Matrix metalloproteinases and their inhibitors

The progressive breakdown of connective tissues of the articular joints is a major feature of the arthritides and becomes an irreversible process leading to permanent loss of function and disability. Recent research has been directed at the analysis of the relative roles of different cell types and the different classes of proteinases that they produce in such deg-radative processes. It is known that proteinases of all mechanistic classes have the potential to degrade individual connective tissue macromolecules in vitro, but the elucidation of their precise role in vivo is more difficult. The current view is that the initial step in the breakdown of the matrix in both physiological and pathological situations is an extracellular process, often involving matrix metalloproteinases (MMPs) which function at neutral pH. In certain special environments, cysteine proteinases with more acidic pH optima are also active and in rapid resorption or inflammatory events, serine proteinases are released by invading cells. Mechanical disruption and the presence of free radicals can also augment the degradative process. Matrix fragments are subsequently phagocytosed for processing intracellularly within the lysosomal system. These processes are normally tightly regulated by a complex interplay of cell-cell and cell-matrix interactions involving the production of proteinases, activators and inhibitors and other regulatory molecules. The accelerated breakdown of connective tissue seen in diseases such as rheumatoid arthritis may be due largely to a breakdown in these regulatory mechanisms.