title: Peroxisome proliferator-activated receptor gamma activators inhibit MMP-1 production in human synovial fibroblasts likely by reducing the binding of the activator protein 1.
abstract: 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.
authors.affiliation: Osteoarthritis Research Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Hôpital Notre-Dame, Montréal, Québec, Canada.
authors.forename: H
authors.initials: H
authors.lastname: Fahmi
authors.forename: J-P
authors.initials: JP
authors.lastname: Pelletier
authors.forename: J A
authors.initials: JA
authors.lastname: Di Battista
authors.forename: H S
authors.initials: HS
authors.lastname: Cheung
authors.forename: J C
authors.initials: JC
authors.lastname: Fernandes
authors.forename: J
authors.initials: J
authors.lastname: Martel-Pelletier
mesh_terms: D000368:Aged; D015152:Blotting, Northern; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004591:Electrophoresis, Polyacrylamide Gel; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism*; D015870:Gene Expression; D006801:Humans; D007375:Interleukin-1 / Q000502:physiology; D020781:Matrix Metalloproteinase 1 / Q000096:biosynthesis*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D015230:Prostaglandin D2 / Q000031:analogs & derivatives* / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000077154:Rosiglitazone; D013583:Synovial Membrane / Q000166:cytology*; D013844:Thiazoles / Q000494:pharmacology; D045162:Thiazolidinediones; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: D007375:Interleukin-1; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D045162:Thiazolidinediones; D014157:Transcription Factors; D000077154:Rosiglitazone; C037112:9-deoxy-delta-9-prostaglandin D2; D020781:Matrix Metalloproteinase 1; D015230:Prostaglandin D2