ArticleArthritis research & therapy2013
CCN4 induces IL-6 production through αvβ5 receptor, PI3K, Akt, and NF-κB singling pathway in human synovial fibroblasts.
Article in Arthritis research & therapy, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 44 papers.
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Who cites it
44 citing papers in PubMed, 70 citations in OpenAlex.
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- Osteoarthritis and dementia: contrasting disorders driven by mutual pathways of autophagy, mTOR, GLP-1, AMPK, Wnt, and WISP1.Expert review of clinical pharmacology · 2026Review
- Apoptotic Cancer Cell-Primed Cancer-Associated Fibroblasts Suppress Immunosuppressive Macrophages via WISP-1-Integrin α5β3-STAT1 Signaling in Lung Cancer.International journal of biological sciences · 2026Article
- Bulk RNAseq Analysis of Cardiac Myosin-Specific CD4Biomedicines · 2025Article
- Understanding chronic inflammation: couplings between cytokines, ROS, NO, CaFrontiers in immunology · 2025Review
- miR-548aj-3p and miR-3127-3p suppress RANKL-facilitated inflammatory cytokines and catabolic factor in osteoarthritis and rheumatoid arthritis.International journal of medical sciences · 2025Article
- Acute COVID-19 and LongCOVID syndrome - molecular implications for therapeutic strategies - review.Frontiers in immunology · 2025Review
- CCN4 (WISP-1) reduces apoptosis and atherosclerotic plaque burden in an ApoE mouse model.Atherosclerosis · 2024Article
- WISP1 and Macrophage Migration Inhibitory Factor in Respiratory Inflammation: Novel Insights and Therapeutic Potentials for Asthma and COPD.International journal of molecular sciences · 2024Review
- The joint protective function of live- and dead-Aging · 2024Article
- An overview of CCN4 (WISP1) role in human diseases.Journal of translational medicine · 2024Review
- WISP1 induces the expression of macrophage migration inhibitory factor in human lung fibroblasts through Src kinases and EGFR-activated signaling pathways.American journal of physiology. Cell physiology · 2024Article
- Head-to-Head Comparison of CCN4, DNMT3A, PTPN11, and SPARC as Suppressors of Anti-tumor Immunity.Cellular and molecular bioengineering · 2023Article
- Irisin Induces Apoptosis in Metastatic Prostate Cancer Cells and Inhibits Tumor Growth In Vivo.Cancers · 2023Article
- Optimal CCN4 Immunofluorescence for Tissue Microarray.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Typical response of CD14Frontiers in medicine · 2022Article
- CCN proteins in the musculoskeletal system: current understanding and challenges in physiology and pathology.Journal of cell communication and signaling · 2021Review
- Aneurysm severity is suppressed by deletion of CCN4.Journal of cell communication and signaling · 2021Article
- Targeting CCN Proteins in Rheumatoid Arthritis and Osteoarthritis.International journal of molecular sciences · 2021Review
- Mechanical Stress Induce PG-E2 in Murine Synovial Fibroblasts Originating from the Temporomandibular Joint.Cells · 2021Article
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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