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Expression and regulation of microsomal prostaglandin E synthase-1 in human osteoarthritic cartilage and chondrocytes
Arthritis Res Thervolume 6, Article number: 83 (2004)
Elevated production of prostaglandin (PG) E2 plays an important role in the pathogenesis of arthritis. Recently, an inducible microsomal prostaglandin E synthase-1 (mPGES-1) was identified. This enzyme is functionally coupled with cyclooxygenase-2 and converts the cyclooxygenase product PGH2 to PGE2. In the present study we analyzed the expression of mPGES-1 in human normal and osteoarthritic (OA) cartilage and determined the effect of different inflammatory agonists on the expression of mPGES-1 in OA chondrocytes.
Expression of mPGES-1 mRNA and protein in cartilage was determined by quantitative real-time RT-PCR and immunohistochemistry, respectively. OA chondrocytes were treated with different inflammatory agents and mPGES-1 protein expression was evaluated by western blot. Activation of the mPGES-1 promoter was assessed in transient transfection experiments.
Levels of mPGES-1 mRNA and protein were markedly elevated in OA versus normal cartilage. Treatment of chondrocytes with IL-1β induced the expression of mPGES-1 protein in a dose-dependent and time-dependent manner. This appears to occur at the transcriptional level as IL-1β induced the expression of mPGES-1 mRNA and the activity of this gene promoter. Tumor necrosis factor alpha and IL-17 also upregulated the expression of mPGES-1 protein and displayed a synergistic effect with IL-1β. 15-Deoxy-Δ12,14-prostaglandin J2 inhibited IL-1β-induced mPGES-1 protein expression, an effect that was reversed by exogenous PGE2.
This study shows for the first time that mPGES-1 expression is upregulated in OA versus normal cartilage and that proinflammatory cytokines increased mPGES-1 expression in chondrocytes. These data suggest that mPGES-1 may prove to be an interesting therapeutic target for controlling PGE2 synthesis.
This work was supported by the Canadian Institutes of Health Research, the Fonds de Recherche en Santé du Québec, and the Fonds de la Recherche du Centre de Recherche du Centre Hospitalier de l'Université de Montréal.