Chondromodulin-I as a novel cartilage-specific growth-modulating factor.

Cartilage is unique among mesenchymal tissues in that it is resistant to vascular invasion due to an intrinsic angiogenesis inhibitor. Chondromodulin-I (ChM-I), a 25-kilodalton glycoprotein purified from bovine epiphyseal cartilage on the basis of growth-promoting activity for chondrocytes, was recently identified as an angiogenesis inhibitor. Human ChM-I cDNA revealed that the mature protein consists of 120 amino acids and is coded as the C-terminal part of a larger transmembrane precursor. Expression of ChM-I cDNA in CHO cells indicated that mature ChM-I molecules were secreted from the cells after post-translational modifications and cleavage from the precursor protein at the predicted processing site. ChM-I stimulated growth and colony formation of cultured chondrocytes, but inhibited angiogenesis in vitro and in vivo. In situ hybridization and immunohistochemistry revealed that ChM-I is specifically expressed in the avascular zone of cartilage in developing bone, but not present in the late hypertrophic and calcified zones that allow vascular invasion. ChM-I actually inhibited vascular invasion into cartilage that was ectopically induced by demineralized bone matrix in nude mice, leading to the suppression of replacement of cartilage by bone in vivo. These results suggest that ChM-I participates in the angiogenic switching of cartilage, and that the withdrawal of its expression allows capillary in-growth, which triggers the replacement of cartilage by bone during endochondral bone development.