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Functional analysis of lubricin as an signaling molecule in regulation and maintenance of the superficial zone of the joint

Research Project

Project/Area Number 20K09428
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 56020:Orthopedics-related
Research InstitutionThe University of Tokyo

Principal Investigator

Uehara Kosuke  東京大学, 医学部附属病院, 病院診療医(出向) (20599063)

Co-Investigator(Kenkyū-buntansha) 齋藤 琢  東京大学, 医学部附属病院, 准教授 (30456107)
森崎 裕  東京大学, 医学部附属病院, 病院診療医(出向) (30508099)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2022: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
KeywordsPrg4 / ルブリシン / Superficial zone (SFZ) / 軟骨 / SFZ / 変形性膝関節症 / 関節最表層
Outline of Research at the Start

関節軟骨組織の最表層(Superficial Zone;SFZ)では、潤滑性維持に必須のタンパクであるルブリシンが豊富に産生され、SFZの破綻は変形性膝関節症(OA)発症に繋がる。また近年はSFZに組織幹細胞の特性を持った関節軟骨前駆細胞が存在することも示唆されている。我々はこれまでの基礎検討において、ルブリシンが潤滑性の維持以外に、シグナル分子としてSFZ細胞の未分化性の維持に直接関わっている可能性を見出した。本研究ではルブリシンタンパクの機能をドメイン別に詳細に解析し、ルブリシンを介したSFZの関節維持機構の全貌解明を目指す。また得られた知見を生かして、SFZ維持を介した関節保護剤の創出を目指す。

Outline of Final Research Achievements

It has been postulated that the PRG4 gene, which encodes lubricin, structurally protects the joint by allowing for lubricity on the joint surface. Patients with mutations in the PRG4 gene develop arthritis at an early age, and Prg4 knockout (Prg4-KO) mice also develop osteoarthritis from juvenile stage. In Prg4-KO mice, their cartilage were thickened and the superficial layer of articular cartilage tissue (superficial zone, hereinafter referred to as SFZ) disappeared at the early postnatal period compared with wild-type mice. The comparison of the gene expressions of SFZ cells between Prg4-KO and wild-type mice revealed that genes associated with immune system processes, inflammation, and extracellular matrix genes were distinct. It was shown that PRG4 contributed to articular cartilage maintenance via the NfkB-Mmp9-TGF-b pathway from the detail analysis of the SFZ cells.

Academic Significance and Societal Importance of the Research Achievements

運動器に関わるルブリシンの研究のほとんどは潤滑性の維持に焦点を当てたものであり、それ以外の働きに関する報告はわずかである。その上、ルブリシンの分子レベルでのメカニズムの解析もほとんど進んでおらず、軟骨細胞を制御するという観点での研究や、ルブリシンをドメイン別に機能を解析した研究はない。我々の研究は、ルブリシンをシグナル伝達分子としての役割を見出した、今までのルブリシン研究とは一線を画したものであり、本研究は軟骨治療の新たな扉を開くものと考えている。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (34 results)

All 2021 2020 Other

All Int'l Joint Research (1 results) Journal Article (15 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 13 results,  Open Access: 6 results) Presentation (14 results) (of which Int'l Joint Research: 5 results,  Invited: 3 results) Book (2 results) Remarks (2 results)

  • [Int'l Joint Research] Harvard University Medical School/Boston Children's Hospital(米国)

    • Related Report
      2020 Research-status Report
  • [Journal Article] TRPV2 is involved in induction of lubricin and suppression of ectopic endochondral ossification in articular joints2021

    • Author(s)
      Nakamoto Hideki、Katanosaka Yuki、Chijimatsu Ryota、Mori Daisuke、Xuan Fengjun、Yano Fumiko、Omata Yasunori、Maenohara Yuji、Murahashi Yasutaka、Kawaguchi Kohei、Yamagami Ryota、Inui Hiroshi、Taketomi Shuji、Taniguchi Yuki、Kanagawa Motoi、Naruse Keiji、Tanaka Sakae、Saito Taku
    • Journal Title

      Arthritis & Rheumatology

      Volume: - Issue: 8 Pages: 1441-1450

    • DOI

      10.1002/art.41684

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Factors Associated With Surgical Intervention for Osteoarthritis of the Thumb Carpometacarpal Joint2021

