Monday, May 7, 2012

Being taller by inhibiting Pax3?

Interplay of nkx3.2, sox9 and pax3 regulates chondrogenic differentiation of muscle progenitor cells.

"Muscle satellite cells make up a stem cell population that is capable of differentiating into myocytes and contributing to muscle regeneration upon injury. Muscle progenitor cells [can] adopt the cartilage [cell] fate. Chick muscle satellite cells that normally would undergo myogenesis can be converted to express cartilage matrix proteins in vitro when cultured in chondrogenic medium containing TGFß3 or BMP2. In the meantime, the myogenic program is repressed, suggesting that muscle satellite cells have undergone chondrogenic differentiation. ectopic expression of the myogenic factor Pax3 prevents chondrogenesis in these cells[so inhibiting Pax3 may be a way to grow taller], while chondrogenic factors Nkx3.2 and Sox9 act downstream of TGFß or BMP2 to promote this cell fate transition[so inducing TGFBeta and BMP2 may automatically induce Nkx3.2 and Sox9]. Nkx3.2 and Sox9 repress the activity of the Pax3 promoter and that Nkx3.2 acts as a transcriptional repressor in this process. Importantly, a reverse function mutant of Nkx3.2 blocks the ability of Sox9 to both inhibit myogenesis and induce chondrogenesis, suggesting that Nkx3.2 is required for Sox9 to promote chondrogenic differentiation in satellite cells. In an in vivo mouse model of fracture healing where muscle progenitor cells were lineage-traced, Nkx3.2 and Sox9 are significantly upregulated while Pax3 is significantly downregulated in the muscle progenitor cells that give rise to chondrocytes during fracture repair.  The balance of Pax3, Nkx3.2 and Sox9 may act as a molecular switch during the chondrogenic differentiation of muscle progenitor cells."

Thus inhibiting Pax3 expression in the epiphyseal bone marrow may be a potential way to help induce chondrogenesis.

"L6 myoblasts and C2C12 myoblasts were reported to differentiate into chondrocytes when treated with demineralized bone matrix or BMP2"

"Nkx3.2 strongly inhibits the adoption of muscle cell fate while Sox9 only weakly inhibits myogenesis in satellite cells. A reverse function mutant of Nkx3.2 blocks the activity of Sox9, suggesting that Nkx3.2 is required for Sox9 to promote cartilage formation in satellite cells."

"Cells that are positive for Tie-2, an endothelial cell marker, contribute to cartilage and bone formation during heterotopic ossification"

"Sox9 [is] expressed in satellite cells" but at lower levels than in chondrocytes.
LSJL inhibits Pax7a and upregulates Pax1.  Although there is no evidence that Pax7a plays a role in the inhibiting of chondrogenesis like Pax3.  Pax7a can combine with Pax3 so there is evidence of an interaction.

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