Co-Stimulatory Effects of Misoprostol and Diclofenac on Glycosaminoglycan Synthesis in Human Cartilage Explants and Their Therapeutic Relevance

Misoprostol, a prostaglandin E(1) analog, is currently available to manage ulcer disease, being used predominantly in the prophylaxis of nonsteroidal anti-inflammatory drug (NSAID)-induced ulceration, a serious side effect of anti-inflammatory therapy in arthritis. The protective effects of misoprostol have now also been shown to extend to cartilage in a series of experiment using an ex vivo system employing normal human and osteoarthritis (OA) cartilage. Misoprostol reproducibly reverses inhibition of proteoglycan synthesis induced by interleukin-1 and certain NSAIDs, and also stimulates synthesis in OA cartilage. The article reviews these findings and also presents the results obtained in a study of 20 OA cartilages in which synergy was demonstrated between misoprostol (at 50 ng/ml) and diclofenac (0.3 &mgr;g/ml) in preventing proteoglycan synthesis. Diclofenac on its own is unusual amongst NSAIDs in exerting virtually no deleterious effect on cartilage. The synergy with misoprostol is of clinical interest in view of the recent introduction of a misoprostol/diclofenac combination product (Arthrotec), the intention of which was to provide antiinflammatory efficacy with a reduced incidence of GI damage. The implications of these cartilage experiments is that such a combination may also offer improvements in the management of the arthritic process in OA, and methods whereby this would be assessed clinically are discussed.