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. 2004 Sep;50(9):2829-38.
doi: 10.1002/art.20437.

Up-regulation of microsomal prostaglandin E synthase 1 in osteoarthritic human cartilage: critical roles of the ERK-1/2 and p38 signaling pathways

Kayo Masuko-Hongo  1 , Francis Berenbaum, Lydie Humbert, Colette Salvat, Mary B Goldring, Sylvie Thirion
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Free article

Up-regulation of microsomal prostaglandin E synthase 1 in osteoarthritic human cartilage: critical roles of the ERK-1/2 and p38 signaling pathways

Kayo Masuko-Hongo et al. Arthritis Rheum. 2004 Sep.
Free article

Abstract

Objective: Microsomal prostaglandin E synthase 1 (mPGES-1) is the final enzyme of the cascade that produces prostaglandin E(2) (PGE(2)), a key actor in arthritis. To study mPGES-1 synthesis in human cartilage and its regulation by interleukin-1beta (IL-1beta), we used human cartilage and an immortalized human chondrocyte cell line. Furthermore, we investigated the signaling pathways involved in mPGES-1 expression.

Methods: We used real-time quantitative reverse transcription-polymerase chain reaction, Northern blotting, and Western blotting to measure mPGES-1 messenger RNA (mRNA) and protein expression in human chondrocytes. PGE(2) production was measured by enzyme-linked immunosorbent assay.

Results: Cartilage specimens from osteoarthritis (OA) patients contained far greater amounts of mPGES-1 and cyclooxygenase 2 (COX-2) mRNA than did normal cartilage. Incubation with IL-1beta markedly increased mPGES-1 mRNA and protein in a dose-dependent and time-dependent manner, in parallel with an increase in PGE(2) levels. Both PD98059, an ERK pathway inhibitor, and SB203580, a p38alpha/beta MAPK inhibitor, abolished the increases in mPGES-1 mRNA and protein in response to IL-1beta. The specific p38alpha MAPK inhibitor SC906 suppressed IL-1beta-induced COX-2 expression but not IL-1beta-induced mPGES-1 expression, suggesting preferential involvement of p38beta MAPK in IL-1beta-induced mPGES-1 expression.

Conclusion: This study is the first to show that mPGES-1 is stimulated in human chondrocytes by the proinflammatory cytokine IL-1beta via activation of both ERK-1/2 and p38 MAPK in an isoform-specific manner. We postulate that mPGES-1 may be a novel target for OA therapy.

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