| CCN4 induces IL-6 production through avb5 receptor, PI3K, Akt, and NF-kB singling pathway in human synovial fibroblasts. | |
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MedLine Citation:
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PMID: 23343403 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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ABSTRACT: INTRODUCTION: Osteoarthritis (OA) is the most common degenerative joint disease that involving in degradation of articular cartilage. The exact etiology of OA is not completely understood. CCN4 is related to up-regulation in the cartilage of patient with osteoarthritis. Previous studies have shown that CCN4 might be associated with the pathogenesis of OA, but the exact signaling pathways in CCN4-mediated IL-6 expression in synovial fibroblasts (SF) are largely unknown. Therefore, we explored the intracellular signaling pathway involved in CCN4-induced IL-6 production in human synovial fibroblast cells. METHODS: CCN4-induced IL-6 production was assessed with quantitative real-time qPCR and ELISA. The mechanisms of action of CCN4 in different signaling pathways were studied by using Western blotting. Neutralization antibodies of integrin were achieved to block the integrin signaling pathway. Luciferase assays were used to study IL-6 and NFkB promoter activity. Immunocytochemistry was used to examine the translocation activity of p65. RESULTS: Osteoarthritis synovial fibroblasts (OASFs) showed significant expression of CCN4, and the expression was higher than in normal SFs. OASFs stimulation with CCN4 induced concentration- and time-dependent increases in IL-6 production. Pretreatment of OASFs with avb5 but not a5b1 and avb3 integrin antibody reduced CCN4-induced IL-6 production. CCN4-mediated IL-6 production was attenuated by PI3K inhibitor (LY294002 and Wortmannin), Akt inhibitor (Akti), or NF-kB inhibitor (PDTC and TPCK). Stimulation of cells with CCN4 also increased PI3K, Akt, and NF-kB activation. CONCLUSIONS: Our results suggest that CCN4 activates avb5 integrin, PI3K, Akt, and NF-kB pathways, leading to up-regulation of IL-6 production. According to our results, CCN4 may be an appropriate target for drug intervention in OA in the future. |
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Authors:
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Chun-Han Hou; Chih-Hsin Tang; Chin-Jung Hsu; Sheng-Mon Hou; Ju-Fang Liu |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-23 |
Journal Detail:
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Title: Arthritis research & therapy Volume: 15 ISSN: 1478-6362 ISO Abbreviation: Arthritis Res. Ther. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-24 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 101154438 Medline TA: Arthritis Res Ther Country: - |
Other Details:
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Languages: ENG Pagination: R19 Citation Subset: - |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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