New Jeffrey Baron study about Growth Plate Regulation

Jeffrey Baron is one of the scientists studying growth plate senescence so his insights could be very helpful in stopping growth plate closure and forming new growth plates.

Recent insights into the regulation of the growth plate.

“Expression in the resting and the proliferative zone was compared to identify pathways involved in the differentiation of resting zone to proliferative zone chondrocytes. This analysis implicated vitamin D receptor / retinoid x receptor (VDR/RXR) activation, platelet-derived growth factor (PDGF) signaling, BMP signaling, and notch signaling. Similar analysis of the proliferative to hypertrophic differentiation step implicated p53 signaling, ephrin receptor signaling, oncostatin M signaling, and BMP signaling”

“evidence for a BMP signaling gradient across the growth plate with the greatest BMP signaling occurring in the hypertrophic zone and the least in the resting zone”<-Maybe this BMP signaling gradient is caused by some other gradient like a pressure gradient.   We know that LSJL induces a gradient so this could be related to LSJL methodology.

“immunolocalization of phosphorylated SMAD-1, – 5, and -8 in the growth plate increases with increasing distance from the epiphysis”

“Low levels of BMP signaling in the resting zone may help maintain the progenitor cell state. Farther from the epiphysis, greater BMP signaling may induce differentiation to proliferative chondrocytes and, even farther from the epiphysis, yet greater BMP signaling may induce terminal differentiation to hypertrophic chondrocytes.”

The BMP gradient described in figure 2 of the study:

Resting Zone: Bmp-3, Gremlin, Chordin

Proliferative Zone:  GDF10, BMP7

Hypertrophic Zone: Bmp2, BMP6

“In the embryonic skeleton, PTHrP is secreted by periarticular chondrocytes of long bones. PTHrP diffuses across the growth cartilage maintaining chondrocytes in the proliferative state. Cells more distant from the source of PTHrP undergo hypertrophic differentiation.”<-LSJL also puts load on the articular cartilage.  Maybe LSJL induces the release of PTHrP.

“The prehypertrophic and hypertrophic chondrocytes then secrete Indian hedgehog (Ihh), which has a negative-feedback effect on PTHrP production and also independent effects on chondrocyte differentiation. More recent evidence suggests that the Ihh–PTHrP system is maintained in postnatal growth plate but the PTHrP source shifts to the resting zone”<-Some more on PTHrP and chondrocyte differentiation.

Genes involved in human growth plate function:

“the IHH-PTHrP system (GLI2, IHH, HHIP, PTCH1, and PTHLH lie within GWAS loci), BMP/TGF superfamily signaling (TGFB2, BMP6, LTBP3, NOG, BMP2, GDF5), C-type natriuretic peptide signaling (NPPC, PRKG2, NPR3), GH-IGF-I signaling (IGF2BP2, IGF2BP3, IGF1R), and FGF signaling (FGF18).”

“At the molecular level, CNP inhibits the extracellular signal-regulated kinase (ERK) and p38 mitogen activated protein kinase (MAPK) pathways, therefore counteracting the growth-inhibitory downstream signaling of fibroblast growth factor (FGF) in the growth plate”

“BNP [which is involved in growth plate regulation] is transcriptionally regulated by the transcription factor SHOX [which also regulates the growth plate]”

“FGFR1 and FGFR3 signaling are growth-inhibiting, while FGFR2 signaling is growth-promoting. Cartilage-specific (Col2a1-Cre) inactivation of Fgfr1 in mice showed a transient increase height in hypertrophic zone, and delayed terminal differentiation of hypertrophic chondrocytes. However, increase in adult body length has not been reported. In contrast, inactivation of Fgfr2 in the mesenchymal condensations (Dermo1-cre), which affects both the osteoblast and chondrocyte lineages, resulted in mice with skeletal dwarfism”

“transgenic mice with activated Fgfr3 in the growth plate show reduced chondrocyte proliferation, decreased numbers of hypertrophic chondrocytes and decreased height of the hypertrophic zone, while Fgfr3 knockout mice showed increased chondrocyte proliferation, increased height of hypertrophic zone, and increased skeletal growth”

“Fgf9 and Fgf18 promote chondrocyte proliferation during early development of the growth plate, but then function to inhibit chondrocyte proliferation and promote hypertrophic differentiation at later stages of development.”

“FGF21 can activate FGFR1 and FGFR3, both of which elicit growth-inhibitory signaling”

“Fgf21 knockout mice showed no significant difference in body weight and body length as compared to wild type mice”<-FGF21 may play a role in fasting induced growth inhibition.  So FGF21 would be a safe target to inhibit for growth.

“GH has no apparent role in fetal growth, despite the presence of its receptor (GHR) in embryos”

“mice lacking both the GH receptor and IGF-I have shorter bones than mice lacking only IGF-I, suggesting that GH, at least at a super-physiologic circulating concentrations, has an IGF-I-independent effect on bone growth”

“GH-induced Socs2-/-  metatarsal bone growth is not accompanied by increase in Igf1 or Igfbp3 transcript levels, and occurred in the presence of an IGF-I receptor inhibitor”

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