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

François, Mathias; Richette, Pascal; Tsagris, Lydia; Raymondjean, Michel; Fulchignoni-Lataud, Marie Claude; Forest, Claude; Savouret, J.-F.; Corvol, Marie-Thérèse

doi:10.1074/jbc.m312708200

Cited by 48 publications

(63 citation statements)

References 45 publications

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“…5). Besides, PPAR␥-dependent inhibitory mechanism has also been reported through competition on a composite PPRE/ AP1 site of the latter promoter (16). Altogether, these results emphasize the multiplicity and complexity of the molecular mechanisms responsible of the gene expression modulation.…”

Section: Discussionmentioning

confidence: 52%

Inhibition of Interleukin-1β-Induced Group IIA Secretory Phospholipase A2 Expression by Peroxisome Proliferator-Activated Receptors (PPARs) in Rat Vascular Smooth Muscle Cells: Cooperation between PPARβ and the Proto-Oncogene BCL-6

Ravaux

Denoyelle

Monne

et al. 2007

Molecular and Cellular Biology

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The inflammation that occurs during atherosclerosis is characterized by the release of large amounts of group IIA secretory phospholipase A2 (sPLA2-IIA). This study was designed to define the function of the three peroxisome proliferator-activated receptors (PPARs) on sPLA2 expression in vascular smooth muscle cells (VSMCs). We found that PPAR ligands decreased sPLA2-IIA activity and inhibited mRNA accumulation under inflammatory conditions. Furthermore, interleukin-1␤-induced sPLA2-IIA promoter activity was inhibited by the three PPAR ligands and in a similar way when cells were cotransfected with PPAR␣, PPAR␤, or PPAR␥, plus retinoid X receptor ␣ (RXR␣). Our study revealed that the regulation of sPLA2-IIA gene transcription by PPAR␣/RXR and PPAR␥/RXR heterodimers requires an interaction with a PPAR response element (PPRE) of the sPLA2-IIA promoter. In contrast, PPAR␤ operates through a PPRE-independent mechanism. In addition, we demonstrated that VSMCs expressed the transcriptional repressor BCL-6. Overexpression of BCL-6 markedly reduced sPLA2-IIA promoter activity in VSMCs, while a dominant negative form of BCL-6 abrogated sPLA2 repression by PPAR␤. The PPAR␤ agonist induced a BCL-6 binding to the sPLA2 promoter in VSMCs under inflammatory conditions. The knockdown of BCL-6 by short interfering RNA abolished the inhibitory effect of the PPAR␤ ligand on sPLA2 activity and prostaglandin E 2 release. Thus, the inhibition of sPLA2-IIA activity by PPAR␤ agonists may provide a promising approach to impacting the initiation and progression of atherosclerosis.The large family of phospholipase A2 (PLA2) enzymes hydrolyze ester bonds at the sn-2 position of glyceroacylphospholipids to produce lysophospholipids and nonesterified fatty acids such as arachidonic acid (C 20:4 [n-6]), the precursor of various proinflammatory lipid mediators, such as eicosanoids (37). To date there are four major families of PLA2. Several observations argue for the implication of type IIA secretory PLA2 (sPLA2-IIA) in the pathogenesis of various inflammatory diseases, including cancer, septic shock, rheumatoid arthritis, and atherosclerosis (38). The plasma of patients with various inflammatory diseases, particularly atherosclerosis, contains high concentrations of sPLA2-IIA (18). The synthesis of sPLA2-IIA is stimulated by inflammatory cytokines, such as interleukin-1␤ (IL-1␤), IL-6, and tumor necrosis factor alpha (TNF-␣) (2, 20). Moreover, sPLA2-IIA is largely expressed in vascular smooth muscle cells (VSMCs) (18) in response to proinflammatory cytokines produced by infiltrated macrophages. Overproduction of human sPLA2-IIA in transgenic mice contributes to atherogenesis (19). This enzyme catalyzes the production of precursors of lipid mediators (mainly prostaglandin E 2 [PGE2]), which in turn amplify the effect of cytokines on the dedifferentiation of VSMCs (11). The enzyme was reported to have other proatherogenic properties linked to its ability to hydrolyze phospholipid monolayers of high-and low-density lipoproteins (21). Previously...

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Section: Discussionmentioning

confidence: 52%

Inhibition of Interleukin-1β-Induced Group IIA Secretory Phospholipase A2 Expression by Peroxisome Proliferator-Activated Receptors (PPARs) in Rat Vascular Smooth Muscle Cells: Cooperation between PPARβ and the Proto-Oncogene BCL-6

Ravaux

Denoyelle

Monne

et al. 2007

Molecular and Cellular Biology

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“…Under the present experimental conditions, 1242 FRANÇ OIS ET AL expression of PPAR␣ in cultured rabbit chondrocytes was ascertained by Northern blotting and EMSA, while transient transfection experiments with a 3xPPRE-Luc reporter construct showed that PPAR␣ was functional and activated at similar levels with 500 M CloF or 1 M WY-14643, but not with 1 M Rtz (data not shown). CloF inhibition of IL-1␤-induced MMP expression was also observed with high-affinity PPAR␣ (1 M WY-14643), as well as high-affinity PPAR␥, ligands (1 M Rtz), as previously described by our group (11). In that work, Rtz was shown to counteract IL-1␤-induced MMP-1 transcription by a PPAR␥-dependent inhibitory mechanism, acting through a composite PPRE/activator protein 1 site at position Ϫ83 to Ϫ71 upstream from the MMP-1 rabbit gene transcription start site.…”

