The clinical potential of matrix metalloproteinase inhibitors in the rheumatic disorders.
Rheumatoid arthritis (RA) and osteoarthritis are chronic diseases that result in cartilage degradation and loss of joint function. Currently available drugs are predominantly directed towards the control of pain and/or the inflammation associated with joint synovitis but they do little to reduce joint destruction. In the future, it will be important to have drugs that prevent 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 control 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 diseases. Synthetic MMP inhibitors have been developed. In animal models of osteoarthritis and/or RA, these agents have shown chondroprotective effects. However, results from clinical trials in RA have been equivocal, with some studies being terminated because of lack of efficacy or safety concerns. Nevertheless, this approach remains promising. Increased understanding of the structure, regulation and function of individual MMPs may lead to more effective strategies, and approaches aimed at multiple steps of the pathogenesis of arthritis may be needed to break the chronic cycle of joint destruction.
Elliott
S
S
Department of Rheumatology, University of Newcastle, Newcastle-upon-Tyne, England.
Cawston
T
T
D000818:Animals; D006801:Humans; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000378:metabolism; D011480:Protease Inhibitors / Q000627:therapeutic use*; D012216:Rheumatic Diseases / Q000188:drug therapy* / Q000201:enzymology*; D019714:Tissue Inhibitor of Metalloproteinases / Q000627:therapeutic use
D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases