REGULATION OF RATE OF CARTILAGE DIFFERENTIATION BY INDIAN HEDGEHOG AND PTH-RELATED PROTEIN

Proper regulation of chondrocyte differentiation is necessary for the morphogenesis of skeletal elements, yet little is known about the mole cular regulation of this process, A chicken homolog of Indian hedgehog (Ihh), a member of the conserved Hedgehog family of secreted proteins that is expressed during bone formation, has now been isolated. Ihh h as biological properties similar to those of Sonic hedgehog (Shh), inc luding the ability to regulate the conserved targets Patched (Ptc) and Gli. Ihh is expressed in the prehypertrophic chondrocytes of cartilag e elements, where it regulates the rate of hypertrophic differentiatio n, Misexpression of Ihh prevents proliferating chondrocytes from initi ating the hypertrophic differentiation process, The direct target of I hh signaling is the perichondrium, where Gli and Ptc flank the express ion domain of Ihh, Ihh induces the expression of a second signal, para thyroid hormone-related protein (PTHrP), in the periarticular perichon drium, Analysis of PTHrP (-/-) mutant mice indicated that the PTHrP pr otein signals to its receptor in the prehypertrophic chondrocytes, the reby blocking hypertrophic differentiation, In vitro application of He dgehog or PTHrP protein to normal or PTHrP (-/-) limb explants demonst rated that PTHrP mediates the effects of Ihh through the formation of a negative feedback loop that modulates the rate of chondrocyte differ entiation.