Osteoarthritis (OA) is a degenerative joint disease that occurs primarily in older persons and is characterized by erosion of the articular cartilage and breakdown of extracellular matrix. Cartilage oligomeric matrix protein (COMP), a noncollagenous matrix component whose prominent degradative fragments have been observed in arthritic patients, shows great promise as a biological marker of cartilage metabolism. The molecular mechanism of COMP degradation and the enzyme(s) responsible for it, however, remain largely unknown. Recent work in our laboratory using a functional genetic screen identified the zinc-metalloproteinase ADAMTS- 7 (ADAMTS: a disintegrin and metalloproteinase with thrombospondin motifs) as the first COMP-binding enzyme. Subsequent sequence and structure analyses revealed that ADAMTS-12 has a domain organization similar to that of ADAMTS-7 and that the two enzymes form a subgroup with unique properties within the ADAMTS family. These findings, along with the fact that ADAMTS-12, and not ADAMTS-7, is significantly upregulated in the OA cartilage, provide a foundation for our hypothesis that ADAMTS-12 is the major physiological enzyme responsible for COMP degradation in OA. The specific aims of the proposed study are (1) to characterize the degradation of COMP by ADAMTS-12 and to identify its cleavage sites; and (2) to identify and characterize the naturally occurring inhibitors of ADAMTS-12. The proposed research will provide new information towards understanding the molecular mechanism of cartilage catabolism, and thusly, aid in the development of novel treatment regimes for the management of OA by directly applying inhibitors of ADAMTS-12 or its analogs. [unreadable] [unreadable] [unreadable]