Gliostatin as a novel therapeutic target for rheumatoid arthritis

• Project/Area Number: 26462309
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Orthopaedic surgery
• Research Institution: Nagoya City University
• Principal Investigator: NAGAYA Yuko 名古屋市立大学, 大学院医学研究科, 教授 (90291583)
• Co-Investigator(Kenkyū-buntansha): 大塚 隆信 名古屋市立大学, 大学院医学研究科, 教授 (10185316) ; 浅井 清文 名古屋市立大学, 大学院医学研究科, 教授 (70212462)
• Research Collaborator: KAWAGUCHI Yohei 名古屋市立大学, 大学院医学研究科, 臨床研究医 (90766734) ; OGURI Yusuke 名古屋市立大学, 大学院医学研究科, 臨床研究医 (80528969) ; TATEMATSU Naoe 名古屋市立大学, 大学院医学研究科, 大学院生
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥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 / チミジンホスホリラーゼ / マトリックスメタロプロテアーゼ / マトリックスメタロプロテイナーゼ / チミジンホスポリラーゼ / TNF alfa / チミジンホスフォリアーゼ / MMP-3

Outline of Final Research Achievements

Treatment of rheumatoid arthritis (RA) has advanced dramatically in the last decade, and it has become possible to aim for remission through strong treatment intervention such as biological and targeted anti-rheumatic drugs. However, there are drug-resistant patients who do not respond to any drug treatment. We have reported for the first time that gliostatin is closely involved in the pathogenesis of RA. In this study, we clarified that this gliostatin can be therapeutically targeted. The mechanism of joint destruction by gliostatin and its suppression mechanism were analyzed by molecular biological method using fibroblast-like synoviocytes derived from patients with RA

