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

Osteoarthritis Cartilage. 2002 Feb;10(2):100-8. doi: 10.1053/joca.2001.0485.


Objective: To investigate the expression and activity of PPARgamma in human synovial fibroblasts and the effects of PPARgamma agonists on the expression of MMP-1. The molecular mechanisms by which PPARgamma agonists modulate MMP-1 expression were also examined.

Methods: PPARgamma expression and activity were measured using reverse-transcription polymerase chain reaction (RT-PCR) and transient transfection assays. Human synovial fibroblasts were cultured with IL-1beta in the absence or presence of PPARgamma activators, and the expression and production of MMP-1 were evaluated by Northern blot and ELISA, respectively. The effect of 15d-PGJ(2) 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: PPARgamma was expressed and transcriptionally functional in human synovial fibroblasts. PPARgamma activators (15d-PGJ(2) and BRL 49653) inhibited IL-1beta-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-PGJ(2), indicating that the inhibitory effect of 15d-PGJ(2) occurs at the transcriptional level. Interestingly, 15d-PGJ(2) reduced both basal and IL-1beta-induced AP-1 binding activity.

Conclusions: These data indicate that PPARgamma agonists inhibit MMP-1 gene expression by transcriptional mechanisms, and suggest that they may be useful in reducing joint tissue destruction.

MeSH terms

  • 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*
  • Promoter Regions, Genetic / drug effects
  • Prostaglandin D2 / analogs & derivatives*
  • Prostaglandin D2 / pharmacology
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rosiglitazone
  • Synovial Membrane / cytology*
  • Thiazoles / pharmacology
  • Thiazolidinediones*
  • Transcription Factors / physiology*
  • Transcription, Genetic


  • Interleukin-1
  • Receptors, Cytoplasmic and Nuclear
  • Thiazoles
  • Thiazolidinediones
  • Transcription Factors
  • Rosiglitazone
  • 9-deoxy-delta-9-prostaglandin D2
  • Matrix Metalloproteinase 1
  • Prostaglandin D2