Application of Hedgehog Proteins as Drugs for Induction of Hard Tissues and Repair of Hard Tissue Defects.

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Recent studies have shown that members of the hedgehog protein family have roles in regulating skeletogenesis in the limb and other sites. A member of the family, Sonic hedgehog (Shh) is indicated to be a morphogenetic molecule regulating patterning along the antero-posterior axis of the limb. Another member of the hedgehog family, Indian hedgehog (Ihh), is suggested to serve as an inhibitor of chondrocyte maturation, acting indirectly by inducing PTHrP. We found that implantation of Shh-expressing fibroblasts in nude mice induces ectopic bone formation. The results raised the possibility that skeletal cells may be responsive to hedgehog protein action. In the present study, we investigated this possibility and further pursuited whether hedgehog proteins may be utilized as drugs for repair of hard tissue defects. We obtained the following results;1.Shh and Ihh acted on osteogenic and chondrogenic cells and stimulated their differentiation.2.Co-exposure of Shh (or Ihh) and BMP2 synergistically stimulated osteogenic and chondrogenic diferentiation.3.Recombinant proteins of the amino-terminal portion of Shh strongly enhanced the ability of bone morphogenetic protein-2 (BMP2) to induce ectopic endochondral ossification, when applied intramuscularly in the inguial region in nude mice.These findings suggest that hedgehog proteins may be used as drugs for repair of hard tissue defects.