A major metabolite of aceclofenac, 4′-hydroxy aceclofenac, suppresses the production of interstitial pro-collagenase/proMMP-1 and pro-stromelysin-1/proMMP-3 by human rheumatoid synovial cells

Objective and Design: We examined the effects of aceclofenac and its metabolites on the production of procollagenase-1/pro-matrix metalloproteinase-1 (proMMP-1), pro-gelatinase A/proMMP-2, pro-stromelysin-1/proMMP-3 and tissue inhibitor of metalloproteinases-1 (TIMP-1) by rheumatoid synovial cells. Materials: Synovial cells were obtained from patients with rheumatoid arthritis. Treatment: Cultures of confluent cells were treated with interleukin-1 beta (IL-1 beta)(1 ng/ml) and/or test drugs (0.3-30 mu M) for 48 h. Methods: Production of proMMPs and TIMP-1 was monitored by Western blotting or gelatin zymography. Prostaglandin E-2 (PGE(2)) was measured by an enzyme immunoassay. Results: 4'-Hydroxy aceclofenac, a major metabolite of aceclofenac, down-regulated both basal and IL-1 beta-induced production of proMMP-1 and proMMP-3 at a concentration sufficient to suppress PGE(2) production without modulating proMMP-2 or TIMP-1, whereas aceclofenac itself had no marked effect on the production of proMMPs. Conclusions: Down-regulation of proMMP-1 and proMMP-3 production by 4'-hydroxy aceclofenac may contribute to the therapeutic effect of aceclofenac on rheumatoid arthritis and osteoarthritis.