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Peroxisome proliferator-activated receptor-gamma down-regulates chondrocyte matrix metalloproteinase-1 via a novel composite element.
J Biol Chem. 2004 Jul 02; 279(27):28411-8.JB

Abstract

Interleukin-1beta (IL-1beta) 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-gamma isotype on IL-1beta-target genes. Immunocytochemistry, electrophoretic mobility shift, and transient transfection assays revealed a functional PPAR-gamma in chondrocytes in vitro. Rtz displayed significant inhibition of IL-1beta effects in chondrocytes. Low Rtz concentrations (close to K(d) values for PPAR-gamma, 0.1 to 1 microm) inhibited the effects of IL-1beta on (35)S-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-1beta-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-gamma enhanced Rtz inhibitory effect in chondrocytes, whereas a mutated dominant negative PPAR-gamma abolished it, supporting the role of PPAR-gamma 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-gamma and c-Fos/c-Jun proteins bind this cis-acting element in a mutually exclusive way. Our data highlight a new PPAR-gamma-dependent inhibitory mechanism on IL-1beta-mediated cartilage degradation occurring through DNA binding competition on the composite PPRE/AP1 site in the MMP1 promoter.

Authors+Show Affiliations

INSERM UMR-S-530, Université Paris 5, UFR Biomédicale, 45 Rue des Saints Pères, 75006 Paris, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15090544

Citation

François, Mathias, et al. "Peroxisome Proliferator-activated Receptor-gamma Down-regulates Chondrocyte Matrix Metalloproteinase-1 Via a Novel Composite Element." The Journal of Biological Chemistry, vol. 279, no. 27, 2004, pp. 28411-8.
François M, Richette P, Tsagris L, et al. Peroxisome proliferator-activated receptor-gamma down-regulates chondrocyte matrix metalloproteinase-1 via a novel composite element. J Biol Chem. 2004;279(27):28411-8.
François, M., Richette, P., Tsagris, L., Raymondjean, M., Fulchignoni-Lataud, M. C., Forest, C., Savouret, J. F., & Corvol, M. T. (2004). Peroxisome proliferator-activated receptor-gamma down-regulates chondrocyte matrix metalloproteinase-1 via a novel composite element. The Journal of Biological Chemistry, 279(27), 28411-8.
François M, et al. Peroxisome Proliferator-activated Receptor-gamma Down-regulates Chondrocyte Matrix Metalloproteinase-1 Via a Novel Composite Element. J Biol Chem. 2004 Jul 2;279(27):28411-8. PubMed PMID: 15090544.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Peroxisome proliferator-activated receptor-gamma down-regulates chondrocyte matrix metalloproteinase-1 via a novel composite element. AU - François,Mathias, AU - Richette,Pascal, AU - Tsagris,Lydia, AU - Raymondjean,Michel, AU - Fulchignoni-Lataud,Marie-Claude, AU - Forest,Claude, AU - Savouret,Jean-François, AU - Corvol,Marie-Thérèse, Y1 - 2004/04/16/ PY - 2004/4/20/pubmed PY - 2004/8/12/medline PY - 2004/4/20/entrez SP - 28411 EP - 8 JF - The Journal of biological chemistry JO - J. Biol. Chem. VL - 279 IS - 27 N2 - Interleukin-1beta (IL-1beta) 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-gamma isotype on IL-1beta-target genes. Immunocytochemistry, electrophoretic mobility shift, and transient transfection assays revealed a functional PPAR-gamma in chondrocytes in vitro. Rtz displayed significant inhibition of IL-1beta effects in chondrocytes. Low Rtz concentrations (close to K(d) values for PPAR-gamma, 0.1 to 1 microm) inhibited the effects of IL-1beta on (35)S-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-1beta-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-gamma enhanced Rtz inhibitory effect in chondrocytes, whereas a mutated dominant negative PPAR-gamma abolished it, supporting the role of PPAR-gamma 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-gamma and c-Fos/c-Jun proteins bind this cis-acting element in a mutually exclusive way. Our data highlight a new PPAR-gamma-dependent inhibitory mechanism on IL-1beta-mediated cartilage degradation occurring through DNA binding competition on the composite PPRE/AP1 site in the MMP1 promoter. SN - 0021-9258 UR - https://www.unboundmedicine.com/medline/citation/15090544/Peroxisome_proliferator_activated_receptor_gamma_down_regulates_chondrocyte_matrix_metalloproteinase_1_via_a_novel_composite_element_ L2 - http://www.jbc.org/cgi/pmidlookup?view=long&pmid=15090544 DB - PRIME DP - Unbound Medicine ER -