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Therapeutic strategy for rheumatoid arthritis with signal cascade control of gliostatin

Research Project

Project/Area Number 16K10913
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Orthopaedic surgery
Research InstitutionNagoya City University

Principal Investigator

Kobayashi Masaki  名古屋市立大学, 大学院医学研究科, 研究員 (20254287)

Co-Investigator(Kenkyū-buntansha) 浅井 清文  名古屋市立大学, 大学院医学研究科, 教授 (70212462)
永谷 祐子  名古屋市立大学, 大学院医学研究科, 教授 (90291583)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords関節リウマチ / 滑膜細胞 / グリオスタチン / マトリックスメタロプロテイナーゼ / チミジンホスホリラーゼ / ヤヌスキナーゼ / Sp1 / プロモーター / マトリックスメタロプロテアーゼ / シグナル伝達
Outline of Final Research Achievements

We found for the first time that gliostatin is closely involved in the pathogenesis of rheumatoid arthritis. In this study, the goal is to apply the signal cascade control of gliostatin to the treatment of rheumatoid arthritis.
We have searched for signal cascade regulators of gliostatin. There are seven Sp1 binding sites in the gliostatin promoter region, and the expression of gliostatin was inhibited by inhibiting Sp1. The knock-on effects were examined using mithramycin, which is an Sp1 transcription factor inhibitor. We also clarified that matrix metalloproteinases-1, 3, 9, 13 that induce cartilage destruction were suppressed by mithramycin.

Academic Significance and Societal Importance of the Research Achievements

関節リウマチの治療はこの10年で劇的に進歩し、発症早期からの抗リウマチ薬、生物学的製剤、低分子シグナル伝達阻害剤の導入により、治療は寛解をめざすものになった。しかしながら未だいずれの治療にも反応しない薬剤耐性難治性患者や炎症が鎮静化されたにも関わらず骨びらんの進行がみられる患者が存在する。
本研究によって、グリオスタチンが新たな治療標的となることが明らかとなった。グリオスタチンの抑制によって骨軟骨破壊に関与するマトリックスプロテアーゼが抑制することから、変形性関節症の進展抑制にも応用可能と考える。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (22 results)

All 2018 2017 2016

All Journal Article (11 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 11 results,  Open Access: 6 results,  Acknowledgement Compliant: 2 results) Presentation (11 results) (of which Int'l Joint Research: 10 results)

  • [Journal Article] Treatment of aneurysmal bone cysts using endoscopic curettage2018

    • Author(s)
      Aiba H, Kobayashi M, Waguri-Nagaya Y, Goto H, Mizutani J, Yamada S, Okamoto H, Nozaki M, Mitsui H, Miwa S, Kobayashi M, Endo K, Saito S, Goto T, Otsuka T.
    • Journal Title

      BMC Musculoskelet Disord

      Volume: 19 Issue: 1 Pages: 268-268

    • DOI

      10.1186/s12891-018-2176-6

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Treatment of simple bone cysts using endoscopic curettage: a case series analysis2018

    • Author(s)
      Aiba H, Kobayashi M, Waguri-Nagaya Y, Goto H, Mizutani J, Yamada S, Okamoto H, Nozaki M, Mitsui H, Miwa S, Kobayashi M, Endo K, Saito S, Goto T, Otsuka T.
    • Journal Title

      J Orthop Surg Res

      Volume: 13 Issue: 1 Pages: 168-168

    • DOI

      10.1186/s13018-018-0869-z

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The Janus kinase inhibitor tofacitinib inhibits TNF-α-induced gliostatin expression in rheumatoid fibroblast-like synoviocytes2018

    • Author(s)
      Kawaguchi Y, Waguri-Nagaya Y, Tatematsu N, Oguri Y, Kobayashi M, Nozaki M, Asai K, Aoyama M, Otsuka T
    • Journal Title

      Clin Exp Rheumatol

      Volume: 36 Pages: 559-567

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mithramycin has inhibitory effects on gliostatin and matrix metalloproteinase expression induced by gliostatin in rheumatoid fibroblast-like synoviocytes.2018

    • Author(s)
      Tatematsu N, Waguri-Nagaya Y, Kawaguchi Y, Oguri Y, Ikuta K, Kobayashi M, Nozaki M, Asai K, Aoyama M, Otsuka T.
    • Journal Title

      Mod Rheumatol.