    • Author(s)
      Nishimura Ken、Uehara Kosuke、Miura Toshiki、Ohe Takashi、Tanaka Sakae、Morizaki Yutaka
    • Journal Title

      The Journal of Hand Surgery

      Volume: 46 Issue: 9 Pages: 817-817

    • DOI

      10.1016/j.jhsa.2021.01.009

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Evaluation of the first annular pulley stretch effect under isometric contraction of the flexor tendon in healthy volunteers and trigger finger patients using ultrasonography2021

    • Author(s)
      Tanaka Shinya、Uehara Kosuke、Sugimura Ryota、Miura Toshiki、Ohe Takashi、Tanaka Sakae、Morizaki Yutaka
    • Journal Title

      BMC Musculoskeletal Disorders

      Volume: 22 Issue: 1

    • DOI

      10.1186/s12891-021-04299-1

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Divergence in chondrogenic potential between in vitro and in vivo of adipose- and synovial-stem cells from mouse and human2021

    • Author(s)
      Chijimatsu Ryota、Miwa Satoshi、Okamura Gensuke、Miyahara Junya、Tachibana Naohiro、Ishikura Hisatoshi、Higuchi Junya、Maenohara Yuji、Tsuji Shinsaku、Sameshima Shin、Takagi Kentaro、Nakazato Keiu、Kawaguchi Kohei、Yamagami Ryota、Inui Hiroshi、Taketomi Shuji、Tanaka Sakae、Saito Taku
    • Journal Title

      Stem Cell Research & Therapy

      Volume: 12 Issue: 1

    • DOI

      10.1186/s13287-021-02485-5

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] 手根管症候群患者における短母指外転筋MMTと患者立脚型評価尺度各質問項目の関連2021

    • Author(s)
      杉村遼太、上原浩介、田中伸弥、田中栄、森崎裕
    • Journal Title

      日本手外科学会雑誌

      Volume: 37 Pages: 617-619

    • Related Report
      2021 Research-status Report
  • [Journal Article] 手根管症候群患者における短母指外転筋CMAPと患者立脚型評価尺度各質問項目の関連2021

    • Author(s)
      杉村遼太、上原浩介、田中伸弥、田中栄、森崎裕
    • Journal Title

      日本手外科学会雑誌

      Volume: 37 Pages: 271-274

    • Related Report
      2021 Research-status Report
  • [Journal Article] Lubricin Contributes to Homeostasis of Articular Cartilage by Modulating Differentiation of Superficial Zone Cells2020

    • Author(s)
      Maenohara Yuji、Chijimatsu Ryota、Tachibana Naohiro、Uehara Kosuke、Xuan Fengjun、Mori Daisuke、Murahashi Yasutaka、Nakamoto Hideki、Oichi Takeshi、Chang Song Ho、Matsumoto Takumi、Omata Yasunori、Yano Fumiko、Tanaka Sakae、Saito Taku
    • Journal Title

      Journal of Bone and Mineral Research

      Volume: 36 Issue: 4 Pages: 792-802

    • DOI

      10.1002/jbmr.4226

    • Related Report
      2021 Research-status Report 2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Evidence that TD‐198946 enhances the chondrogenic potential of human synovium‐derived stem cells through the NOTCH3 signaling pathway2020

    • Author(s)
      Kobayashi Masato、Chijimatsu Ryota、Hart David A.、Hamamoto Shuichi、Jacob George、Yano Fumiko、Saito Taku、Shimomura Kazunori、Ando Wataru、Chung Ung‐il、Tanaka Sakae、Yoshikawa Hideki、Nakamura Norimasa
    • Journal Title

      Journal of Tissue Engineering and Regenerative Medicine

      Volume: 15 Issue: 2 Pages: 103-115

    • DOI

      10.1002/term.3149

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Ear Cartilage Reconstruction Combining Induced Pluripotent Stem Cell-Derived Cartilage and Three-Dimensional Shape-Memory Scaffold2020

    • Author(s)
      Uto Sakura、Hikita Atsuhiko、Sakamoto Tomoaki、Mori Daisuke、Yano Fumiko、Ohba Shinsuke、Saito Taku、Takato Tsuyoshi、Hoshi Kazuto
    • Journal Title

