Peroxisome proliferator-activated receptor gamma activators inhibit MMP-1 production in human synovial fibroblasts likely by reducing the binding of the activator protein 1

Objective: To investigate the expression and activity of PPARγ in human synovial fibroblasts and the effects of PPARγ agonists on the expression of MMP-1. The molecular mechanisms by which PPARγ agonists modulate MMP-1 expression were also examined. Methods: PPARγ expression and activity were measured using reverse-transcription polymerase chain reaction (RT-PCR) and transient transfection assays. Human synovial fibroblasts were cultured with IL-1β in the absence or presence of PPARγ activators, and the expression and production of MMP-1 were evaluated by Northern blot and ELISA, respectively. The effect of 15d-PGJ₂, on MMP-1 promoter activation was analysed in transient transfection experiments, while electrophoretic mobility shift assays were performed to study the binding activity of the transcription factor AP-1. Results: PPARγ was expressed and transcriptionally functional in human synovial fibroblasts. PPARγ activators (15d-PGJ₂, and BRL 49653) inhibited IL-1β-induced MMP-1 synthesis in a dose-dependent manner. Similarly, both activators inhibited IL-1-induced MMP-1 mRNA expression. Activation of the human MMP-1 promoter was also attenuated by 15d-PGJ₂, indicating that the inhibitory effect of 15d-PGJ₂ occurs at the transcriptional level. Interestingly, 15d-PGJ₂ reduced both basal and IL-1β-induced AP-1 binding activity. Conclusions: These data indicate that PPARγ agonists inhibit MMP-1 gene expression by transcriptional mechanisms, and suggest that they may be useful in reducing joint tissue destruction.