      Volume: 28(3) Issue: 3 Pages: 495-505

    • DOI

      10.1080/14397595.2017.1350332

    • Related Report
      2018 Annual Research Report 2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Inhibition of IL-6 production from rheumatoid synovial fibroblasts by isoform-specific histone deacetylase (HDAC) inhibitor.2018

    • Author(s)
      Ha M, Hibi Y, Kanazawa S, Fukuta T, Waguri-Nagaya Y, Wada I, Otsuka T, Okamoto T.
    • Journal Title

      Nagoya Med J

      Volume: 56 Pages: 39-52

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Comparison of quantitative evaluation between cutaneous and transosseous inertial sensors in anterior cruciate ligament deficient knee: A cadaveric study.2017

    • Author(s)
      Murase A, Nozaki M, Kobayashi M, Goto H, Yasuma S, Takenaga T, Nagaya Y, Mizutani J, Okamoto H, Iguchi H, Otsuka T.
    • Journal Title

      J Orthop Sci

      Volume: 22 Issue: 5 Pages: 874-879

    • DOI

      10.1016/j.jos.2017.04.010

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Septic spondylodiscitis due to non-typhoidal Salmonella in a patient with rheumatoid arthritis treated with a TNF inhibitor and methotrexate.2017

    • Author(s)
      Kawaguchi Y, Waguri-Nagaya Y, Oguri Y, Nozaki M, Kobayashi M, Otsuka T.
    • Journal Title

      Modern Rheumatology Case Reports

      Volume: - Issue: 2 Pages: 125-129

    • DOI

      10.1080/24725625.2017.1417673

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Expression and subcellular localization of AT motif binding factor 1 in colon tumours.2017

    • Author(s)
      Kataoka H, Miura Y, Kawaguchi M, Suzuki S, Okamoto Y, Ozeki K, Shimura T, Mizoshita T, Kubota E, Tanida S, Takahashi S, Asai K, Joh T.
    • Journal Title

      Mol Med Rep

      Volume: 16 Issue: 3 Pages: 3095-3102

    • DOI

      10.3892/mmr.2017.7016

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Neuroprotective erythropoietin attenuates microglial activation, including morphological changes, phagocytosis, and cytokine production.2017

    • Author(s)
      Tamura T, Aoyama M, Ukai S, Kakita H, Sobue K, Asai K
    • Journal Title

      Brain Res

      Volume: 1662 Pages: 65-74

    • DOI

      10.1016/j.brainres.2017.02.023

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Do Mesenchymal Stem Cells Derived From Atypical Lipomatous Tumors Have Greater Differentiation Potency Than Cells From Normal Adipose Tissues?2017

    • Author(s)
      Inatani H, Yamamoto N, Hayashi K, Kimura H, Takeuchi A, Miwa S, Higuchi T, Abe K, Taniguchi Y, Yamada S, Asai K, Otsuka T, Tsuchiya H.
    • Journal Title

      Clin Orthop Relat Res

      Volume: 印刷中 Issue: 6 Pages: 1693-1701

    • DOI

      10.1007/s11999-017-5259-z

    • Related Report
      2017 Research-status Report 2016 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] CXCR4+CD45- cells are niche forming for osteoclastogenesis via the SDF-1, CXCL7, and CX3CL1 signaling pathways in bone marrow.2016

    • Author(s)
      Goto Y, Aoyama M, Sekiya T, Waguri-Nagaya Y, Miyazawa K, Asai K, Goto S.
    • Journal Title

      Stem Cells

      Volume: 34 Issue: 11 Pages: 2733-2743

    • DOI

      10.1002/stem.2440

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Circulating gliostatin correlates with serological feature and response to IL-6 inhibitor therapy in patients with RA2018

    • Author(s)
      Oguri Y, Kawaguchi Y, Nozaki M, Asai K, Waguri-Nagaya Y
    • Organizer
      39th SICOT Orthopaedic World Congress 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Serum GLS levels were significantly decreased in patients with RA who were treated with tofacitinib.2018

    • Author(s)
      Kawaguchi Y, Oguri Y, Nozaki M, Asai K, Waguri-Nagaya Y
    • Organizer
      39th SICOT Orthopaedic World Congress 2018
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] トシリズマブを使用した関節リウマチ患者血清中グリオスタチン濃度と疾患活動性の推移.2018