Section: Discussionmentioning

confidence: 84%

“…These fatty acids are natural ligands for PPAR␣ and PPAR␥, both of which have been shown by us and others to be expressed in cartilage of different species (11,19). Whether these fatty acids exert their protective effects through binding and activation of PPAR␣ or PPAR␥ in chondrocytes remains to be demonstrated.…”

Section: Discussionmentioning

confidence: 99%

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Activation of the peroxisome proliferator–activated receptor α pathway potentiates interleukin‐1 receptor antagonist production in cytokine‐treated chondrocytes

François¹,

Richette²,

Tsagris³

et al. 2006

Arthritis & Rheumatism

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Objective. To determine whether peroxisome proliferator-activated receptor ␣ (PPAR␣) agonists protect chondrocytes against the effects of interleukin-1␤ (IL-1␤).Methods. PPAR␣ expression and function in cultured rabbit articular chondrocytes were studied by Northern blotting, electrophoretic mobility shift assay, Conclusion. Our findings support the notion that there is a PPAR␣-dependent mechanism that inhibits IL-1␤ function in chondrocytes, which operates via an increase in sIL-1Ra production.

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“…Previous studies characterizing LG268 (41)(42)(43) indicated that treatment with this rexinoid activates a limited number of RXR-containing NHR dimers, including RXR-RXR, RXR-farnesoid X receptor, RXR-liver X receptor, RXR-peroxisome proliferator-activated receptor ␣ [PPAR␣], and RXR-PPAR␥. In reviewing the literature, we found substantial data linking specific ligands for PPAR␥ to inhibition of MMP production and therapeutic activity in models of arthritis (44)(45)(46)(47)(48). Thus, we posit that both ligands work through similar mechanisms to inhibit MMP expression.…”

Section: Discussionmentioning

confidence: 97%

Regulation of matrix metalloproteinase gene expression by a retinoid X receptor–specific ligand

Burrage¹,

Huntington²,

Sporn³

et al. 2007

Arthritis & Rheumatism

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Objective. To evaluate the effects of LG100268 (LG268), a synthetic ligand for the nuclear hormone receptor retinoid X receptor, on the expression of matrix metalloproteinase 1 (MMP-1) and MMP-13 induced by proinflammatory cytokines in a chondrocyte model.Methods. SW-1353 human chondrosarcoma cells were used to study the effects of LG268 on interleukin-1␤ (IL-1␤)-stimulated MMP production and collagen degradation. Gene expression was determined by quantitative real-time reverse transcriptionpolymerase chain reaction, and protein levels were determined by Western blot analysis. Collagen degradation was determined by an in vitro matrix destruction assay. The effects of LG268 on nuclear protein binding and histone acetylation were determined by electrophoretic mobility shift assay and chromatin immunoprecipitation assay, respectively.Results.LG268 treatment specifically antagonized the IL-1␤-mediated induction of MMP-1 and MMP-13 heterogeneous nuclear RNA, messenger RNA, and protein. The inhibitory effect of LG268 was found to be due to a decrease in the rate of MMP-1 and MMP-13 transcription.LG268 treatment also prevented the in vitro degradation of a type I collagen matrix by IL-1␤-treated SW-1353 cells. The inhibitory effect of LG268 on MMP-1 and MMP-13 transcription appears to be mediated, at least in part, through modulation of histone modification in regions of the MMP-1 and MMP-13 promoters that contain binding sites for activator protein 1 transcription factors.Conclusion. These data indicate that LG268 treatment selectively inhibits inflammatory cytokineinduced production of MMP-1 and MMP-13 at the level of gene transcription and blocks collagen destruction by proinflammatory cytokine-stimulated chondrocytic cells. This study is among the first to describe how rexinoids affect gene expression, and the findings suggest that the rexinoid class of compounds may have a future role in preventing the irreversible collagen destruction seen in the arthritides.The destruction of joint tissues that is a hallmark of rheumatoid arthritis (RA) and osteoarthritis (OA) is mediated largely by members of the matrix metalloproteinase (MMP) family of enzymes (1-3). At low expression levels, these zinc-dependent endopeptidases maintain connective tissue homeostasis in a wide range of biologic functions (4). However, abnormally high levels of MMP expression have been linked to multiple pathologic states, including tumor invasion, atherosclerosis, and the arthritides (4). In humans, the MMP family currently encompasses 23 unique members, which degrade all constituents of the extracellular matrix (ECM) (5). The MMPs can be subdivided into 6 main classes (1,4,5), consisting of the collagenases (MMPs 1, 8, and 13), the gelatinases (MMPs 2 and 9), the stromelysins (MMPs 3, 10, and 11), the matrilysins (MMPs 7 and 26), the membrane-type MMPs (MMPs 14,15,16,17,24,and 25), and a diverse subgroup.The collagenase subgroup is unique in its ability to cleave fibrillar collagens, and their enzymatic activity represents a rate-limiting step...

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

Abstract: Interleukin-1␤ (IL-1␤

Cited by 48 publications

References 45 publications

Inhibition of Interleukin-1β-Induced Group IIA Secretory Phospholipase A2 Expression by Peroxisome Proliferator-Activated Receptors (PPARs) in Rat Vascular Smooth Muscle Cells: Cooperation between PPARβ and the Proto-Oncogene BCL-6

Inhibition of Interleukin-1β-Induced Group IIA Secretory Phospholipase A2 Expression by Peroxisome Proliferator-Activated Receptors (PPARs) in Rat Vascular Smooth Muscle Cells: Cooperation between PPARβ and the Proto-Oncogene BCL-6

Activation of the peroxisome proliferator–activated receptor α pathway potentiates interleukin‐1 receptor antagonist production in cytokine‐treated chondrocytes

Regulation of matrix metalloproteinase gene expression by a retinoid X receptor–specific ligand

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