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Development of novel treatment for intervertebral disc degeneration

Research Project

Project/Area Number 19K09634
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56020:Orthopedics-related
Research InstitutionFujita Health University

Principal Investigator

Fujita Nobuyuki  藤田医科大学, 医学部, 教授 (30348685)

Co-Investigator(Kenkyū-buntansha) 堀内 圭輔  防衛医科大学校(医学教育部医学科進学課程及び専門課程、動物実験施設、共同利用研究施設、病院並びに防衛, 整形外科学, 准教授 (30327564)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords椎間板変性 / ヒアルロン酸 / 慢性炎症 / 髄核 / 椎間板 / 腰部脊柱管狭窄症 / 黄色靭帯 / 変性 / 炎症 / 脊椎
Outline of Research at the Start

本研究は1) 髄核の組織恒常性維持におけるFlt-1の機能解明、2) 繊維輪における変性とヒアルロン酸代謝の関係の二つに大別され、方法はそれぞれ以下の通りである。
1)無血管性組織におけるFlt-1の役割を解明するために、soluble Flt-1 knockoutマウスの椎間板における表現型を解析する。2)椎間板変性におけるヒアルロン酸代謝を検討するため、ラット繊維輪細胞を用いてin vitroでHYBIDの発現制御メカニズム及びその機能を解析し、更にHYBID knockoutマウスの提供を用いて、in vivoにおける機能解析を行う。

Outline of Final Research Achievements

RT-PCR and Western blot analysis showed that TNF-α-mediated induction of the expression of TNF-α and COX2 was clearly neutralized by HA treatment, and the expression of TNF-α and COX2 was significantly induced by hyaluronidase treatment in both cell types. Additionally, Western blot analysis showed that hyaluronidase-induced phosphorylation of p38 and Erk1/2, and that TNF-α-mediated phosphorylation of p38 and Erk1/2 was clearly reduced by HA addition. In degenerating human IVD samples, immunohistochemistry for hyaluronidase showed that the expression of hyaluronidases including HYAL1, HYAL2, and CEMIP tended to increase in accordance with IVDD. In particular, HYAL1 showed statistically significant differences.

Academic Significance and Societal Importance of the Research Achievements

腰椎変性疾患の原因の一つに椎間板変性が挙げられるが、現在のところ、椎間板変性を抑制する有効な治療法は確立されていない。本研究結果より、ヒアルロン酸がp38とErk1/2経路を制御することで、椎間板の炎症を抑制する可能性が示された。更に、HYAL1の発現が椎間板変性の進行と相関していることも示された。以上より、HYAL1がHA代謝を介して、椎間板変性の治療標的分子となる可能性が示唆された。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (6 results)

All 2022 2021 2020 2019

All Journal Article (2 results) (of which Peer Reviewed: 2 results) Presentation (4 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results)

  • [Journal Article] Impact of oxidized LDL/LOX-1 system on ligamentum flavum hypertrophy2022

    • Author(s)
      Nagai S, Hachiya K, Takeda H, Ikeda D, Kawabata S, Watanabe K, Kaneko S, Fujita N.
    • Journal Title

      J Orthop Sci .

      Volume: - Issue: 3 Pages: 669-676

    • DOI

      10.1016/j.jos.2022.01.006

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Efficacy of hyaluronic acid on intervertebral disc inflammation: An in vitro study using notochordal cell lines and human disc cells2021

    • Author(s)
      Yamamoto T, Suzuki S, Fujii T, Mima Y, Watanabe K, Matsumoto M, Nakamura M, Fujita N
    • Journal Title

      J Orthop Res

      Volume: - Issue: 10 Pages: 2197-2208

    • DOI

      10.1002/jor.24933

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] 黄色靭帯肥厚と酸化LDL/LOX-1シグナルの関係2021

    • Author(s)
      永井聡太、武田太樹、池田大樹、金子慎二郎、藤田順之
    • Organizer
      日本整形外科学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 腰部脊柱管狭窄症の基礎と臨床2020

    • Author(s)
      藤田 順之
    • Organizer
      第93回日本整形外科学会学術総会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Hyaluronic acid metabolism in intervertebral disc degeneration2020

    • Author(s)
      Tatsuya Yamamoto, Satoshi Suzuki, Takeshi Fujii, Yuichiro Mima, Kota Watanabe, Morio Matsumoto, Masaya Nakamura, Nobuyuki Fujita
    • Organizer
      ORS Annual Meeting
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research
  • [Presentation] 椎間板変性におけるヒアルロン酸代謝2019

    • Author(s)
      山本竜也、 鈴木悟士、藤井 武、美馬 雄一郎、渡辺航太、松本守雄、中村雅也、藤田順之
    • Organizer
      日本整形外科学会基礎学術集会
    • Related Report
      2019 Research-status Report

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Published: 2019-04-18   Modified: 2023-01-30  

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