate-induced chondrocyte apoptosis., states

Like with Estrogen, an optimal amount of phosphate levels in the growth plate is required.  Levamisole is an Alkaline Phosphatase inhibitor and may be worth investigating.  Teriparatide may be the best solution... 

Parathyroid hormone 1-34[Teriparatide] inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats.

"Parathyroid hormone 1-34 (PTH[1-34]), a parathyroid hormone analog, shares the same receptor, PTH receptor 1, with parathyroid hormone-related peptide (PTHrP). This study was undertaken to address the hypothesis that PTH(1-34) inhibits terminal differentiation of articular chondrocytes and in turn suppresses the progression of osteoarthritis (OA).
METHODS: We studied the effect of PTH(1-34) on human articular chondrocytes with azacytidine (azaC)-induced terminal differentiation in vitro and on papain-induced OA in the knee joints of rats. In the in vitro study, we measured the levels of messenger RNA for SOX9, aggrecan, type II collagen, type X collagen, alkaline phosphatase (AP), Indian hedgehog (IHH), Bcl-2, and Bax by real-time polymerase chain reaction, levels of glycosaminoglycan (GAG) by dimethylmethylene blue assay, and rate of apoptosis by TUNEL staining. In the in vivo study, we evaluated the histologic changes in GAG, type II collagen, type X collagen, and chondrocyte apoptosis in the articular cartilage of rat knees.
RESULTS: AzaC induced terminal differentiation of human chondrocytes, including down-regulation of aggrecan, type II collagen, and GAG and up-regulation of type X collagen, alkaline phosphatase, and IHH. Apoptosis was reversed by 3-10 days of treatment with 10 nM PTH(1-34). SOX9 expression was not changed by either azaC or PTH(1-34) treatment. Bcl-2 and Bax were up-regulated on day 10 and day 14, respectively, after azaC induction of terminal differentiation, but PTH(1-34) treatment did not reverse this effect. Furthermore, PTH(1-34) treatment reversed papain-induced OA changes (decreasing GAG and type II collagen, and increasing type X collagen and chondrocyte apoptosis) in the knee joints of rats.
CONCLUSION: Our findings indicate that PTH(1-34) inhibits the terminal differentiation of human articular chondrocytes in vitro and inhibits progression of OA in rats in vivo, and may be used to treat OA."

However:

"In this study, we also found that PTH(1–34) treatment of human articular chondrocytes without azaC induction of terminal differentiation and of rat knee joints without OA did not significantly alter the expression of type II collagen, type X collagen, AP, aggrecan, or GAG in articular chondrocytes. This finding suggests that PTH(1–34) may not affect chondrocyte functions in healthy joints. No significant difference in the tested markers was found in the contralateral control knees between the OA and OA plus PTH groups, indicating that PTH(1–34) may have an effect on articular cartilage locally, and only on OA-affected cartilage."

So, perhaps Teriparatide may not increase growth in normal growth plates.

MSX2 stimulates chondrocyte maturation by controlling Ihh expression. 

"A homeobox gene, Msx2, is implicated in regulation of skeletal development by controlling enchondral ossification as well as membranous ossification. We examined the role of Msx2 in chondrocyte differentiation using mouse primary chondrocytes and embryonic metatarsal explants. Treatment with BMP2 up-regulated the expression of Msx2 mRNA along with chondrocyte differentiation in murine primary chondrocytes. Overexpression of wild-type Msx2 stimulated calcification of primary chondrocytes in the presence of BMP2. We also found that constitutively active Msx2 (caMsx2) enhanced BMP2-dependent calcification more efficiently than wild-type Msx2. Consistently, caMsx2 overexpression up-regulated the expression of alkaline phosphatase and collagen type X induced by BMP2. Furthermore, organ culture experiments using mouse embryonic metatarsals indicated that caMsx2 clearly stimulated the maturation of chondrocytes into the prehypertrophic and hypertrophic stages in the presence of BMP2. In contrast, knockdown of Msx2 inhibited maturation of primary chondrocytes. The stimulatory effect of Msx2 on chondrocyte maturation was enhanced by overexpression of Smad1 and Smad4 but inhibited by Smad6, an inhibitory Smad for BMP2 signaling. These data suggest that Msx2 requires BMP2/Smad signaling for its chondrogenic action. In addition, caMsx2 overexpression induced Ihh (Indian hedgehog) expression in mouse primary chondrocytes. Importantly, treatment with cyclopamine, a specific inhibitor for hedgehogs, blocked Msx2-induced chondrogenesis. Msx2 promotes the maturation of chondrocytes, at least in part, through up-regulating Ihh expression." 

