ABSTRACT
Degradation of cartilage matrix impairs joint function and is a common feature of rheumatoid arthritis (RA) and osteoarthritis (OA), although the etiology of the two diseases is different. The cartilage consists of a relatively small number of chondrocytes and abundant extracellular matrix (ECM) components, of which about 40-45% are aggregated proteoglycans, aggrecans, and a similar amount of type II collagen. The type II collagen forms a fibrillar network, together with type IX and XI collagens, which provides the tissue with tensile strength. Aggrecans present within this meshwork are highly hydrated due to the anionic property of chondroitin sulfate and keratan sulfate polysaccharide chains attached to the core protein, and this property is important for the tissue to withstand compressive forces. During the progression of RA and OA, degradation of aggrecan occurs initially, followed by the degradation of collagen fibrils. These two events are effected by elevated metalloproteinase activities, which arise primarily from proliferative synovial tissues in RA and from cartilage in OA. The predominant metalloproteinases involved in cartilage degradation are the matrix metalloproteinases (MMPs) and the metalloproteinases
with disintegrin and thrombospondin domains (ADAMTSs). In addition, the metalloproteinases with disintegrin domains (ADAMs) that cleave and release cell surface cytokines, growth factors and their receptors also play key roles in inflammation and subsequent tissue destruction. A number of reviews have described the importance of MMPs in arthritis and their inhibitor development as potential therapeutics.1-3 In this review, we briefly introduce the members of the MMP family, but the main focus is to describe the roles of ADAMTSs and ADAMs in joint destruction and current approaches to intervening in arthritic diseases by developing metalloproteinase inhibitors.
