Aurothiomalate inhibits the expression of mPGES-1 in primary human chondrocytes.

OBJECTIVES: Microsomal prostaglandin E synthase-1 (mPGES-1) is a terminal enzyme in the production of prostaglandin E2 (PGE2) and its expression is upregulated during inflammation. mPGES-1 is considered as a potential drug target for the treatment of arthritis to reduce adverse effects related to the current non-steroidal anti-inflammatory drugs (NSAIDs). Our aim was to study the expression of mPGES-1 in primary human chondrocytes and whether the expression is affected by clinically used antirheumatic drugs.

METHOD: Primary human chondrocytes were isolated from cartilage samples obtained from patients undergoing total knee replacement surgery. Expression of mPGES-1 was studied by quantitative real-time polymerase chain reaction (PCR) and Western blot analysis. PGE2 levels were measured by enzyme-linked immunosorbent assay (ELISA).

RESULTS: mPGES-1 expression in primary human chondrocytes was enhanced when the cells were exposed to interleukin-1β (IL-1β) and mPGES-1 protein levels continued to increase up to the 96-h follow-up. Aurothiomalate inhibited mPGES-1 expression and PGE2 production in a dose-dependent manner, as did the anti-inflammatory steroid dexamethasone. Other disease-modifying antirheumatic drugs (DMARDs) studied (sulfasalazine, methotrexate, and hydroxychloroquine) did not alter mPGES-1 expression.

CONCLUSIONS: The results introduce aurothiomalate as the first, and so far the only, DMARD found to be able to inhibit mPGES-1 expression. The effect is likely involved in the mechanisms of action of this gold-containing DMARD in rheumatic diseases. The results are implicated in the regulatory mechanisms of mPGES-1 expression, which are under intensive research.