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

被引:115
作者
Masuko-Hongo, K
Berenbaum, F
Humbert, L
Salvat, C
Goldring, MB
Thirion, S
机构
[1] Univ Paris 06, CNRS, UMR 7079, F-75252 Paris 5, France
[2] UFR St Antoine, CNRS, UMR 7079, Paris, France
[3] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA
[4] Harvard Univ, Inst Med, New England Baptist Bone & Joint Inst, Boston, MA USA
来源
ARTHRITIS AND RHEUMATISM | 2004年 / 50卷 / 09期
关键词
D O I
10.1002/art.20437
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Microsomal prostaglandin E synthase I (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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收藏
页码:2829 / 2838
页数:10
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