      Tissue Engineering Part A

      Volume: - Issue: 9-10 Pages: 604-617

    • DOI

      10.1089/ten.tea.2020.0106

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] The small compound, TD-198946, protects against intervertebral degeneration by enhancing glycosaminoglycan synthesis in nucleus pulposus cells2020

    • Author(s)
      Kushioka Junichi、Kaito Takashi、Chijimatsu Ryota、Okada Rintaro、Ishiguro Hiroyuki、Bal Zeynep、Kodama Joe、Yano Fumiko、Saito Taku、Chung Ung-il、Tanaka Sakae、Yoshikawa Hideki
    • Journal Title

      Scientific Reports

      Volume: 10 Issue: 1 Pages: 14190-14190

    • DOI

      10.1038/s41598-020-71193-6

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Associations of clinical outcomes and MRI findings in intra-articular administration of autologous adipose-derived stem cells for knee osteoarthritis2020

    • Author(s)
      Higuchi Junya、Yamagami Ryota、Matsumoto Takumi、Terao Tomohiro、Inoue Keita、Tsuji Shinsaku、Maenohara Yuji、Matsuzaki Tokio、Chijimatsu Ryota、Omata Yasunori、Yano Fumiko、Tanaka Sakae、Saito Taku
    • Journal Title

      Regenerative Therapy

      Volume: 14 Pages: 332-340

    • DOI

      10.1016/j.reth.2020.04.003

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Wrist Contracture Caused by Adhesion of the Extensor Carpi Radialis Tendon after Distal Radius Fracture: A Case Report2020

    • Author(s)
      Nishimura Ken、Morizaki Yutaka、Uehara Kosuke、Tabira Yoshihiko、Tanaka Sakae
    • Journal Title

      The Journal of Hand Surgery (Asian-Pacific Volume)

      Volume: 26 Issue: 01 Pages: 100-102

    • DOI

      10.1142/s2424835521720036

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Development of a patient-oriented outcome measure for patients with hand and elbow disorder: HandQ2020

    • Author(s)
      Uehara Kosuke、Miura Toshiki、Takashi Ohe、Doi Tokuhide、Tanaka Sakae、Morizaki Yutaka
    • Journal Title

      Journal of Orthopaedic Surgery

      Volume: 28 Issue: 3

    • DOI

      10.1177/2309499020959151

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Author's reply to 'bone metastasis of limb segments: Is mesometastasis another poor prognostic factor of cancer patients?'2020

    • Author(s)
      Tani Shoichiro、Morizaki Yutaka、Uehara Kosuke、Sawada Ryoko、Kobayashi Hiroshi、Shinoda Yusuke、Kawano Hirotaka、Tanaka Sakae
    • Journal Title

      Japanese Journal of Clinical Oncology

      Volume: 50 Issue: 10 Pages: 1226

    • DOI

      10.1093/jjco/hyaa102

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Journal Article] Bone metastasis of limb segments: Is mesometastasis another poor prognostic factor of cancer patients?2020

    • Author(s)
      Tani Shoichiro、Morizaki Yutaka、Uehara Kosuke、Sawada Ryoko、Kobayashi Hiroshi、Shinoda Yusuke、Kawano Hirotaka、Tanaka Sakae
    • Journal Title

      Japanese Journal of Clinical Oncology

      Volume: 50 Issue: 6 Pages: 688

    • DOI

      10.1093/jjco/hyaa024

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] Motion is essential to maintain the synovial condition and joint homeostasis.2021

    • Author(s)
      Ishikura H, Chijimatsu R, Okada H, Suzuki Y, Miyahara J, Omata Y, Yano F, Tanaka S, Saito T
    • Organizer
      ASBMR 2021 Annual Meeting
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Rspo2/Prg4-positive cells contribute ligament/tendon homeostasis through suppression of ectopic endochondral ossification.2021

