Proteases and Cartilage Degradation in Osteoarthritis

Osteoarthritis, the most common joint disease, affecting millions people world-wide, involves the degradation of the articular cartilage which provides frictionless contact between the bones in a joint during movement. To a first approximation, this tissue is composed of two components, a collagen framework and entrapped proteoglycans. The framework consists of type II collagen fibrils built on a type XI collagen core, and decorated with type IX collagen molecules and small proteoglycans. These composite fibrils give the tissue its integrity, tensile strength and ability to retain large proteoglycan aggregates. The extremely large size of the proteoglycan aggregates and their high negative charge endows them with an immense hydration capacity, giving cartilage the ability to absorb compressive loading by the slow displacement of bound water. Partial destruction or loss of the proteoglycans is the first step in the deterioration of cartilage as seen in arthritis. Subsequently, irreversible loss of collagen occurs leading to permanent cartilage degeneration. While glycosylhydrolases and free radicals could also participate, it is believed that proteolytic enzymes are the main agents responsible for the degradation of cartilage components in osteoarthritis. Currently two classes of proteases are thought to be the major mediators of collagen and proteoglycan cleavage. Collagen degradation was thought to be majorly due to the action of MMP (matrix metalloproteinase) collagenases while members of both MMP and ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) families are important mediators of the degradation of proteoglycans which due to their extended core protein conformation are susceptible to the action of many proteases (Mort and Billington, 2001). Recently however, there is increasing evidence for the role of the cysteine protease cathepsin K in collagen degradation in articular cartilage (Konttinen et al., 2002). The cleavage of cartilage proteins often occurs at specific sites on these molecules depending on the particular protease mediating the event. This results in the generation of characteristic Nand C-terminal epitopes that can be used for the production of antibodies specific for these cleavage products (anti-neoepitope antibodies) (Mort et al., 2003). A series of such antibodies has been produced and their specificities validated. These allow evaluation of the roles of different proteases in the degradation of collagen and proteoglycans in mouse models of osteoarthritis and in human and equine osteoarthritic cartilage using immunohistochemical methods and immunoassays.

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