Too much BMP-2 is bad and results in premature ossification of growth plate chondrocytes. But BMP-2 is necessary for chondrocyte hypertrophy and for normal growth. 

Collagen/annexin V interactions regulate chondrocyte mineralization. 

"Physiological mineralization in growth plate cartilage is restricted to terminally differentiated chondrocytes. Types II and X collagen interacted with cell surface-expressed annexin V. These interactions led to a stimulation of annexin V-mediated Ca(2+) influx resulting in an increased intracellular Ca(2+) concentration, [Ca(2+)](i), and ultimately increased alkaline phosphatase activity and mineralization of growth plate chondrocytes. Consequently, stimulation of these interactions (ascorbate to stimulate collagen synthesis, culturing cells on type II collagen-coated dishes, or overexpression of full-length annexin V) resulted in increase of [Ca(2+)](i), alkaline phosphatase activity, and mineralization of growth plate chondrocytes, whereas inhibition of these interactions (3,4-dehydro-l-proline to inhibit collagen secretion, K-201, a specific annexin channel blocker, overexpression of N terminus-deleted mutant annexin V that does not bind to type II collagen and shows reduced Ca(2+) channel activities) decreased [Ca(2+)](i), alkaline phosphatase activity, and mineralization. In conclusion, the interactions between collagen and annexin V regulate mineralization of growth plate cartilage. Because annexin V is up-regulated during pathological mineralization events of articular cartilage, it is possible that these interactions also regulate pathological mineralization."

Now, just because mineralization is enhanced doesn't mean growth is reduced.  The only study that showed an increase in growth was inhibiting F-spondin.  Therefore, the best tool for height increase and curing conditions such as dwarfism is to research these F-spondin inhibitors and antibodies.

Here's a study linking Alkaline Phosphatase to c-Fos.  LSJL upregulates c-Fos as well.

The function of heterodimeric AP-1 comprised of c-Jun and c-Fos in activin mediated Spemann organizer gene expression.

"Overexpression of heterodimeric AP-1 comprised of c-jun and c-fos (AP-1(c-Jun/c-Fos)) induces the expression of BMP-antagonizing organizer genes (noggin, chordin and goosecoid) that were normally expressed by high dose of activin[BMP-2 is good for height growth, however LSJL does not upregulate c-Jun]. AP-1(c-Jun/c-Fos) enhanced the promoter activities of organizer genes but reduced that of PV.1, a BMP4-response gene[BMP-4 is an inducer of chondrogenesis]. A loss of function study clearly demonstrated that AP-1(c-Jun/c-Fos) is required for the activin-induced organizer and neural gene expression. Moreover, physical interaction of AP-1(c-Jun/c-Fos) and Smad3 cooperatively enhanced the transcriptional activity of goosecoid via direct binding on this promoter. Interestingly, Smad3 mutants at c-Jun binding site failed in regulation of organizer genes, indicating that these physical interactions are specifically necessary for the expression of organizer genes.
AP-1(c-Jun/c-Fos) plays a specific role in organizer gene expression in downstream of activin signal during early [an amphibian organism] embryogenesis."

" functional cooperatives of between Smad3 and AP-1 in TGFβ signaling and a crucial role of Smad3 in the regulation of chordin"

"Smad3 significantly induced AP-1 activity"