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Pathophysiological study and image analysis of early-stage knee OA by focusing on osteochondrophytes

Research Project

Project/Area Number 19H03788
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 56020:Orthopedics-related
Research InstitutionJuntendo University

Principal Investigator

Okada Yasunori  順天堂大学, 大学院医学研究科, 特任教授 (00115221)

Co-Investigator(Kenkyū-buntansha) 金子 晴香  順天堂大学, 医学部, 准教授 (50445516)
石島 旨章  順天堂大学, 大学院医学研究科, 教授 (70365576)
デベガ スサーナ  順天堂大学, 医学部, 非常勤助教 (30623590)
チレッキ メフメット・ゼイネル  順天堂大学, 医学部, 博士研究員 (10827538)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2021: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2019: ¥7,410,000 (Direct Cost: ¥5,700,000、Indirect Cost: ¥1,710,000)
Keywords変形性関節症 / 骨棘 / ヒアルロン酸 / HYBID / 関節軟骨破壊 / 画像解析 / 変形性膝関節症 / 骨軟骨棘 / 関節軟骨破壊再生 / 組織内微小環境 / 画像診断
Outline of Research at the Start

変形性関節症(OA)は、超高齢社会の我が国において罹患率の高い運動器疾患であり、OAの病態解明に基づく早期診断・治療法開発は重要な研究課題である。本研究では、膝OA関節病態における骨軟骨棘(骨棘)に焦点を当てて、骨軟骨棘形成に参画する細胞成分や組織内微小環境因子の探索、膝OA動物モデルでの骨軟骨棘形成と内側半月板逸脱との関係、骨軟骨棘形成に着目した早期膝OAの画像解析に関して詳細な研究を進める。

Outline of Final Research Achievements

We examined pathophysiology of osteoarthritis (OA) and obtained the following data: 1) Cartilage part of osteophyte contained larger numbers of mesenchymal stem cells compared to OA cartilage and spheroid culture method for osteophytic and articular chondrocytes was established. 2) HYBID was efficiently up-regulated in OA synovial fibroblasts by IL-6 and involved in hyaluronan degradation in OA synovial fluid. 3) Knee OA models in HYBID knock-out mice indicated that HYBID plays a key role via hyaluronan degradation in OA progression. 4) ADAMTS4 is synergistically overexpressed in OA synovial fibroblasts by IL-1α, TNF-α and TGF-β, and the expression is completely inhibited by combined treatment with adalimumab and inhibitors for TAK1 or ALK5. 5) MRI analyses of the patients with anterior cruciate ligament rupture or healthy elderlies showed that medial meniscus extrusion, a risk factor of knee OA progression, is closely related to medial tibial osteophyte.

Academic Significance and Societal Importance of the Research Achievements

OAは運動器疾患の中でも最も頻度が高く、健康寿命延伸阻害の主因であるが、その進展機構や制御法に関する研究は遅れている。本研究で得られたHYBIDやADAMTS4に関するデータは、OA関節軟骨破壊早期に生じるヒアルロン酸-アグリカンネットワーク破壊の理解と制御にきわめて重要な情報を与えている。また、脛骨内側部の骨軟骨棘は内側半月板逸脱誘導を介してOA進展リスク因子となっており、本研究で骨軟骨棘をin vitroにおいて解析できる方法を開発したことは、OA進展制御に向けての今後の研究に重要な足掛かりになると期待される。

Report

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

    (30 results)

All 2021 2020 2019 2018

All Journal Article (19 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 14 results,  Open Access: 4 results) Presentation (11 results) (of which Int'l Joint Research: 1 results,  Invited: 4 results)

  • [Journal Article] Synergistic upregulation of ADAMTS4 (aggrecanase-1) by cytokines and its suppression in knee osteoarthritic synovial fibroblasts2021

    • Author(s)
      Cilek Mehmet Zeynel、de Vega Susana、Shiozawa Jun、Yoshinaga Chiho、Miyamae Yuka、Chijiiwa Miyuki、Mochizuki Satsuki、Ito Masatoshi、Kaneko Haruka、Kaneko Kazuo、Ishijima Muneaki、Okada Yasunori
    • Journal Title

