Retinoblastoma suppression of matrix metalloproteinase 1, but not interleukin‐6, through a p38‐dependent pathway in rheumatoid arthritis synovial fibroblasts

Bradley, Kathleen; Scatizzi, John C.; Fiore, Stefano; Shamiyeh, Eli; Koch, Alisa E.; Firestein, Gary S.; Gorges, Laura L.; Kuntsman, Kevin; Pope, Richard M.; Moore, Terry L.; Han, Jiahuai; Perlman, Harris

doi:10.1002/art.11482

Cited by 19 publications

(12 citation statements)

References 75 publications

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“…Combined use of conventional medication and smCDK inhibitors may well have a synergistic antiarthritic effect. As was revealed by our recent report and others (30,39,40), CDKI may have broader activity than anticipated. We found recently that both alvocidib and compound A suppressed matrix metalloproteinase-3 production by synovial fibroblasts and osteoclastogenesis of macrophages (data not shown).…”

Section: Discussionsupporting

confidence: 55%

Successful Treatment of Animal Models of Rheumatoid Arthritis with Small-Molecule Cyclin-Dependent Kinase Inhibitors

Sekine

Sugihara

Miyake

et al. 2008

The Journal of Immunology

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Intraarticular gene transfer of cyclin-dependent kinase (CDK) inhibitors to suppress synovial cell cycling has shown efficacy in treating animal models of rheumatoid arthritis. Endogenous CDK inhibitors also modulate immune function via a CDK-independent pathway. Accordingly, systemic administration of small molecules that inhibit CDK may or may not ameliorate arthritis. To address this issue, alvocidib (flavopiridol), known to be tolerated clinically for treating cancers, and a newly synthesized CDK4/6-selective inhibitor were tested for antiarthritic effects. In vitro, they inhibited proliferation of human and mouse synovial fibroblasts without inducing apoptosis. In vivo, treatment of collagen-induced arthritis mice with alvocidib suppressed synovial hyperplasia and joint destruction, whereas serum concentrations of anti-collagen type II (CII) Abs and proliferative responses to CII were maintained. Treatment was effective even when therapeutically administered. Treated mice developed arthritis after termination of treatment. Thus, immune responses to CII were unimpaired. The same treatment ameliorated arthritis induced by K/BxN serum transfer to lymphocyte-deficient mice. Similarly, the CDK4/6-selective inhibitor suppressed collagen-induced arthritis. Both small-molecule CDK inhibitors were effective in treating animal models of rheumatoid arthritis not by suppressing lymphocyte function. Thus, the two small-molecule CDK inhibitors ameliorated arthritis models in a distinctive way, compared with other immunosuppressive drugs.

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Section: Discussionsupporting

confidence: 55%

Successful Treatment of Animal Models of Rheumatoid Arthritis with Small-Molecule Cyclin-Dependent Kinase Inhibitors

Sekine

Sugihara

Miyake

et al. 2008

The Journal of Immunology

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“…Moreover, it has been reported that its direct inhibitor pRb is constitutively inactivated in RASF 19. In order to investigate whether the TNFα-induced expression of EZH2 might be due to the activation of E2F, we performed reporter gene assays with luciferase vectors containing the EZH2 promoter with the wildtype or a mutated binding site for E2F (figure 3D).…”

Section: Resultsmentioning

confidence: 99%

Expression and function of EZH2 in synovial fibroblasts: epigenetic repression of the Wnt inhibitor SFRP1 in rheumatoid arthritis

Trenkmann

Brock

Kolling

et al. 2011

Annals of the Rheumatic Diseases

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OBJECTIVES: /st> To study the expression, regulation and function of the histone methyltransferase enhancer of zeste homologue 2 (EZH2) in synovial fibroblasts (SF) from patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: /st> SF were obtained from RA and OA patients undergoing joint surgery. Expression levels were assessed by quantitative real-time PCR and western blot. Kinase inhibitors and reporter gene assays were employed to study signalling pathways. Functional analyses included EZH2 overexpression by plasmid transfection and gene silencing by small interfering RNA. Chromatin immunoprecipitation assay was used to analyse histone methylation within distinct promoter regions. RESULTS: /st> By studying the expression and function of EZH2 in SF the authors found that EZH2 is overexpressed in rheumatoid arthritis synovial fibroblasts (RASF) and further induced by tumour necrosis factor alpha through the nuclear factor kappa B and Jun kinase pathways. As a target gene of EZH2 the authors identified secreted frizzled-related protein 1 (SFRP1), an inhibitor of Wnt signalling, which is associated with the activation of RASF, and show that SFRP1 expression correlates with the occupation of its promoter with activating and silencing histone marks. CONCLUSIONS: /st> These data strongly suggest that the chronic inflammatory environment of the RA joint induces EZH2 and thus might cause changes in the epigenetic programmes of SF. Expression and function of EZH2 in synovial fibroblasts: epigenetic repression of the Wnt inhibitor SFRP1 in rheumatoid arthritis ResultsBy studying expression and function of EZH2 in SF we found that EZH2 is overexpressed in RASF and further induced by tumour necrosis factor alpha through the NF-B and Jun kinase pathways. As a target gene of EZH2 we identified secreted frizzled related protein (SFRP)1, an inhibitor of Wnt signalling, which is associated with the activation of RASF, and show that SFRP1 expression correlates with the occupation of its promoter with activating and silencing histone marks. ConclusionsOur data strongly suggest that the chronic inflammatory environment of the RA joint induces EZH2and, thus, might cause changes in the epigenetic programmes of SF.

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“…Moreover, it has been demonstrated that restoration of Rb to appropriate levels inhibits the cell cycle as well as down-regulates the production of IL-6 and MMP-1 in RASF [22].…”

Section: Cell Cycle Regulation and Oncogenesmentioning

confidence: 99%

Synovial cell activation

Stańczyk

Ospelt

Gay

et al. 2006

Current Opinion in Rheumatology

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The key role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis has been highlighted by the fact that these cells not only are the main executors of cartilage and bone destruction but also modulate numerous interactions in rheumatoid joints. Moreover, it has become evident that integration of a large body of information is indispensable to get a comprehensive outlook on synovial activation in the pathology of rheumatoid arthritis.

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Retinoblastoma suppression of matrix metalloproteinase 1, but not interleukin‐6, through a p38‐dependent pathway in rheumatoid arthritis synovial fibroblasts

Cited by 19 publications

References 75 publications

Successful Treatment of Animal Models of Rheumatoid Arthritis with Small-Molecule Cyclin-Dependent Kinase Inhibitors

Successful Treatment of Animal Models of Rheumatoid Arthritis with Small-Molecule Cyclin-Dependent Kinase Inhibitors

Expression and function of EZH2 in synovial fibroblasts: epigenetic repression of the Wnt inhibitor SFRP1 in rheumatoid arthritis

Synovial cell activation

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