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J. Biol. Chem., Vol. 279, Issue 27, 28411-28418, July 2, 2004

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Peroxisome Proliferator-activated Receptor- Down-regulates Chondrocyte Matrix Metalloproteinase-1 via a Novel Composite Element^*

Mathias François, Pascal Richette, Lydia Tsagris, Michel Raymondjean, Marie-Claude Fulchignoni-Lataud, Claude Forest, Jean-François Savouret, and Marie-Thérèse Corvol¶

From the INSERM UMR-S-530, Université Paris 5, UFR Biomédicale, 45 Rue des Saints Pères, 75006 Paris and CNRS UMR 7079, 7 Quai Saint Bernard, 75005 Paris, France

Interleukin-1 (IL-1) induces degradation via hyperexpression of an array of genes, including metalloproteinases (MMP), in cartilage cells during articular degenerative diseases. In contrast, natural ligands for peroxisome proliferator-activated receptors (PPARs) display protective anti-cytokine effects in these cells. We used the PPAR agonist rosiglitazone (Rtz) to investigate PPAR- isotype on IL-1-target genes. Immunocytochemistry, electrophoretic mobility shift, and transient transfection assays revealed a functional PPAR- in chondrocytes in vitro. Rtz displayed significant inhibition of IL-1 effects in chondrocytes. Low Rtz concentrations (close to K_d values for PPAR-, 0.1 to 1 µM) inhibited the effects of IL-1 on ³⁵S-sulfated proteoglycan production and gelatinolytic activities and downregulated MMP1 expression at mRNA and protein levels. We have investigated the mechanism of action of Rtz against IL-1-mediated MMP1 gene hyperexpression. Rtz effect occurs at the transcriptional level of the MMP1 promoter, as observed in transiently transfected cells with pMMP1-luciferase vector. Transient expression of wild type PPAR- enhanced Rtz inhibitory effect in chondrocytes, whereas a mutated dominant negative PPAR- abolished it, supporting the role of PPAR- in this effect. MMP1 gene promoter analysis revealed the involvement of a cis-acting element located at -83 to -77, shown to be a composite PPRE/AP1 site. Gel mobility and supershift assays demonstrated that PPAR- and c-Fos/c-Jun proteins bind this cis-acting element in a mutually exclusive way. Our data highlight a new PPAR--dependent inhibitory mechanism on IL-1-mediated cartilage degradation occurring through DNA binding competition on the composite PPRE/AP1 site in the MMP1 promoter.

Received for publication, November 20, 2003 , and in revised form, April 15, 2004.

^* This work was supported by INSERM and by the Association de Recherche sur la Polyarthrite (Paris, France). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed. Tel.: 33-1-42-86-38-71; Fax: 33-1-42-86-38-68; E-mail: maite.corvol{at}univ-paris5.fr.

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