PGE2 inhibits MMP expression by suppressing MKK4–JNK MAP kinase–c‐JUN pathway via EP4 in human articular chondrocytes

Nishitani, Kohei; Ito, Hiromu; Hiramitsu, Teruko; Tsutsumi, Ryosuke; Tanida, Seiichi; Kitaori, Toshiyuki; Kobayashi, Masahiko; Nakamura, Takashi

doi:10.1002/jcb.22421

Cited by 44 publications

(43 citation statements)

References 39 publications

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“…The JNK pathway is one of the signaling intermediates activated by adiponectin [28,29], and adiponectin-induced JNK activation has been shown to follow AMPK activation [30,31]. Furthermore, JNK is involved in MMPs and iNOS expression in human articular chondrocytes [32-36]. Therefore, we expect that adiponectin induces iNOS and MMP expression via JNK downstream to AMPK in human chondrocytes and that the AMPK/JNK axis is a major signaling system responsible for the adiponectin-induced degradation of cartilage matrix.…”

Section: Discussionmentioning

confidence: 99%

Adiponectin is a potential catabolic mediator in osteoarthritis cartilage

et al. 2010

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IntroductionAdiponectin has been implicated in the pathogenesis of osteoarthritis (OA). We studied the effects of adiponectin on the OA cartilage homeostasis.MethodsImmunohistochemical analysis was performed to evaluate differential expression of adiponectin receptors (AdipoRs) in nonlesional and lesional areas of OA cartilage. Cartilage and chondrocytes from the knee joints of primary OA patients were cultured in the presence of adiponectin (0~30 μg/ml). The levels of total nitric oxide (NO), matrix metalloproteinase (MMP)-1, -3, and -13, and tissue inhibitor of metalloproteinase (TIMP)-1 were measured in the conditioned media. The levels of inducible NO synthase (iNOS) and MMPs were determined with the quantitative real-time reverse transcription-polymerase chain reaction. The concentrations of collagenase-cleaved type II collagen neoepitope (C1-2C) were determined in the supernatant of adiponectin-stimulated OA cartilage explants. The effects of kinase and NOS inhibitors were evaluated in the adiponectin-stimulated chondrocytes.ResultsThe expression levels of both AdipoR1 and AdipoR2 were significantly higher in lesional than in nonlesional areas of OA cartilage. The increased rate of AdipoR1-positive chondrocytes was twice that of AdipoR2-positive chondrocytes when compared between nonlesional and lesional areas. Adiponectin-stimulated OA chondrocytes showed increased total NO and MMP-1, -3, and -13 levels compared with nonstimulated cells. The TIMP-1 level was not affected. The C1-2C levels were increased by adiponectin in OA cartilage explant culture. AMP-activated protein kinase (AMPK) and c-Jun N-terminal kinase (JNK) inhibitors (compound C and SP600125) significantly suppressed adiponectin-induced production of total NO and MMP-1, -3, and -13. Inducible NOS inhibitors enhanced the expression of the adiponectin-induced MMPs.ConclusionsAdiponectin causes matrix degradation in OA cartilage and increases MMPs and iNOS expression via the AMPK and JNK pathways in human OA chondrocytes. The catabolic effects of adiponectin may be counteracted by NO.

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Section: Discussionmentioning

confidence: 99%

Adiponectin is a potential catabolic mediator in osteoarthritis cartilage

et al. 2010

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“…Moreover, blocking EP4 receptor inhibited MMP-13 expression induced by PGE 2 (29). Therefore, it seems that in inflammatory conditions, both EP2 and EP4 receptors (58,59) are implicated in chondrocytes in response to PGE 2 . As the first one can trigger anabolic responses, the second one, which is the only one upregulated in arthritis cartilage, may mainly be implicated in transducing the catabolic processes of PGE 2 .…”

Section: Figurementioning

confidence: 93%

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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“…The activation of these cascades coordinates the induction and activation of transcription factors, including members of the AP-1, ETS, and C/EBP families, that regulate the expression of genes involved in catabolic and inflammatory events. JNK-driven AP-1 activation, MEK/ERK-induced phosphorylation of ETS factors, and p38-mediated activation of C/EBPβ and RUNX2 participate in the induction of MMPs, including MMP-13 [25,26]. Such actions of particular kinases may be isoform-specific, as in the case of p38γ, which actually suppresses MMP-13 production [27].…”

Section: The Role Of Cytokines and Other Inflammatory Mediatorsmentioning

confidence: 99%

Inflammation in osteoarthritis

Goldring

Otero

2011

Current Opinion in Rheumatology

1,202

972

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Purpose of review This review focuses on the novel stress-induced and proinflammatory mechanisms underlying the pathogenesis of osteoarthritis, with particular attention to the role of synovitis and the contributions of other joint tissues to cellular events that lead to the onset and progression of the disease and irreversible cartilage damage. Recent findings Studies during the past 2 years have uncovered novel pathways that, when activated, cause the normally quiescent articular chondrocytes to become activated and undergo a phenotypic shift, leading to the disruption of homeostasis and ultimately to the aberrant expression of proinflammatory and catabolic genes. Studies in animal models and retrieved human tissues indicate that proinflammatory factors may be produced by the chondrocytes themselves or by the synovium and other surrounding tissues, even in the absence of overt inflammation, and that multiple pathways converge on the upregulation of aggrecanases and collagenases, especially MMP-13. Particular attention has been paid to the contribution of synovitis in posttraumatic joint injury, such as meniscal tears, and the protective role of the pericellular matrix in mediating chondrocyte responses through receptors, such as discoidin domain receptor-2 and syndecan-4. New findings about intracellular signals, including the transcription factors NF-κB, C/EBPβ, ETS, Runx2, and hypoxia-inducible factor-2α, and their modulation by inflammatory cytokines, chemokines, adipokines, Toll-like receptor ligands, and receptor for advanced glycation end-products, as well as CpG methylation and microRNAs, are reviewed. Summary Further work on mediators and pathways that are common across different models and occur in human osteoarthritis and that impact the osteoarthritis disease process at different stages of initiation and progression will inform us about new directions for targeted therapies.

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PGE2 inhibits MMP expression by suppressing MKK4–JNK MAP kinase–c‐JUN pathway via EP4 in human articular chondrocytes

Cited by 44 publications

References 39 publications

Adiponectin is a potential catabolic mediator in osteoarthritis cartilage

Adiponectin is a potential catabolic mediator in osteoarthritis cartilage

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

Inflammation in osteoarthritis

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