      Laboratory Investigation

      Volume: 102 Issue: 1 Pages: 102-111

    • DOI

      10.1038/s41374-021-00685-4

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Deletion of Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization (HYBID) Results in Attenuation of Osteoarthritis in Mice2021

    • Author(s)
      Momoeda Masahiro、de Vega Susana、Kaneko Haruka、Yoshinaga Chiho、Shimoda Masayuki、Nakamura Tomomi、Endo Yoko、Yoshida Hiroyuki、Kaneko Kazuo、Ishijima Muneaki、Okada Yasunori
    • Journal Title

      The American Journal of Pathology

      Volume: 191 Issue: 11 Pages: 1986-1998

    • DOI

      10.1016/j.ajpath.2021.07.008

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Medial meniscus extrusion is a determinant factor for the gait speed among MRI-detected structural alterations of knee osteoarthritis2021

    • Author(s)
      Arita Hitoshi、Kaneko Haruka、Ishibashi Masayoshi、Sadatsuki Ryo、Liu Lizu、Hada Shinnosuke、Kinoshita Mayuko、Aoki Takako、Negishi Yoshifumi、Momoeda Masahiro、Adili Arepati、Kubota Mitsuaki、Okada Yasunori、Kaneko Kazuo、Ishijima Muneaki
    • Journal Title

      Osteoarthritis and Cartilage Open

      Volume: 3 Issue: 3 Pages: 100176-100176

    • DOI

      10.1016/j.ocarto.2021.100176

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] An antibacterial coated polymer prevents biofilm formation and implant-associated infection2021

    • Author(s)
      Ishihama Hiroko、Ishii Ken、Nagai Shigenori、Kakinuma Hiroaki、Sasaki Aya、Yoshioka Kenji、Kuramoto Tetsuya、Shiono Yuta、Funao Haruki、Isogai Norihiro、Tsuji Takashi、Okada Yasunori、Koyasu Shigeo、Toyama Yoshiaki、Nakamura Masaya、Aizawa Mamoru、Matsumoto Morio
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 3602-3602

    • DOI

      10.1038/s41598-021-82992-w

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] HYBID derived from tumor cells and tumor-associated macrophages contribute to the glioblastoma growth2021

    • Author(s)
      Tsuji Shohei、Nakamura Shinsuke、Yamada Tetsuya、de Vega Susana、Okada Yasunori、Inoue Shintaro、Shimazawa Masamitsu、Hara Hideaki
    • Journal Title

      Brain Research

      Volume: 1764 Pages: 147490-147490

    • DOI

      10.1016/j.brainres.2021.147490

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] 早期変形性膝関節症におけるHA分解酵素HYBID(CEMIP/KIAA1199)の意義2021

    • Author(s)
      塩澤淳、石島旨章、岡田保典
    • Journal Title

      整形・災害外科

      Volume: 64 Pages: 253-261

    • Related Report
      2021 Annual Research Report
  • [Journal Article] 総論 変形性膝関節症における軟骨細胞外マトリックス分解の分子病態2021

    • Author(s)
      塩澤淳、石島旨章、岡田保典
    • Journal Title

      Pharma Medica

      Volume: 39 Pages: 19-23

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Stromal metalloproteinases: Crucial contributors to the tumor microenvironment2020

    • Author(s)
      Shimoda Masayuki、Ohtsuka Takashi、Okada Yasunori、Kanai Yae
    • Journal Title

      Pathology International

      Volume: 71 Issue: 1 Pages: 1-14

    • DOI

      10.1111/pin.13033

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Implication of HYBID (Hyaluronan-Binding Protein Involved in Hyaluronan Depolymerization) in Hyaluronan Degradation by Synovial Fibroblasts in Patients with Knee Osteoarthritis.2020

