Abstract
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.
Original language | English (US) |
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Pages (from-to) | 100-108 |
Number of pages | 9 |
Journal | Osteoarthritis and Cartilage |
Volume | 10 |
Issue number | 2 |
DOIs | |
State | Published - 2002 |
Keywords
- AP-1
- MMP-1
- PPARγ
- Synovial fibroblasts
ASJC Scopus subject areas
- Orthopedics and Sports Medicine