Abstract
IntroductionOsteoarthritis (OA) is the most common degenerative joint disease that is involved in the degradation of articular cartilage. The exact etiology of OA is not completely understood. CCN4 is related to up-regulation in the cartilage of patients 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.MethodsCCN4-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. Neutralizing antibodies of integrin were used to block the integrin signaling pathway. Luciferase assays were used to study IL-6 and NF-κB promoter activity. Immunocytochemistry was used to examine the translocation activity of p65.ResultsOsteoarthritis synovial fibroblasts (OASFs) showed significant expression of CCN4 and the expression was higher than in normal SFs. OASF stimulation with CCN4 induced concentration- and time-dependent increases in IL-6 production. Pretreatment of OASFs with αvβ5 but not α5β1 and αvβ3 integrin antibodies reduced CCN4-induced IL-6 production. CCN4-mediated IL-6 production was attenuated by PI3K inhibitor (LY294002 and Wortmannin), Akt inhibitor (Akti), and NF-κB inhibitor (PDTC and TPCK). Stimulation of cells with CCN4 also increased PI3K, Akt, and NF-κB activation.ConclusionsOur results suggest that CCN4 activates αvβ5 integrin, PI3K, Akt, and NF-κB 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.
Highlights
Osteoarthritis (OA) is the most common degenerative joint disease that is involved in the degradation of articular cartilage
CCN4-mediated IL-6 production was attenuated by PI3K inhibitor (LY294002 and Wortmannin), Akt inhibitor (Akti), and NF-B inhibitor (PDTC and TPCK)
Our results suggest that CCN4 activates avb5 integrin, PI3K, Akt, and NF-B pathways, leading to up-regulation of IL-6 production
Summary
Osteoarthritis (OA) is the most common degenerative joint disease that is involved in the degradation of articular cartilage. Osteoarthritis (OA) is the most common degenerative disease of the synovial joint that involves the degradation of articular cartilage, subchondral bone sclerosis, abnormal bone remodeling, osteophyte formation, and chronic inflammation of the synovial membrane [1,2]. The synovial membrane is responsible for the inflammatory reaction leading to macrophagederived proinflammatory cytokines, such as IL-1b, IL-6, IL-8 and TNF-a, that promote inflammation, neovascularization and cartilage degradation via activation of matrix-degrading enzymes, such as matrix metalloproteinases (MMPs) [4,5,6]. Chondrocytes produce low levels of IL-6 under normal conditions These data suggest that IL-6 plays an important role during OA pathogenesis. Phosphorylation of IBa at Ser and Ser and IBa at Ser and Ser produces ubiquitination of IBa/b at lysine residues and degradation by the 26S proteasome [15,16]
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