Agonists of peroxisome proliferators-activated receptors (PPAR) α, β/δ or γ reduce transforming growth factor (TGF)-β-induced proteoglycans' production in chondrocytes

Poleni, Paul-Emile; Bianchi, Arnaud; Étienne, S.; Koufany, Meriem; Sébillaud, Sylvie; Netter, Patrick; Terlain, Bernard; Jouzeau, Jean‐Yves

doi:10.1016/j.joca.2006.10.009

Cited by 36 publications

(39 citation statements)

References 77 publications

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“…Given the anti-inflammatory and anti-catabolic functions of PPARγ, it is reasonable to speculate that the suppression of PPARγ expression by inflammatory mediators in chondrocytes presents a new and additional mechanism by which these mediators contribute to the pathogenesis of OA. Our findings are consistent with other studies showing that pro-inflammatory stimuli downregulate PPARγ expression in chondrocytes [31-33] and synovial fibroblasts [34,35]. In contrast, Shan and colleagues [36] found that IL-1 upregulates PPARγ expression in chondrocytes.…”

Section: Discussionsupporting

confidence: 93%

Peroxisome proliferator-activated receptor γ1 expression is diminished in human osteoarthritic cartilage and is downregulated by interleukin-1β in articular chondrocytes

et al. 2007

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Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor involved in the regulation of many cellular processes. We and others have previously shown that PPARγ activators display anti-inflammatory and chondroprotective properties in vitro and improve the clinical course and histopathological features in an experimental animal model of osteoarthritis (OA). However, the expression and regulation of PPARγ expression in cartilage are poorly defined. This study was undertaken to investigate the quantitative expression and distribution of PPARγ in normal and OA cartilage and to evaluate the effect of IL-1β, a prominent cytokine in OA, on PPARγ expression in cultured chondrocytes. Immunohistochemical analysis revealed that the levels of PPARγ protein expression were significantly lower in OA cartilage than in normal cartilage. Using real-time RT-PCR, we demonstrated that PPARγ1 mRNA levels were about 10-fold higher than PPARγ2 mRNA levels, and that only PPARγ1 was differentially expressed: its levels in OA cartilage was 2.4-fold lower than in normal cartilage (p < 0.001). IL-1 treatment of OA chondrocytes downregulated PPARγ1 expression in a dose- and time-dependent manner. This effect probably occurred at the transcriptional level, because IL-1 decreases both PPARγ1 mRNA expression and PPARγ1 promoter activity. TNF-α, IL-17, and prostaglandin E2 (PGE2), which are involved in the pathogenesis of OA, also downregulated PPARγ1 expression. Specific inhibitors of the mitogen-activated protein kinases (MAPKs) p38 (SB203580) and c-Jun N-terminal kinase (SP600125), but not of extracellular signal-regulated kinase (PD98059), prevented IL-1-induced downregulation of PPARγ1 expression. Similarly, inhibitors of NF-κB signaling (pyrrolidine dithiocarbamate, MG-132, and SN-50) abolished the suppressive effect of IL-1. Thus, our study demonstrated that PPARγ1 is downregulated in OA cartilage. The pro-inflammatory cytokine IL-1 may be responsible for this downregulation via a mechanism involving activation of the MAPKs (p38 and JNK) and NF-κB signaling pathways. The IL-1-induced downregulation of PPARγ expression might be a new and additional important process by which IL-1 promotes articular inflammation and cartilage degradation.

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Section: Discussionsupporting

confidence: 93%

Peroxisome proliferator-activated receptor γ1 expression is diminished in human osteoarthritic cartilage and is downregulated by interleukin-1β in articular chondrocytes

et al. 2007

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“…Wy14643, a PPARα agonist,21 had no effect on production of cytokines by IPFP and synovium in culture conditions without IL-1β (data not shown). To investigate whether PPARα activation could inhibit IL-1β induced cytokine production, we treated the IL-1β stimulated IPFP explants with 10 −4 M Wy14643.…”

Section: Resultsmentioning

confidence: 92%

Cytokine production by infrapatellar fat pad can be stimulated by interleukin 1β and inhibited by peroxisome proliferator activated receptor α agonist

Clockaerts

Bastiaansen-Jenniskens

Feijt

et al. 2012

Ann Rheum Dis

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“…Specifically, they have been shown to block profibrotic actions of transforming growth factor (TGF)-␤1 by inhibiting binding of the nuclear transcription factor activator protein-1 (21), by interfering with the Smad2 and Smad3 signaling pathways, and by reducing phosphorylation of ERK1/2 (49,72). Recent studies have demonstrated significant potential roles for PPAR-␥ agonists with respect to pulmonary pathobiology (28,61).…”

mentioning

confidence: 99%

PPAR-γ agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis

Milam

Keshamouni

Phan³

et al. 2008

American Journal of Physiology-Lung Cellular and Molecular Phys

184

171

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Pulmonary fibrosis is characterized by alterations in fibroblast phenotypes resulting in excessive extracellular matrix accumulation and anatomic remodeling. Current therapies for this condition are largely ineffective. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear hormone receptor superfamily, the activation of which produces a number of biological effects, including alterations in metabolic and inflammatory responses. The role of PPAR-gamma as a potential therapeutic target for fibrotic lung diseases remains undefined. In the present study, we show expression of PPAR-gamma in fibroblasts obtained from normal human lungs and lungs of patients with idiopathic interstitial pneumonias. Treatment of lung fibroblasts and myofibroblasts with PPAR-gamma agonists results in inhibition of proliferative responses and induces cell cycle arrest. In addition, PPAR-gamma agonists, including a constitutively active PPAR-gamma construct (VP16-PPAR-gamma), inhibit the ability of transforming growth factor-beta1 to induce myofibroblast differentiation and collagen secretion. PPAR-gamma agonists also inhibit fibrosis in a murine model, even when administration is delayed until after the initial inflammation has largely resolved. These observations indicate that PPAR-gamma is an important regulator of fibroblast/myofibroblast activation and suggest a role for PPAR-gamma ligands as novel therapeutic agents for fibrotic lung diseases.

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Agonists of peroxisome proliferators-activated receptors (PPAR) α, β/δ or γ reduce transforming growth factor (TGF)-β-induced proteoglycans' production in chondrocytes

Cited by 36 publications

References 77 publications

Peroxisome proliferator-activated receptor γ1 expression is diminished in human osteoarthritic cartilage and is downregulated by interleukin-1β in articular chondrocytes

Peroxisome proliferator-activated receptor γ1 expression is diminished in human osteoarthritic cartilage and is downregulated by interleukin-1β in articular chondrocytes

Cytokine production by infrapatellar fat pad can be stimulated by interleukin 1β and inhibited by peroxisome proliferator activated receptor α agonist

PPAR-γ agonists inhibit profibrotic phenotypes in human lung fibroblasts and bleomycin-induced pulmonary fibrosis

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