Arthritis is characterized by the breakdown of extracellular matrix compounds and subsequent loss of articular cartilage. Cartilage oligomeric matrix protein (COMP), a noncollagenous matrix component whose prominent degradative fragments have been observed in patients with osteoarthritis and rheumatoid arthritis, shows great promise as a biological marker of cartilage metabolism in arthritis. The molecular mechanism of COMP degradation and the enzyme(s) responsible, however, remain unknown. The applicant's recent finding that COMP binds to the newly identified zinc-metalloproteinase ADAMTS-7B (ADAMTS: a disintegrin and wetalloprotease with rtirombospondin motifs) provides a foundation for our central hypothesis that ADAMTS-7B is the physiological enzyme responsible for endogenous COMP degradation in arthritis.
The specific aims of the study proposed to test this hypothesis are (1) to clone and characterize human ADAMTS-7B; (2) to characterize the mechanism by which ADAMTS-7B cleaves COMP; and (3) to identify and characterize the naturally occurring inhibitors of ADAMTS-7B. The proposed study will extend our understanding of the degradative events that occur in patients with arthritic disorders and may provide us with inhibitors designed to serve as therapeutics for the treatment of arthritis. ? ? ? ?
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