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 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.
Fahmi
H
H
Osteoarthritis Research Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Hôpital Notre-Dame, Montréal, Québec, Canada.
Pelletier
J-P
JP
Di Battista
J A
JA
Cheung
H S
HS
Fernandes
J C
JC
Martel-Pelletier
J
J
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
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