    • Author(s)
      小栗雄介, 永谷祐子, 川口洋平, 立松尚衞, 小林正明, 浅井清文, 大塚隆信.
    • Organizer
      第62回日本リウマチ学会総会・学術集会
    • Related Report
      2018 Annual Research Report 2017 Research-status Report
  • [Presentation] The inhibitory effects of tacrolimus on gliostatin production in RA synoviocytes.2017

    • Author(s)
      Ikuta K, Kawaguchi Y, Waguri-Nagaya Y, Tatematsu N, Kobayashi M, Goto H, Nozaki M, Aoyama M, Asai K, Otsuka T.
    • Organizer
      Annual European Congress of Rheumatology (EULAR2017)
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Quantitative Evaluation of the Biomechanical Function of the Anterolateral structure using an inertial sensor2017

    • Author(s)
      Sanshiro Yasuma, Masahiro Nozaki, Atsunori Murase, Masaaki Kobayashi, Hideyuki Goto, Yuko Nagaya, , Hirotaka Iguchi, Takanobu Otsuka
    • Organizer
      Orthopedic Research Society Annual Meeting 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] Sp1 inhibitor modulates the autocrine action of gliostatin/thymidine phosphorylase (GLS/TYMP) in rheumatoid fibroblast-like synoviocytes.2016

    • Author(s)
      Tatematsu N, Waguri-Nagaya Y, Kawaguchi Y, Ikuta K, Kobayashi M, Goto H, Nozaki M, Aoyama M, Asai K, Otsuka T.
    • Organizer
      Annual European Congress of Rheumatology (EULAR2016)
    • Place of Presentation
      ExCel London, London (United Kingdom)
    • Year and Date
      2016-06-08
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Sp1 interference prevents joint destruction of RA through inhibitory effects of gliostatin and matrix metalloproteinase-3.2016

    • Author(s)
      Ikuta K, Kawaguchi Y, Waguri-Nagaya Y, Tatematsu N, Kobayashi M, Goto H, Nozaki M, Aoyama M, Asai K, Otsuka T.
    • Organizer
      Annual European Congress of Rheumatology (EULAR2016)
    • Place of Presentation
      ExCel London, London (United Kingdom)
    • Year and Date
      2016-06-08
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] The JAK inhibitor (Tofacitinib) inhibits TNF-induced gliostatin/thymidine phosphorylase expression in human fibroblast-like synoviocytes.2016

    • Author(s)
      Kawaguchi Y, Waguri-Nagaya Y, Tatematsu N, Kobayashi M, Goto H, Nozaki M, Ikuta K, Aoyama M, Asai K, Otsuka T.
    • Organizer
      Annual European Congress of Rheumatology (EULAR2016)
    • Place of Presentation
      ExCel London, London (United Kingdom)
    • Year and Date
      2016-06-08
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Anterolatelal ligament injury increases rotational instability in ACL defidient knee2016

    • Author(s)
      Nozaki M, Murase A, Kobayashi M, Yasuma S, Sakai H, Goto H, Nagaya Y, Otsuka T
    • Organizer
      17th ESSKA Congress
    • Place of Presentation
      Centre Convencions Internacional Barcelona, Barcelona (Spain)
    • Year and Date
      2016-05-04
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Anterolateral ligament controls rotational instability as a secondary restraint in ACL deficient knee2016

    • Author(s)
      Yasuma S, Nozaki M, Murase A, Kobayashi M, Sakai H, Goto H, Mitsui H, Nagaya Y, Iguchi H, Otsuka T
    • Organizer
      17th ESSKA Congress
    • Place of Presentation
      Centre Convencions Internacional Barcelona, Barcelona (Spain)
    • Year and Date
      2016-05-04
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research
  • [Presentation] Comparison of the rotational instability in anterior cruciate ligament deficient patients using an inertial sensor2016

    • Author(s)
      Murase A, Nozaki M, Yasuma S, Sakai H, Kobayashi M, Goto H, Izumida M, Otsuka T
    • Organizer
      17th ESSKA Congress
    • Place of Presentation
      Centre Convencions Internacional Barcelona, Barcelona (Spain)
    • Year and Date
      2016-05-04
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research

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Published: 2016-04-21   Modified: 2020-03-30  

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