    • Author(s)
      Tachibana N, Chijimatsu R, Okada H, Oichi T, Taniguchi Y, Miyahara J, Ishikura H, Nagata K, Nakamoto H, Kato S, Doi T, Matsubayashi Y, Oshima Y, Omata Y, Yano F, Maeda S, Ikegawa S, Tanaka S, Saito T
    • Organizer
      ASBMR 2021 Annual Meeting
    • Related Report
      2021 Research-status Report
    • Int'l Joint Research
  • [Presentation] Motion is essential to maintain synovial condition and joint homeostasis2021

    • Author(s)
      石倉久年、千々松良太、岡田寛之、鈴木譲、宮原潤也、小俣康徳、矢野文子、田中栄、斎藤琢
    • Organizer
      第39回日本骨代謝学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 新しい体表指標による爪母位置の把握2021

    • Author(s)
      三宅崇文、上原浩介、木幡一博、三浦俊樹、大江隆史、田中栄、森崎裕
    • Organizer
      第64回日本手外科学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] 狭窄性屈筋腱腱鞘炎における超音波検査の信頼性評価2021

    • Author(s)
      三宅崇文、上原浩介、木幡一博、三浦俊樹、大江隆史、田中栄、森崎裕
    • Organizer
      第64回日本手外科学会学術集会
    • Related Report
      2021 Research-status Report
  • [Presentation] ルブリシンは関節軟骨最表層細胞の分化を抑制し、関節軟骨の恒常性を維持している2021

    • Author(s)
      前之原悠司
    • Organizer
      軟骨代謝学会
    • Related Report
      2020 Research-status Report
  • [Presentation] Taceは変形性関節症を促進的に制御する2020

    • Author(s)
      金子泰三、千々松良太、矢野文子、堀内圭輔、田中栄、齋藤琢
    • Organizer
      第38回日本骨代謝学会学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] Notchは最表層細胞の維持を介して関節軟骨の恒常性に貢献する2020

    • Author(s)
      岩永康秀、永田向生、千々松良太、矢野文子、田中栄、齋藤琢
    • Organizer
      第35回日本整形外科学会基礎学術集会
    • Related Report
      2020 Research-status Report
  • [Presentation] 関節軟骨層ごとの主要シグナルの役割2020

    • Author(s)
      齋藤琢
    • Organizer
      第35回日本整形外科学会基礎学術集会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] OAの病態における軟骨と周囲組織との関連2020

    • Author(s)
      齋藤琢
    • Organizer
      第48回日本関節病学会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 関節軟骨の維持機構2020

    • Author(s)
      齋藤琢
    • Organizer
      第64回日本リウマチ学会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] Runx3 protects articular cartilage by direct induction of Prg42020

    • Author(s)
      Kosei Nagata, Taku Saito, Fumiko Yano, Hirnori Hojo, Yasuhide Iwanaga, and Sakae Tanaka.
    • Organizer
      ASBMR 2020 Annual Meeting
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] ADAM17/TACE accerates osteoarthritis develpoment through EGFR signaling and TNF pathway2020

    • Author(s)
      Kaneko T, Yano F, Chijimatsu R, Tanaka S, Saito T
    • Organizer
      2021 Auunal Meeting of the Orthopaedic Resarch Society
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Presentation] Notch signaling contributes to articular cartilage homeostasis by suppressing differentiation of superficial zone cells2020

    • Author(s)
      Iwanaga Y, Nagata K, Yano F, Tanaka S, Saito T
    • Organizer
      ASBMR 2020 Annual Meeting
    • Related Report
      2020 Research-status Report
    • Int'l Joint Research
  • [Book] 変形性関節症の分子病態と治療法開発2020

    • Author(s)
      齋藤琢
    • Total Pages
      5
    • Publisher
      日本整形外科学会雑誌
    • Related Report
      2020 Research-status Report
  • [Book] 関節軟骨のメカノバイオロジー2020

    • Author(s)
      齋藤琢
    • Total Pages
      6
    • Publisher
      実験医学
    • Related Report
      2020 Research-status Report
  • [Remarks] 東京大学医学部附属病院 整形外科・脊椎外科

    • URL

      http://www.u-tokyo-ortho.jp/

    • Related Report
      2022 Annual Research Report 2021 Research-status Report
  • [Remarks] 東京大学医学部附属病院 整形外科

    • URL

      http://www.u-tokyo-ortho.jp/

    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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