    • Author(s)
      Shiozawa J, de Vega S, Cilek MZ, Yoshinaga C, Nakamura T, Kasamatsu S, Yoshida H, Kaneko H, Ishijima M, Kaneko K, Okada Y.
    • Journal Title

      American Journal of Pathology

      Volume: 190 Issue: 5 Pages: 1046-1058

    • DOI

      10.1016/j.ajpath.2020.01.003

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] HYBID and hyaluronan synthase coordinately regulate hyaluronan metabolism in histamine-stimulated skin fibroblasts.2020

    • Author(s)
      Yoshida H., Aoki M., Komiya A., Sakai S., Sayo T., Okada Y., and Takahashi Y.
    • Journal Title

      J Biol Chem

      Volume: 295 Issue: 8 Pages: 2483-2494

    • DOI

      10.1074/jbc.ra119.010457

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Expression and characterization of hyaluronan binding protein involved in hyaluronan depolymerization: HYBID, alias KIAA1199 and CEMIP.2020

    • Author(s)
      de Vega S., Yoshida H. and Okada Y.
    • Journal Title

      Methods Mol Biol

      Volume: 2132 Pages: 129-138

    • DOI

      10.1007/978-1-0716-0430-4_13

    • ISBN
      9781071604298, 9781071604304
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Hyaluronan degradation by Cemip regulates host defense against Staphylococcus aureus skin infection.2020

    • Author(s)
      Dokoshi T., Zhang L., Li F., Nakatsuji T., Butcher A., Yoshida H., Shimoda M., Okada Y. and Gallo R.L.
    • Journal Title

      Cell Rep

      Volume: 30 Issue: 1 Pages: 61-68

    • DOI

      10.1016/j.celrep.2019.12.001

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] HYBID(KIAA1199/CEMIP)2020

    • Author(s)
      塩澤淳、岡田保典
    • Journal Title

      整形外科

      Volume: 71 Pages: 357-357

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 線維症とメタロプロテアーゼーMMP・ADAM・ADAMTS2020

    • Author(s)
      望月早月、岡田保典
    • Journal Title

      医学の歩み

      Volume: 275 Pages: 21450-21456

    • Related Report
      2020 Annual Research Report
  • [Journal Article] Inhibitory effects of Sanguisorba officinalis root extract on HYBID (KIAA1199)-mediated hyaluronan degradation and skin wrinkling2019

    • Author(s)
      Yoshida H.、Yamazaki K.、Komiya A.、Aoki M.、Kasamatsu S.、Murata T.、Sayo T.、Cilek M. Z.、Okada Y.、Takahashi Y.
    • Journal Title

      International Journal of Cosmetic Science

      Volume: 41 Issue: 1 Pages: 12-20

    • DOI

      10.1111/ics.12505

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Role of HYBID (Hyaluronan Binding Protein Involved in Hyaluronan Depolymerization), Alias KIAA1199/CEMIP, in Hyaluronan Degradation in Normal and Photoaged Skin2019

    • Author(s)
      Yoshida Hiroyuki、Okada Yasunori
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 20 Issue: 22 Pages: 5804-5804

    • DOI

      10.3390/ijms20225804

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 変形性膝関節症におけるHYBID(CEMIP/KIAA1199)の発現と役割―早期変形性膝関節症のバイオマーカーとしての可能性も含めてー2019

    • Author(s)
      塩澤淳, 石島旨章, 金子和夫, 岡田保典
    • Journal Title

      整形・災害外科

      Volume: 62 Pages: 1519-1525

    • Related Report
      2019 Annual Research Report
  • [Journal Article] 変形性膝関節症における慢性疼痛2019

    • Author(s)
      石島旨章、金子晴香、根岸義文、百枝雅裕、岡田保典、金子和夫
    • Journal Title

      日本臨床

      Volume: 77 Pages: 2027-2034

    • Related Report
      2019 Annual Research Report
  • [Journal Article] Inhibition of HYBID (KIAA1199)-mediated hyaluronan degradation and anti-wrinkle effect of Geranium thunbergii extract2018

