Effects of agonists of peroxisome proliferator-activated receptor γ on proteoglycan degradation and matrix metalloproteinase production in rat cartilage in vitro

Sabatini, Massimo; Bardiot, A.; Lesur, C.; Moulharat, Natacha; Thomas, Mireille; Richard, Isabelle; Fradin, Armel

doi:10.1053/joca.2002.0827

Cited by 34 publications

(30 citation statements)

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“…In addition, each cell type has pathophysiologic relevance to joint inflammation by their production of mediators of inflammation or matrix-degrading enzymes and can therefore be considered a pharmacologic target for PPAR␥ agonists (37). Consistent with this idea, PPAR␥ ligands have been shown to decrease the expression of TNF␣ in activated synoviocytes (28) and macrophages (19) and the production of various matrix metalloproteinases in chondrocytes (25,38) and synoviocytes (39). Synoviocytes may play a crucial role because of their ability to proliferate under inflammatory conditions (40) and to cooperate with both macrophages in the synovial pannus and chondrocytes at the synovium-cartilage junction (41).…”

Section: Discussionmentioning

confidence: 81%

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

Moulin¹,

Bianchi²,

Boyault³

et al. 2005

Arthritis & Rheumatism

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Objective. To study the potency of 2 peroxisome proliferator-activated receptor ␥ (PPAR␥) agonists, 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15-deoxy-PGJ 2 ) and rosiglitazone, to modulate the expression of interleukin-1 receptor antagonist (IL-1Ra) in rat synovial fibroblasts.Methods. Levels of messenger RNA for IL-1Ra and PPAR isotypes (␣, ␤/␦, ␥) were assessed by realtime polymerase chain reaction in rat synovial fibroblasts exposed to 10 ng/ml of IL-1␤. PPAR levels were assessed by Western blotting and secreted IL-1Ra levels by immunoassay. The potency of PPAR␥ agonists and the PPAR␤/␦ agonist GW-501516 on IL-1Ra levels was tested in the range of 1-10 M and at 100 pM, respectively. The contribution of PPAR␥ to the effects of rosiglitazone on IL-1Ra secretion was examined either by its overexpression or by inhibition using wild-type or dominant-negative constructs and the antagonist GW-9662 (10 M), respectively. The dominant-negative strategy was also performed to investigate the possible contribution of PPAR␤/␦ and NF-B activation.Results. IL-1␤-induced IL-1Ra production was increased by 10 M rosiglitazone but was reduced dose-dependently by 15-deoxy-PGJ 2 . Both agonists lowered IL-1␤ secretion, but rosiglitazone alone reduced the imbalance of IL-1␤/IL-1Ra toward basal levels. Enhancement of IL-1␤-induced IL-1Ra production by rosiglitazone was not affected by PPAR␥ overexpression or by its inhibition with dominant-negative PPAR␥ or GW-9662. Inhibition of NF-B was also ineffective against rosiglitazone but abolished the stimulating effect of IL-1␤ on IL-1Ra. All PPAR isotypes were expressed constitutively in rat synoviocytes, but PPAR␥ decreased dramatically upon IL-1␤ exposure, whereas PPAR␤/␦ remained stable. Dominant-negative PPAR␤/␦ abolished the enhancement of IL-1Ra by rosiglitazone, whereas GW-501516 reproduced the effect of rosiglitazone on IL-1Ra secretion.Conclusion. Rosiglitazone stimulates IL-1Ra production by a PPAR␤/␦ mechanism in activated rat synovial fibroblasts, further contributing to its potential antiarthritic properties and opening new perspectives for the modulation of inflammatory genes by specific PPAR agonists in articular cells.

