The role of proteinases in cartilage destruction

Most of the organic, extracellular matrix of articular cartilage consists of collagens and proteoglycans. Their degradation is initiated extra- or peri-cellularly by proteinases produced locally by cells in and around the joint. Although enzymes from all four classes of proteinases can degrade the cartilagenous matrix, serine proteinases, particularly plasmin, and various neutral metalloproteinases (NMPs) are likely to be the key enzymes in this process. Much attention has been paid to members of the latter group, which are synthesised both by the resident, mesenchymal cells of the joint and by various types of white blood cells which colonise it during inflammation. NMPs can be conveniently grouped into three classes, the collagenases, the stromelysins and the gelatinases. Two members are known for each class, with the recently identified "pump" (Putative Metalloproteinase) probably constituting a third member of the stromelysin group. Regulation of these enzymes is complex. Cells normally synthesise NMPs at low rates, but their production increases markedly following cellular activation by cytokines or certain other stimuli. Major control points for enzyme synthesis occur at the levels of transcription and the conversion of proenzyme to active enzyme; enzyme activity is further regulated through the action of inhibitors. Alpha-2 macroglobulin is the major systemic inhibitor, while a number of tissue inhibitors act as local regulators. These include at least two TIMPs and several IMPs. Pharmacologic manipulation of NMP activity holds promise as an approach to anti-erosive therapy in arthritis.