Indian hedgehog (Ihh), one of the three mammalian hedgehog (Hh) proteins, coordinates proliferation and differentiation of chondrocytes during endochondral bone

Much of the vertebrate skeleton arises from a cartilage template, which subsequently undergoes endochondral bone formation (Erlebacher et al., 1995; Hinchcliffe and Johnson, 1990). At the earliest stage of this process, mesenchymal cells condense to form a cartilage anlage. Initially, all chondrocytes within the anlage proliferate. Thereafter, cells in the center of this structure exit the cell cycle, undergo hypertrophy, which is a hallmark of terminal differentiation, and eventually die. Concomitantly, a bone collar is formed from the perichondrium surrounding the cartilaginous core. After apoptosis of the hypertrophic chondrocytes, blood vessels invade the cartilage and form the bone marrow cavity; blood vessels are also thought to bring in osteoblasts that produce the endochondral bone. Upon formation of the bone marrow cavity, immature chondrocytes are restricted to the ends of the cartilage that form the growth region, where cells undergo an orderly progression from proliferation to differentiation, which culminates in hypertrophy and to the eventual replacement by bone (Poole, 1991). Thus, the precise coordination between chondrocyte proliferation and differentiation is essential for the proper formation of an endochondral bone. Recent studies have identified several molecules regulating the proliferation and differentiation of chondrocytes. Indian hedgehog (Ihh), one of the three mammalian homologs of the Drosophila Hedgehog (Hh), regulates multiple aspects of endochondral bone formation. Ihh-null mutants (Ihhn/Ihhn) exhibit a severe reduction in skeletal growth, resulting in long bones that are only one-fifth to one-third (varying among different bones) of the normal length at birth (St-Jacques et al., 1999). Chondrocyte differentiation in these mice is profoundly disturbed, as indicated by an initial delay in hypertrophy followed by the rapid apositional hypertrophy throughout the bulk of the cartilage (St-Jacques et al., 1999). This regulation of differentiation by Ihh appears to be mediated indirectly through the regulation of parathyroid hormone related peptide (PTHrP; Pthlh – Mouse Genome Informatics), expressed within the periarticular region (Karp et al., 2000; Lanske et al., 1996; Vortkamp et al., 1996). Furthermore, Ihhn/Ihhn embryos display a 50% reduction in chondrocyte proliferation (St-Jacques et al., 1999), although the precise mechanism for the proliferative role of Ihh is currently unknown. Thus, Ihh signaling controls growth of the skeleton by coordinating chondrocyte proliferation and differentiation. The bone morphogenetic protein (BMP) family of proteins may interact with Ihh signaling to regulate cartilage 5099 Development 128, 5099-5108 (2001) Printed in Great Britain © The Company of Biologists Limited 2001 DEV2774