PTHrP and skeletal development.

Parathyroid hormone-related protein (PTHrP) participates in the regulation of endochondral bone development. After the cartilage mold is established in fetal life, perichondrial cells and chondrocytes at the ends of the mold synthesize PTHrP. This ligand then acts on PTH/PTHrP receptors on chondrocytes. As chondrocytes go through a program of proliferation and then further differentiation into post-mitotic, hypertrophic chondrocytes, PTHrP action keeps chondrocytes proliferating and delays their further differentiation. Indian hedgehog (Ihh) is synthesized by chondrocytes that have just stopped proliferating and is required for synthesis of PTHrP. The feedback loop between PTHrP and Ihh serves to regulate the pace of chondrocyte differentiation and the sites at which perichondrial cells first differentiate into osteoblasts. Activation of the PTH/PTHrP receptor leads to stimulation of both Gs and Gq family heterotrimeric G proteins. Genetic analyses demonstrate that Gs activation mediates the action of PTHrP to keep chondrocytes proliferating, while Gq activation opposes this action. Downstream from Gs activation, synthesis of the cyclin-cdk inhibitor, p57, is suppressed, thereby increasing the pool of proliferating chondrocytes. PTHrP's actions to delay chondrocyte differentiation are mediated by the phosphorylation of the transcription factor, SOX9, and by suppression of synthesis of mRNA encoding the transcription factor, Runx2. These pathways and undoubtedly others cooperate to regulate the pace of differentiation of growth plate chondrocytes in response to PTHrP.