    • Author(s)
      Yoshida Hiroyuki、Yamazaki Kohei、Komiya Aya、Aoki Mika、Nakamura Tomomi、Kasamatsu Shinya、Murata Takeshi、Sayo Tetsuya、Okada Yasunori、Takahashi Yoshito
    • Journal Title

      Journal of Cosmetic Dermatology

      Volume: - Issue: 4 Pages: 1-9

    • DOI

      10.1111/jocd.12813

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Presentation] 新規ヒアルロニダーゼHYBID及びTMEM2の膝OA関節軟骨組織における機能解析2021

    • Author(s)
      塩澤淳、Susana de Vega、良永知穂、中村智美、吉田浩之、金子晴香、金子和夫、石島旨章、岡田保典
    • Organizer
      第13回日本関節鏡・膝・スポーツ整形外科学会(JOSKAS)
    • Related Report
      2021 Annual Research Report
  • [Presentation] Hybid(hyaluronan-binding protein involved in hyaluronan depolymerization)によるHA分解はマウスでの変形性膝関節症(膝OA)を促進する2021

    • Author(s)
      百枝雅裕、スサーナ・デ・ベガ、金子晴香、良永知穂、下田将之、中村朋美、遠藤洋子、吉田浩之、金子和夫、石島旨章、岡田保典
    • Organizer
      第53回日本結合組織学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 変形性膝関節症滑膜組織でのHYBID過剰発現は関節液中ヒアルロン酸(HA)分解に関わる。2020

    • Author(s)
      塩澤淳、Susana de Vega、Mehmet Z. Cilek、良永知穂、中村智美、笠松慎也、吉田浩之、石島旨章、金子晴香、金子和夫、岡田保典
    • Organizer
      第109回日本病理学会総会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 変形性関節症の関節軟骨破壊と再生:概論2020

    • Author(s)
      岡田保典
    • Organizer
      第64回日本リウマチ学会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 変形性膝関節症(膝OA)の関節軟骨組織におけるヒアルロン酸分解酵素(HYBIDとTMEM2)の発現と発現調節機構2020

    • Author(s)
      塩澤淳、Susana de Vega、中村智美、吉田浩之、石島旨章、金子晴香、金子和夫、岡田保典
    • 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] 日本創傷治癒学会における50年の歩みと今後の展望2020

    • Author(s)
      岡田保典
    • Organizer
      第50回日本創傷治癒学会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 関節軟骨破壊と再生の基礎研究2019

    • Author(s)
      岡田保典
    • Organizer
      第32回日本軟骨代謝学会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] HYBIDの変形性関節症(OA)関節軟骨での発現亢進とヒアルロン酸(HA)分解における役割2019

    • Author(s)
      下田将之、清水英德、望月早月、吉田浩之、塩澤淳、石島旨章、金子和夫、中村雅也、戸山芳昭、岡田保典
    • Organizer
      第108回日本病理学総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] HYBIDは変形性膝関節症滑膜組織で過剰発現し関節液中ヒアルロン酸分解に関与する2019

    • Author(s)
      塩澤淳、Susan de Vega、Mehmet Z. Cilek、良永知穂、中村智美、笠松慎也、吉田浩之、金子晴香、石島旨章、金子和夫、岡田保典
    • Organizer
      第51回 日本結合組織学会学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Expression and roles of HYBID (Hyaluronan-binding protein involved in hyaluronan depolymerization), alias CEMIP/KIAA1199, in osteoarthritis2019

    • Author(s)
      Yasunori Okada
    • Organizer
      The 11th International Conference on Proteoglycans
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] IL-6を介した変形性関節症滑膜線維芽細胞によるHYBID(KIAA1199)過剰発現は関節液中ヒアルロン酸分解に関わる2019

    • Author(s)
      塩澤淳、Susana de Vega、Mehmet Z. Cilek、良永知穂、中村智美、笠松慎也、吉田浩之、金子晴香、石島旨章、金子和夫、岡田保典
    • Organizer
      第34回 日本整形外科学会基礎学術集会
    • Related Report
      2019 Annual Research Report

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

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