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

Cartilage is unique among mesenchymal tissues in that it is resistant to va scular invasion due to an intrinsic angiogenesis inhibitor. Chondromodulin- I (ChM-I), a 25-kilodalton glycoprotein purified from bovine epiphyseal car tilage on the basis of growth-promoting activity for chondrocytes, was rece ntly 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-termi nal part of a larger transmembrane precursor. Expression of ChM-I cDNA in C HO cells indicated that mature ChM-I molecules were secreted from the cells after post-translational modifications and cleavage from the precursor pro tein at the predicted processing site. ChM-I stimulated growth and colony f ormation 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 al low vascular invasion. CIM-T actually inhibited vascular invasion into cart ilage that was ectopically induced by demineralized bone matrix in nude mic e, leading to the suppression of replacement of cartilage by bone in vivo. These results suggest that ChM-I participates in the angiogenic switching o f cartilage, and that the withdrawal of its expression allows capillary ing rowth, which triggers the replacement of cartilage by bone during endochond ral bone development.