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

• Published in: Osteoarthritis and cartilage Vol. 10; no. 2; pp. 100 - 108
• Main Authors: Fahmi, H., Pelletier, J.-P., Di Battista, J.A., Cheung, H.S., Fernandes, J.C., Martel-Pelletier, J.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.02.2002
• Subjects: Aged; Blotting, Northern; Cells, Cultured; Dose-Response Relationship, Drug; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Fibroblasts - metabolism; Gene Expression; Humans; Interleukin-1 - physiology; Matrix Metalloproteinase 1 - biosynthesis; PPARγ, MMP-1, Synovial fibroblasts, AP-1; Promoter Regions, Genetic - drug effects; Prostaglandin D2 - analogs & derivatives; Prostaglandin D2 - pharmacology; Receptors, Cytoplasmic and Nuclear - physiology; Reverse Transcriptase Polymerase Chain Reaction; Synovial Membrane - cytology; Thiazoles - pharmacology; Thiazolidinediones; Transcription Factors - physiology; Transcription, Genetic; PPARγ, MMP-1, Synovial fibroblasts, AP-1
• ISSN: 1063-4584; 1522-9653
• DOI: 10.1053/joca.2001.0485

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.