Angiogenesis Inhibitors Localized in Hypovascular Mesenchymal Tissues: Chondromodulin-I and Tenomodulin

Abstract

The majority of mesenchymal tissues obtain their nutrients via a well-developed network of capillaries. Cartilage, however, is normally devoid of capillary networks and, with the exception of endochondral bone formation, is resistant to vascular invasion from surrounding tissues. However, because of its avascular nature, cartilage is widely regarded as an enriched source of endogenous angiogenesis inhibitors, and many previous attempts have been made to identify these factors. We have identified chondromodulin-I (ChM-I) as an angiogenesis inhibitor derived from extracts of fetal epiphyseal cartilage, based upon its growth inhibitory activity in vascular endothelial cells in vitro. In the musculoskeletal system, ChM-I is specifically expressed in the avascular zones of cartilage. Upon functional expression of human ChM-I precursor cDNA, the purified recombinant protein was found to block the growth of solid tumors by inhibiting angiogenesis. Recently, we also cloned a cDNA that encodes a novel type II transmembrane glycoprotein containing a cysteine rich C-terminal domain homologous to ChM-I. We termed this glycoprotein “tenomodulin” (TeM) after tendons that were found to be the predominant expression sites in addition to other dense connective tissues including ligaments and cornea. Subsequently, by employing an adenovirus-mediated expression system, we demonstrated that the ChM-I-like domain of TeM is both antiangiogenic and antitumorigenic. In this article, we summarize the structural characteristics and biological activities of these two antiangiogenic molecules.