Timp-3 Inhibits Proteoglycan Loss and Collagen Cleavage Induced by Il-1 and Injury

INTRODUCTION Traumatic injury to cartilage is often associated with acutely elevated levels of pro-inflammatory cytokines, such as interleukin-1 (IL-1), that promote the accumulation and activation of degradative enzymes, including collagenases (MMP-1, MMP-13) and aggrecanases (ADAMTS-4, ADAMTS-5) in the synovial joint [1]. These enzymes prompt degradation of major extracellular matrix components, which leads to the initiation and progression of osteoarthritis [2]. The activation of aggrecanases is effectively regulated by an endogenous inhibitor, called tissue inhibitor of metalloproteinases 3 (TIMP-3) [3]. Recent studies show that TIMP-3 can also bind to collagenases with undefined affinity [4]. However, the role of TIMP-3 in prevention of cartilage degradation remains unclear. In this study, we hypothesize that TIMP-3 would prevent proteoglycan loss and collagen degradation induced by IL-1 and post-traumatic injury. The specific aims of this study were to determine the efficacy of the ability of TIMP-3 to inhibit MMP-1 and MMP-13, and to determine the efficacy of TIMP-3 on preventing both IL-1 induced and post-injury (in the presence and absence of loading) cartilage degradation.