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      miR-708-5p promotes fibroblast-like synoviocytes’ cell apoptosis and ameliorates rheumatoid arthritis by the inhibition of Wnt3a/β-catenin pathway

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          Abstract

          Aim

          MicroRNAs (miRNA) are a class of small, highly conserved noncoding RNA molecules, which contain 18–28 nucleotides and are involved in the regulation of gene expression. It has been proved that microRNAs play a very important role in several key cellular processes, such as cell differentiation, cell cycle progression, and apoptosis, as well as in autoimmune disease. One recently identified miRNA, miR-708-5p, has been demonstrated to have profound roles in suppressing oncogenesis in different types of tumors. However, the role of miR-708-5p in rheumatoid arthritis (RA) remains to be fully elucidated. Therefore, in this study, we are aiming to identify the role of miR-708-5p in RA.

          Methods

          The expression level of miR-708-5p in synovial tissues of patients with RA is much lower than in non-RA controls. The effects of miR-708-5p on cell apoptosis, colony formation, and migration in fibroblast-like synoviocytes were assessed in MH7A cells.

          Results

          Results showed that delivery of miR-708-5p mimics into synovial fibroblasts MH7A could induce cell apoptosis and inhibit colony formation and migration. In addition, miR-708-5p mimics significantly inhibit Wnt3a/β-catenin pathway activity both in transcription and protein level, which could be reversed by the addition of R-spondin 1, an activator of Wnt pathway. R-spondin 1 could also reverse the inhibition of cell survival and proliferation, which was induced by miR-708-5p mimics in MH7A. Moreover, injection of miR-708-5p mimics into collagen-induced rat RA model could ameliorate the RA index and decrease Wnt3a/β-catenin expression in rat joint tissues.

          Conclusion

          Therefore, we concluded that miR-708-5p is likely to be involved in RA pathogenesis via inhibition of Wnt3a/β-catenin pathway.

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          Most cited references 15

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          Diagnostic and predictive value of anti-cyclic citrullinated protein antibodies in rheumatoid arthritis: a systematic literature review.

          To evaluate the two generations of anti-cyclic citrullinated protein (CCP) antibodies as a diagnostic marker of rheumatoid arthritis (RA) and as a predictor of future development of RA in healthy subjects and in patients with early undifferentiated arthritis. A systematic analysis of the literature published between 1999 and February 2006 was conducted. Data were collected on the sensitivity and specificity of the two generations of anti-CCP antibodies for diagnosing RA and predicting future development of the disease. Among 107 studies initially identified, 68 had interpretable data and were analysed. Diagnostic properties were assessed in 58 studies: mean (SD) sensitivity was 53 (10)% (range 41-68) and 68 (15)% (range 39-94) for anti-CCP1 and anti-CCP2, respectively; mean (SD) specificity was 96 (3)% (range 90-99) and 95 (5)% (range 81-100) for anti-CCP1 and anti-CCP2, respectively. Predictive properties were assessed in 14 studies; odds ratio (95% confidence interval) of anti-CCP1 and anti-CCP2 for the future development of RA were 20 (14 to 31) and 25 (18 to 35), respectively, among patients with early undifferentiated arthritis and 64.5 (8.5 to 489) and 28 (8 to 95), respectively, among healthy subjects. Sensitivity of the second generation of anti-CCP is close to that of rheumatoid factor, with a higher specificity, for distinguishing RA from other rheumatic diseases. Moreover, anti-CCP antibodies appear to be highly predictive of the future development of RA in both healthy subjects and patients with undifferentiated arthritis.
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            MicroRNA-124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis.

            To elucidate the role of microRNA (miRNA) in the pathogenesis of rheumatoid arthritis (RA), we analyzed synoviocytes from RA patients for their miRNA expression. Synoviocytes derived from surgical specimens obtained from RA patients were compared with those obtained from osteoarthritis (OA) patients for their expression of a panel of 156 miRNA with quantitative stem-loop reverse transcription-polymerase chain reaction. The miRNA whose expression decreased or increased in RA synoviocytes as compared with OA synoviocytes were identified, and their target genes were predicted by computer analysis. We used an in vitro system of enhancing the expression of specific miRNA by transfection of precursors into synoviocytes, and then we performed proliferation, cell cycle, and apoptosis assays, as well as enzyme-linked immunosorbent assays for cytokine production. The effects of transfection on predicted target protein and messenger RNA (mRNA) were then examined by Western blot analysis and luciferase reporter assay. We found that miR-124a levels significantly decreased in RA synoviocytes as compared with OA synoviocytes. Transfection of precursor miR-124a into RA synoviocytes significantly suppressed their proliferation and arrested the cell cycle at the G1 phase. We identified a putative consensus site for miR-124a binding in the 3'-untranslated region of cyclin-dependent kinase 2 (CDK-2) and monocyte chemoattractant protein 1 (MCP-1) mRNA. Induction of miR-124a in RA synoviocytes significantly suppressed the production of the CDK-2 and MCP-1 proteins. Luciferase reporter assay demonstrated that miR-124a specifically suppressed the reporter activity driven by the 3'-untranslated regions of CDK-2 and MCP-1 mRNA. The results of this study suggest that miR-124a is a key miRNA in the posttranscriptional regulatory mechanisms of RA synoviocytes.
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              MicroRNAs in rheumatoid arthritis: altered expression and diagnostic potential.

              Rheumatoid arthritis (RA) is a polygenic disease characterized by autoimmunity and systemic inflammation with progressive impairment of joints that results in lifelong disability and increased mortality. Early diagnosis and therapeutic intervention or treatment can prevent severe disease manifestations in patients suffering from RA. The use of appropriate predictive biomarkers may improve the efficiency of RA therapy. The general aim of this review is to highlight the most recent findings on miRNAs expression profiles in RA patients and to discuss their potential as new biomarkers for diagnostic purposes. The current literature demonstrates that a variety of miRNAs is frequently dysregulated in RA patients. To date, the majority of miRNAs have been found to be overexpressed during the natural course of RA. MiR-16, miR-146a/b, miR-150, miR-155, and miR-223 described here were shown to be overexpressed at the systemic level: in both the periphery and RA joints. Circulating peripheral blood miRNAs, especially miR-16, miR-21, miR-24, miR-26a, miR-125a-5p, miR-125b, miR-126-3p, miR-223, and miR-451, which are elevated in the plasma or serum, are considered to be the most promising non-invasive biomarkers for the detection of RA.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2018
                10 October 2018
                : 12
                : 3439-3447
                Affiliations
                [1 ]Department of Rheumatology and Immunology, Central Hospital of Xinxiang, Henan 453000, People’s Republic of China, fanwen_qiang@ 123456sina.com
                [2 ]Department of Endocrinology, Central Hospital of Xinxiang, Henan 453000, People’s Republic of China
                Author notes
                Correspondence: Wenqiang Fan, Department of Rheumatology and Immunology, Central Hospital of Xinxiang, Jinsui Road 56, Henan 453000, People’s Republic of China, Email fanwen_qiang@ 123456sina.com
                Article
                dddt-12-3439
                10.2147/DDDT.S177128
                6186895
                © 2018 Wu et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                wnt, cell proliferation, rheumatoid arthritis, mir-708-5p

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