The author posed some 5 questions and indicated how research at the Strangeways Laboratory has progressed in attempting to find answers to them. In work both here and elsewhere it has been shown that proteolytic cleavage, initially of proteoglycan and secondly of collagen, is responsible for the damage in the articular cartilage of the arthritic patient. He considers that the enzymes involved are almost certainly a combination of metalloproteinases and cathepsins. The extent to which each enzyme is quantitatively important is not yet known, but it may well vary both spatially and temporarily depending upon local conditions. He thinks it likely that these enzymes work principally in the pericellular environment of the cell and that the chondrocyte may be the key cell in causing breakdown of cartilage matrix. He suggests that this is a physiological mechanism, perhaps important in the normal remodelling of cartilage, and under pathological stimulation the shift in the dynamic equilibrium between synthesis and degradation of matrix by chondrocytes is caused by local increase in active enzyme secretion. The control of such chondrocyte function may be due at least in part to the release from adjacent synovial tissues of factors, provisionally named 'catabolins', that can act directly on cartilage cells. How the production of synovial catabolin is controlled is totally unknown, but research into this question might well prove to be of crucial importance to the future regulation of joint disease. It may be that pharmacologically active compounds modify the secretion of such material by inflammatory tissues. if this proves to be true, development of the targeting of drugs to specific cells, by such means as liposomal encapsulation, may prove useful in the treatment of both the acute phase of inflammation and the damage to the articular cartilage. The author hopes to have shown that research into the catabolism of articular cartilage has moved from the description of the biochemical changes, via studies on the isolation, properties, and localisation of the degradative enzymes to the investigation of the control of cellular functions that mediate the pathological damage. Work in Dr Strangeways's Research Hospital and elsewhere during the coming years should prove to be exciting and important, and could yield information that the physician may be able to utilise in controlling these painful and crippling diseases.
