Expression and regulation of microsomal prostaglandin E synthase-1 in human osteoarthritic cartilage and chondrocytes

Objective

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.

Methods

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.

Results

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-Δ^12,14-prostaglandin J₂ inhibited IL-1β-induced mPGES-1 protein expression, an effect that was reversed by exogenous PGE₂.

Conclusion

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.