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Research Article| Volume 24, ISSUE 12, P2153-2161, December 2016

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Inhibition of microRNA-449a prevents IL-1β-induced cartilage destruction via SIRT1

  • K.W. Park
    Affiliations
    Department of Orthopedic Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea

    Brain Korea 21 Project Plus for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
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  • K.-M. Lee
    Affiliations
    Department of Orthopedic Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea

    Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
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  • D.S. Yoon
    Affiliations
    Department of Orthopedic Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
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  • K.H. Park
    Affiliations
    Department of Orthopaedic Surgery, CHA Bundang Medical Center, CHA University, Kyeonggi-do, South Korea
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  • W.J. Choi
    Affiliations
    Department of Orthopedic Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
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  • J.W. Lee
    Affiliations
    Department of Orthopedic Surgery, Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea

    Brain Korea 21 Project Plus for Medical Science, Yonsei University College of Medicine, Seoul, South Korea

    Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, South Korea
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  • S.-H. Kim
    Correspondence
    Address correspondence and reprint requests to: S.-H. Kim, Department of Orthopedic Surgery, Yonsei University College of Medicine, Gangnam Severance Hospital, 211 Eonju-ro, Gangnam-gu, Seoul 06273, South Korea. Fax: 82-2-573-5393.
    Affiliations
    Department of Orthopedic Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
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      Summary

      Objective

      SIRT1 has anti-inflammatory as well as protective effects in chondrocytes. The object of this study was to investigate whether microRNA-449a regulates expression of SIRT1, which inhibits expression of catabolic genes in IL-1β-induced cartilage destruction.

      Materials and methods

      MicroRNA-449a expression was determined in OA chondrocytes and IL-1β-induced chondrocytes by real-time PCR. MicroRNA-449a binding sites on the 3′-UTR of SIRT1 mRNA and binding site conservation were examined using microRNA target prediction tools. SIRT1-overexpressing or knockdown chondrocytes were transfected with microRNA-449a or anti-microRNA-449a mimic and stimulated by IL-1β. Expression of catabolic and anabolic genes was examined by real-time PCR and western blotting. Finally, positive effects of anti-microRNA-449a on expression of these genes were confirmed by western analysis of OA chondrocytes.

      Results

      Expression of microRNA-449a was increased in OA chondrocytes and IL-1β-induced chondrocytes. MMP-13 expression was enhanced, whereas type II collagen and SIRT1 expression were decreased in IL-1β-induced chondrocytes. SIRT1 overexpression resulted in decreased expression of catabolic genes such as MMPs and ADAMTSs in response to IL-1β, but these effects were moderated by microRNA-449a. Suppression of microRNA-449a by anti-microRNA-449a inhibited expression of catabolic genes despite IL-1β stimulation, but these effects were abolished in SIRT1 knockdown chondrocytes. Furthermore, expression of catabolic genes was decreased and expression of type II collagen as well as SIRT1 was restored by anti-microRNA-449a in OA chondrocytes as well as in IL-1β-induced chondrocytes.

      Conclusion

      Silencing of microRNA-449a had a protective effect, inhibiting catabolic gene expression and restoring anabolic gene expression, by targeting SIRT1 in IL-1β-induced cartilage destruction.

      Keywords

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