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.