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Section: Discussionmentioning

confidence: 81%

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

Moulin¹,

Bianchi²,

Boyault³

et al. 2005

Arthritis & Rheumatism

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“…Moreover, PPARg agonist inhibited IL-1b-induced MMP-13 expression in human chondrocytes at the transcriptionnal level, probably by interfering with the activation of AP-1 (61). Finally, this effect was also described for MMP-3 because PPARg inhibited MMP-3 production and subsequent proteoglycan degradation in rat cartilage explants (62). Therefore, besides the downregulation of PGE 2 release in mPGES-1 null iMACs, an increased release of PPARg may be implicated in downregulation of IL-1b-induced MMP-3 and MMP-13 expression.…”

Section: Figurementioning

confidence: 75%

Inhibition of Matrix Metalloproteinase-3 and -13 Synthesis Induced by IL-1β in Chondrocytes from Mice Lacking Microsomal Prostaglandin E Synthase-1

Gosset

Pigenet

Salvat

et al. 2010

The Journal of Immunology

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Joint destruction in arthritis is in part due to the induction of matrix metalloproteinase (MMP) expression and their inhibitors, especially MMP-13 and -3, which directly degrade the cartilage matrix. Although IL-1β is considered as the main catabolic factor involved in MMP-13 and -3 expression, the role of PGE2 remains controversial. The goal of this study was to determine the role of PGE2 on MMP synthesis in articular chondrocytes using mice lacking microsomal PGE synthase-1 (mPGES-1), which catalyses the rate-limiting step of PGE2 synthesis. MMP-3 and MMP-13 mRNA and protein expressions were assessed by real-time RT-PCR, immunoblotting, and ELISA in primary cultures of articular chondrocytes from mice with genetic deletion of mPGES-1. IL-1β–induced PGE2 synthesis was dramatically reduced in mPGES-1−/− and mPGES-1+/− compared with mPGES-1+/+ chondrocytes. A total of 10 ng/ml IL-1β increased MMP-3 and MMP-13 mRNA, protein expression, and release in mPGES-1+/+ chondrocytes in a time-dependent manner. IL-1β–induced MMP-3 and MMP-13 mRNA expression, protein expression, and release decreased in mPGES-1−/− and mPGES-1+/− chondrocytes compared with mPGES-1+/+ chondrocytes from 8 up to 24 h. Otherwise, MMP inhibition was partially reversed by addition of 10 ng/ml PGE2 in mPGES-1−/− chondrocytes. Finally, in mPGES-1−/− chondrocytes treated by forskolin, MMP-3 protein expression was significantly decreased compared with wild-type, suggesting that PGE2 regulates MMP-3 expression via a signaling pathway dependent on cAMP. These results demonstrate that PGE2 plays a key role in the induction of MMP-3 and MMP-13 in an inflammatory context. Therefore, mPGES-1 could be considered as a critical target to counteract cartilage degradation in arthritis.

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“…Intra-articular injection of 15d-PGJ2 inhibits adjuvantinduced arthritis in rats (1) and addition of 15d-PGJ2 to IL-1␤-treated human or rat chondrocytes in culture counteracts IL-1␤-induced effects (2)(3)(4). As IL-1␤ plays a central role in the degradation of cartilage in rheumatoid arthritis and osteoarthritis (5,6), the above data suggest a role for PPAR-␥ in cartilage homeostasis leading to new directions in therapeutic research.…”

mentioning

confidence: 95%

“…Numerous synthetic PPAR-␥ activators have been identified, including thiazolidinediones (such as rosiglitazone (Rtz)) used in the treatment of type II diabetes (8). PPAR-␥ was first demonstrated to regulate adipocyte differentiation, and it has been recognized recently (9) to be implicated in the modulation of cancer cells growth and inhibition of the inflammatory process in immunocompetent cells (10 -13) and other cell types (14), including cartilage cells (2)(3)(4). Most anti-inflammatory effects have been observed with 15d-PGJ2, a poor agonist of PPAR-␥, whereas synthetic PPAR-␥ ligands such as Rtz were less effective or not active, despite their higher affinity for the receptor (Rtz K d Յ 100 nM).…”

mentioning

confidence: 99%

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

François

Richette

Tsagris

et al. 2004

Journal of Biological Chemistry

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Effects of agonists of peroxisome proliferator-activated receptor γ on proteoglycan degradation and matrix metalloproteinase production in rat cartilage in vitro

Cited by 34 publications

References 30 publications

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

Rosiglitazone induces interleukin‐1 receptor antagonist in interleukin‐1β–stimulated rat synovial fibroblasts via a peroxisome proliferator–activated receptor β/δ–dependent mechanism

Inhibition of Matrix Metalloproteinase-3 and -13 Synthesis Induced by IL-1β in Chondrocytes from Mice Lacking Microsomal Prostaglandin E Synthase-1

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

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