Figure 2

Importance of IHH and PTHrP signaling in the modulation of chondrocyte proliferation and differentiation during endochondral bone formation. PTHrP is synthesized by chondrocytes and perichondrial cells in the periarticular growth plate. PTHrP diffuses toward the prehypertrohic zone where it binds to and activates its receptor, the PTHR1, and thereby maintains chondrocyte proliferation and delays chondrocyte differentiation into pre-hypertrophic and hypertrophic chondrocytes. After chondrocytes stop proliferating at the transition from a proliferating into a hypertrophic phenotype, they synthesize IHH. IHH acts to indirectly increase the synthesis of PTHrP. IHH and PTHrP thus participate in a negative feed-back loop that serves to regulate the rate and synchrony of growth plate chondrocytes. Besides increasing PTHrP synthesis, IHH also stimulates, both directly and indirectly, chondrocyte proliferation and inhibits their terminal differentiation. Parathyroid hormone-related protein (PTHrP) Indian Hedgehog (IHH) Parathyroid hormone receptor 1 (PTHR1)