The clinical potential of matrix metalloproteinase inhibitors in the rheumatic disorders

Rheumatoid arthritis (RA) and osteoarthritis are chronic diseases that resu lt in cartilage degradation and loss of joint function. Currently available drugs are predominantly directed towards the control of pain and/or the in flammation associated with joint synovitis but they do little to reduce joi nt destruction. In the future, it will be important to have drugs that prev ent the structural damage caused by bone and cartilage breakdown. In this review, we will outline the structure and function of cartilage and the key features of matrix metalloproteinases (MMPs), enzymes involved in joint destruction. We will present evidence for the role of MMPs in RA and osteoarthritis, and describe the potential of synthetic inhibitors to contr ol MMP activity and so prevent joint destruction. MMPs are able to cleave all components of the cartilage matrix. Regulation of MMPs is aberrant in osteoarthritis and RA, and MMPs have been implicated in the collagen breakdown that contributes to joint destruction in these d iseases. Synthetic MMP inhibitors have been developed. In animal models of osteoarthritis and/or RAI these agents have shown chondroprotective effects . However, results from clinical trials in RA have been equivocal, with som e studies being terminated because of lack of efficacy or safety concerns. Nevertheless, this approach remains promising. Increased understanding of t he structure, regulation and function of individual MMPs may lead to more e ffective strategies, and approaches ai med at multiple steps of the pathoge nesis of arthritis may be needed to break the chronic cycle of joint destru ction.