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For treatment of knee osteoarthritis with HAS2 transgene

Research Project

Project/Area Number 18K16655
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 56020:Orthopedics-related
Research InstitutionNagoya University

Principal Investigator

Ishizuka Shinya  名古屋大学, 医学部附属病院, 病院助教 (40813316)

Project Period (FY) 2018-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2018: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Keywordsヒアルロン酸 / HAS2 / 変形性膝関節症 / 4-MU / Osteoarthritis / Hyaluronan / HAS2
Outline of Final Research Achievements

We evaluated the effect of methylumbelliferone (4-MU), that we previously showed its anti-inflammatory features in activated osteoarthritic (OA) chondrocytes in vitro, using in vivo model to confirm whether 4-MU was effective at limiting the effects of OA on articular cartilage in vivo. The progression of OA was evaluated after destabilization of the medial meniscus (DMM) surgery on C57BL/6 mice in the presence or absence of 4‐MU‐containing chow. Mice fed 4-MU after DMM surgery exhibited significant suppression of OA starting from an early stage in vivo. Mice fed 4-MU exhibited lower OARSI scores after DMM; reduced osteophyte formation and reduced MMP3 and MMP13 immunostaining. 4-MU also exerted pronounced chondroprotective effects on murine joint cartilage exposed to IL1β in vitro and, blocked IL1β-enhanced lactate production in cartilage explants. We will evaluate HAS2 overexpression effect using similar experimental model.

Academic Significance and Societal Importance of the Research Achievements

変形性膝関節症(膝OA)に対する保存的治療にひとつとして広く行われているヒアルロン酸の関節内投与は頻回の注射の痛み、また感染の危険性などのマイナスな面もある。我々は細胞を用いた実験で後顆が確認されているヒアルロン酸合成酵素の関節内組織、細胞への遺伝子導入による新たな膝OAに対する治療を目指しており、今回の研究成果では膝OAモデルマウスの作成の確立、薬剤の関節内投与による効果の確認、ヒアルロン酸阻害による抗炎症効果までを動物実験で示すことができた。今回の成果をもとにウイルスベクターによる遺伝子導入とそれによる膝OAの進行抑制効果を今後の研究につなげていく予定である。

Report

(4 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • 2018 Research-status Report
  • Research Products

    (5 results)

All 2021 2019

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (4 results) (of which Int'l Joint Research: 3 results)

  • [Journal Article] Hyaluronan synthase 2 (HAS2) overexpression diminishes the procatabolic activity of chondrocytes by a mechanism independent of extracellular hyaluronan.2019

    • Author(s)
      Ishizuka S, Tsuchiya S, Ohashi Y, Terabe K, Askew EB, Ishizuka N, Knudson CB, Knudson W.
    • Journal Title

      J Biol Chem

      Volume: 294 Issue: 37 Pages: 13562-13579

    • DOI

      10.1074/jbc.ra119.008567

    • Related Report
      2019 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Anti-inflammatory effect of 4-methylumbelliferone (4-MU) in human ACL-derived cells2021

    • Author(s)
      Idota M, Ishizuka S
    • Organizer
      2021 Annual Meeting of Orthopaedic Research Society
    • Related Report
      2020 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ヒト前十字靱帯由来細胞における4-Methylumbelliferone(4-MU)およびヒアルロン酸合成酵素2(HAS2)過剰発現による抗炎症作用2021

    • Author(s)
      井戸田 大, 平岩 秀樹, 石塚 真哉
    • Organizer
      第35回日本整形外科学会基礎学術集会
    • Related Report
      2020 Annual Research Report
  • [Presentation] HAS2 Overexpression in Chondrocytes Downregulates Cytokine Activated Metabolism2019

    • Author(s)
      Saho Tsuchiya, Shinya Ishizuka, Kenya Terabe, Yoshifumi Ohashi, Naoko Ishizuka, Emily B. Askew, Cheryl B. Knudson, Warren Knudson
    • Organizer
      2019 Annual Meeting of Orthopaedic Research Society
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] HAS2 Overexpression in Chondrocytes Downregulates Cytokine Activated Metabolism2019

    • Author(s)
      Saho Tsuchiya, Shinya Ishizuka, Warren Knudson
    • Organizer
      Orthpaedic Research Society
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research

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Published: 2018-04-23   Modified: 2022-01-27  

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