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

最近的研究表明，刺猬蛋白家族的成员在调节肢体和其他部位的骨骼形成方面发挥了作用。Sonic hedgehog(Shh)是Sonic Hedgehog(Shh)家族的成员之一，被认为是一种形态发生分子，调节肢体前后轴的图案。刺猬家族的另一成员印度刺猬(IHH)被认为是软骨细胞成熟的抑制因子，通过诱导甲状旁腺激素释放酶(PTHrP)间接发挥作用。我们发现，表达Shh的成纤维细胞移植到裸鼠体内可以诱导异位成骨。这一结果提高了骨骼细胞可能对刺猬蛋白的作用做出反应的可能性。在本研究中，我们对这种可能性进行了研究，并进一步探讨了Hedgehog蛋白是否可以用作修复硬组织缺损的药物。结果表明：1.Shh和IHH作用于成骨细胞和软骨细胞并促进其分化；2.Shh(或IHH)和BMP2共同作用协同刺激成骨和软骨细胞分化；3.Shh氨基末端重组蛋白可增强骨形态发生蛋白-2(BMP2)在裸鼠腹股沟肌肉内诱导异位软骨内成骨的能力，提示Hedgehog蛋白可用于修复硬组织缺损。

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.