ADAMTS-5 Inhibition is Required for Potent Inhibition of Aggrecan Degradation in IL-1 Stimulated Bovine Cartilage Explant Culture

Introduction: Osteoarthritis (OA) is a complex disease that is mainly characterized by degradation of articular cartilage with an imbalance of the anabolic and catabolic pathways resulting in an increase of proteolysis of aggrecan and collagen [1]. Aggrecan, a highly glycosylated protein, is a major component of articular cartilage that provides impact absorption and load bearing abilities. In osteoarthritis, aggrecan loss is thought to be primarily mediated by the action of ADAMTS-4 (aggrecanase-1) and ADAMTS-5 (aggrecanase-2), metalloproteinases in the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family. Murine knockout studies indicate that deletion of the ADAMTS-5 gene, not the ADAMTS-4 gene, significantly protects mouse cartilage from degradation in two models of joint disease [2, 3]. However, questions remain regarding the relative importance of these enzymes in human disease, and spontaneous or induced osteoarthritis in other species. A very common in vitro model of cartilage degradation involves exposure of bovine articular cartilage explants to inflammatory cytokines that results in marked induction of aggrecanase activity and release of degraded extracellular matrix aggrecan. Similar to the questions in human osteoarthritis, the relative contribution of ADAMTS-4 and ADAMTS-5 is not clear in this in vitro system. Identification of highly selective aggrecanase inhibitors and their use in in vivo and in vitro systems would elucidate the relative contributions of these enzymes to cartilage breakdown. This study compares the ability of selective aggrecanase inhibitors, with differing ADAMTS-4 and ADAMTS-5 inhibitory activities, to inhibit release of aggrecan into culture media from IL-1∝ –stimulated bovine cartilage explants.