Editorial Rogerson Cartilage matrix degradation : an appropriate therapeutic target in osteoarthritis Editorial

Osteoarthritis (OA) is a complex disease, now recognized to involve all structural elements of the articulating joint. Different therapies will be required to tackle different aspects of the condition. Cartilage loss associated with OA is a major determinant for joint replacement surgery. Preventing, or even reversing, articular cartilage matrix degradation in OA has long been considered an important therapeutic aim by the research community and the pharmaceutical industry. There are still a number of hurdles to leap before blocking cartilage matrix breakdown becomes a standard part of OA therapy, but there are good grounds to argue that the cartilage matrix is a relevant, worthwhile target for therapeutics that will improve patient outcomes. Articular cartilage degradation associated with OA is an enzyme-driven process, and is, therefore, an excellent candidate for the develop ment of inhibitory, disease-modifying OA drugs (DMOADs). Research has concentrated on the two major components of articular cartilage, collagen type II and aggrecan. Collagen II provides cartilage with its tensile strength and aggrecan is responsible for its weight-bearing properties. Together these molecules make up 70–80% of the dry weight of the tissue. The loss of collagen II and aggrecan in OA cartilage is well documented [1]. Cartilage loss associated with OA is likely to be irreversible due to the poor ability of the tissue to repair the collagen framework. The importance of aggrecan degradation in cartilage erosion was confirmed in a genetically modified mouse strain, in which aggrecan was made resistant to enzymatic degradation; these mice had less aggrecan loss and cartilage erosion in a model of OA [2]. A wealth of in vitro and in vivo data from both human tissues and animal models have identified specific zinc metallo proteinases as the major mediators of both collagen II and aggrecan loss; matrix metallo proteinase (MMP)-13 is the major collagenase [3], and a disintegrin and metallo proteinase with thrombo spondin motifs (ADAMTS)-4 and -5 are the major aggrecanases [4]. The importance of these enzymes is underlined by targeted deletion of either MMP-13 [5] or ADAMTS-5 [6] in mice, which are both resistant to cartilage erosion in a model of OA. One limitation of using ‘knockout’ mice to identify the role of specific proteinases is that enzymatic activity is completely blocked at disease onset, a situation unlikely to be replicated in the treatment of human OA. However, in many patients, the disease remains stable for long periods of time before progressing [7,8], and DMOADs could be used to prevent further cartilage loss. An alternative is to give these drugs prophylactically to patients with acute traumatic joint injury that is likely to lead to OA. Cathepsin K has been implicated in collagen degradation [9], and calpain [10] and HtrA1 [11] degrade human aggrecan in vivo, but the significance of these enzymes in OA remains to be determined. An alternative therapeutic target is tissue inhibitor of metalloproteinase-3, a potent endogenous inhibitor of MMP-13, and ADAMTS-4 and -5 [12]. In the tissue, inhibitor of metalloproteinase-3 knockout mouse, there is significant, spontaneous cartilage degradation, characterized by both collagen and aggrecan loss [13]. A number of small-molecule inhibitors have been developed that target MMP-13 and ADAMTS-4 and -5. The results of previous clinical trials of MMP inhibitors for the treatment of arthritis and cancer were disappointing, as there were side effects, such as muscle