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

Abstract.

Objective and Design: We examined the effects of aceclofenac and its metabolites on the production of pro-collagenase-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-1β (IL-1β)(1 ng/ml) and/or test drugs (0.3-30 μM) for 48 h.¶Methods: Production of proMMPs and TIMP-1 was monitored by Western blotting or gelatin zymography. Prostaglandin E₂ (PGE₂) was measured by an enzyme immunoassay.¶Results: 4′-Hydroxy aceclofenac, a major metabolite of aceclofenac, down-regulated both basal and IL-1β-induced production of proMMP-1 and proMMP-3 at a concentration sufficient to suppress PGE₂ 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.