Actions of hedgehog proteins on skeletal cells

Recent advances in developmental and molecular biology during embryogenesis and organogenesis have provided new insights into the mechanism of bone fo rmation. Members of the hedgehog gene family were initially characterized a s patterning factors in embryonic development, but recently they have been shown to regulate skeletal formation in vertebrates. The amino terminal Fra gment of Sonic hedgehog (Shh-N), which is an active domain of Shh, has the ability to induce ectopic cartilage and bone formation in vivo. Shh-N stimu lates chondrogenic differentiation in cultures of chondrogenic cell line ce lls in vitro and inhibits chondrogenesis in primary limb bud cells. These f indings suggest that the regulation of chondrogenesis by hedgehog proteins depends on the cell populations being studied. Indian hedgehog (Ihh) is pro minently expressed in developing cartilage. Ectopic expression of Ihh decre ases type X collagen expression and induces the up-regulation of parathyroi d hormone-related peptide (PTHrp) gene expression in perichondrium cells. A negative feedback loop consisting of Ihh and PTHrp, induced by Ihh. appear s to regulate the rate of chondrocyte maturation. The direct actions of Shh and Ihh on stimulation of osteoblast differentiation are evidenced by the findings that these factors stimulate alkaline phosphatase activity in cult ures of pluripotent mesenchymal cell line cells and osteoblastic cells and that these cells express putative receptors of hedgehog proteins. In conclu sion, hedgehog proteins seem to be significantly involved in skeletal forma tion through multiple actions on chondrogenic mesenchymal cells, chondrocyt es, and osteogenic cells.