Parathyroid hormone related peptide (PTHrP), the bone morphogenetic proteins (BMPs) and Indian hedgehog (IHH) are key regulators of chondrocyte maturation. The role of these agents in regulating chondrocyte maturation will be studied in two complementary cell culture models: 1) embryonic sternal chondrocytes, which are uncommitted and require ascorbate to undergo maturation; and 2) adolescent growth plate chondrocytes, which are committed to rapidly complete the maturation process, but which can be maturationally arrested by PTHrP. The utilization of these cell culture models permits the investigation of the role of BMPs (-2, -4, -6 and -7) and their receptors during the two important stages in endochondral bone formation: 1) the commitment of cells to undergo differentiation; and 2) the regulation and control of chondrocyte maturation in committed cells. Since preliminary results suggest that BMPs may commit cells to differentiation, as well as accelerate maturation, regulation of chondrocyte maturation by the BMPs will be assessed in these cultures. The effect of BMP-2 and BMP-6 on the PTH/PTHrP receptor will be evaluated, as data also show that the BMPs can reverse the suppressive effects of PTHrP on chondrocyte maturation. Possible paracrine interactions between epiphyseal and growth plate chondrocytes will be investigated by defining the expression and regulation of IHH, patched and gli in these chondrocytes. To explore the hypothesis that epiphyseal cells may regulate chondrocyte maturation through paracrine effect mediated by PTHrP, regulation of PTHrP in epiphyseal chondrocytes will be examined. Finally, the hypothesis that epiphyseal chondrocytes inhibit the maturation of growth plate will be tested using chondrocytes in co-culture experiments.
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