Research Products

• [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
  • Peer Reviewed / Open Access
• [Journal Article] Regulation by AMP-activated protein kinase of PGE2-induced osteoprotegerin synthesis in osteoblasts. (2016)
  • Author(s): Kainuma S, Otsuka T, Kuroyanagi G, Yamamoto N, Matsushima-Nishiwaki R, Kozawa O and Tokuda H.
  • Journal Title: Mol Med Rep. Volume: 4 Issue: 4 Pages: 3363-3369
  • DOI: 10.3892/mmr.2016.4900
  • Peer Reviewed / Open Access
• [Journal Article] Possible involvement of AMP-activated protein kinase in PGE(1)-induced synthesis of osteoprotegerin in osteoblasts. (2016)
  • Author(s): Kainuma S, Otsuka T, Kuroyanagi G, Yamamoto N, Matsushima-Nishiwaki R, Kozawa O, Tokuda H.
  • Journal Title: Exp Ther Med Volume: 11 Pages: 2042-2048
  • Peer Reviewed / Open Access
• [Journal Article] Thrombin Receptor-Activating Protein (TRAP)-Activated Akt Is Involved in the Release of Phosphorylated-HSP27 (HSPB1) from Platelets in DM Patients. (2016)
  • Author(s): Tokuda H, Kuroyanagi G, Tsujimoto M, Matsushima-Nishiwaki R, Akamatsu S, Enomoto Y, Iida H, Otsuka T, Ogura S, Iwama T, Kojima K, Kozawa O.
  • Journal Title: Int J Mol Sci Volume: 17 Issue: 5 Pages: 737-737
  • DOI: 10.3390/ijms17050737
  • Peer Reviewed / Open Access
• [Journal Article] Heat shock protein 22 (HSPB8) limits TGF-β-stimulated migration of osteoblasts. (2016)
  • Author(s): Yamamoto N, Tokuda H, Kuroyanagi G, Kainuma S, Matsushima-Nishiwaki R, Fujita K, Kozawa O, Otsuka T.
  • Journal Title: Mol Cell Endocrinol Volume: 436 Pages: 1-9
  • DOI: 10.1016/j.mce.2016.07.011
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Postoperative evaluation of drill holes for arthroscopic Bankart repair with suture anchors by the use of computed tomography. (2015)
  • Author(s): Yoshida M, Goto H, Nozaki M, Nishimori Y, Takenaga T, Murase A, Nagaya Y, Iguchi H, Kobayashi M, Sugimoto K, Otsuka T.
  • Journal Title: J Orthop Sci Volume: 20 Issue: 3 Pages: 481-487
  • DOI: 10.1007/s00776-015-0703-y
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Quantitative analysis of attachment of the labrum to the glenoid fossa: a cadaveric study. (2015)
  • Author(s): Yoshida M, Goto H, Nozaki M, Nishimori Y, Takenaga T, Murase A, Nagaya Y, Iguchi H, Kobayashi M, Sugimoto K, Nishiyama T, Otsuka T.
  • Journal Title: J Orthop Sci Volume: 20 Issue: 5 Pages: 823-829
  • DOI: 10.1007/s00776-015-0742-4
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] New Protocol to Optimize iPS Cells for Genome Analysis of Fibrodysplasia Ossificans Progressiva. (2015)
  • Author(s): Matsumoto Y, Ikeya M, Hino K, Horigome K, Fukuta M, Watanabe M, Nagata S, Yamamoto T, Otsuka T, Toguchida J.
  • Journal Title: Stem Cells. Volume: 印刷中 Issue: 6 Pages: 1730-1742
  • DOI: 10.1002/stem.1981
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Resveratrol suppresses TGF-β-induced VEGF synthesis in osteoblasts: Inhibition of the p44/p42 MAPKs and SAPK/JNK pathways. (2015)
  • Author(s): Kuroyanagi G, Otsuka T, Yamamoto N, Matsushima-Nishiwaki R, Kozawa O, Tokuda H.
  • Journal Title: Exp Ther Med Volume: 9 Issue: 6 Pages: 2303-2310
  • DOI: 10.3892/etm.2015.2389
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Unphosphorylated HSP27 (HSPB1) regulates the translation initiation process via a direct association with eIF4E in osteoblasts. (2015)
  • Author(s): Kuroyanagi G, Tokuda H, Yamamoto N, Matsushima-Nishiwaki R, Kozawa O, Otsuka T
  • Journal Title: Int J Mol Med Volume: 36 Issue: 3 Pages: 881-889
  • DOI: 10.3892/ijmm.2015.2274
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Tumor necrosis factor stimulates osteoclastogenesis from human bone marrow cells under hypoxic conditions. (2014)
  • Author(s): Nomura T, Aoyama M, Waguri-Nagaya Y, Goto Y, Suzuki M, Miyazawa K, Asai K, Goto S.
  • Journal Title: Exp Cell Res Volume: 321 Pages: 167-177
  • Peer Reviewed
• [Journal Article] Progression of hip joint deformity during the management of pelvic insufficiency fracture in a patient with rheumatoid arthritis: a case report. (2014)
  • Author(s): Ikuta K, Waguri-Nagaya Y, Nozaki M, Mizutani J, Goto H, Kobayashi M, Otsuka T.
  • Journal Title: J Spine Volume: 3 Issue: 05 Pages: 6-6
  • DOI: 10.4172/2165-7939.1000188
  • Peer Reviewed / Open Access
• [Journal Article] Suppression by resveratrol of prostaglandin D2-stimulated osteoprotegerin synthesis in osteoblasts. (2014)
  • Author(s): Kuroyanagi G, Mizutani J, Kondo A, Yamamoto N, Matsushima-Nishiwaki R, Otsuka T, Kozawa O, Tokuda H.
  • Journal Title: Prostaglandins Leukot Essent Fatty Acids. Volume: S0952-3278(14) Issue: 3 Pages: 72-76
  • DOI: 10.1016/j.plefa.2014.04.003
  • Peer Reviewed
• [Journal Article] Resveratrol inhibits BMP-4-stimulated VEGF synthesis in osteoblasts: suppression of S6 kinase. (2014)
  • Author(s): Kondo A, Otsuka T, Kuroyanagi G, Yamamoto N, Matsushima-Nishiwaki R, Mizutani J, Kozawa O, Tokuda H.
  • Journal Title: Int J Mol Med. Volume: 33(4) Issue: 4 Pages: 1013-1018
  • DOI: 10.3892/ijmm.2014.1626
  • Peer Reviewed / Open Access
• [Presentation] 関節リウマチ線維芽細胞様滑膜細胞に置いてグリオスタチンによって誘導されたMMPsはSp１阻害剤によって抑制される. (2016)
  • Author(s): 立松 尚衞, 永谷祐子, 川口洋平, 生田憲史, 小栗雄介, 小林正明,野崎正浩, 青山峰芳, 浅井清文, 大塚隆信.
  • Organizer: 第31回日本整形外科基礎学術集会
  • Place of Presentation: 福岡国際会議場 (福岡県, 福岡市)
  • Year and Date: 2016-10-13
• [Presentation] グリオスタチン発現抑制はリウマチ滑膜細胞に対するJAK阻害剤の新規作用機序である. (2016)
  • Author(s): 川口洋平, 永谷祐子, 立松 尚衞, 小林正明, 後藤英之, 野崎正浩, 青山峰芳, 浅井清文, 大塚隆信.
  • Organizer: 第31回日本整形外科基礎学術集会
  • Place of Presentation: 福岡国際会議場 (福岡県, 福岡市)
  • Year and Date: 2016-10-13
• [Presentation] 関節リウマチ線維芽細胞様滑膜細胞においてTNF alfaによるグリオスタチンの発現は JAK阻害剤により抑制される. (2016)
  • Author(s): 川口洋平, 永谷祐子, 小林正明, 後藤英之, 野崎正浩, 青山峰芳, 浅井清文, 大塚隆信.
  • Organizer: 第160回名古屋市立大学医学会例会.
  • Place of Presentation: 名古屋市立大学大学院医学研究科研究棟 (愛知県 .名古屋市)
  • Year and Date: 2016-06-20
• [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
  • 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
  • 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
  • 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
  • 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
  • Int'l Joint Research
• [Presentation] 関節リウマチ患者の血清 N-acetyl-seryl-aspartyl-lysyl-proline(AcSDKP) 濃度は治療の有効性を反映している. (2016)
  • Author(s): 立松 尚衞, 永谷 祐子, 川口 洋平, 井之上 浩一, 浅井 清文, 大塚 隆信.
  • Organizer: 第89回日本整形外科学会学術集会.
  • Place of Presentation: パシフィコ横浜 (神奈川県, 横浜市)
  • Year and Date: 2016-05-12
• [Presentation] 関節リウマチ患者の血清 N-acetyl-seryl-aspartyl-lysyl-proline(AcSDKP) 濃度は治療の有効性を反映している. (2016)
  • Author(s): 立松 尚衞, 永谷 祐子, 川口 洋平, 井之上 浩一, 浅井 清文, 大塚 隆信.
  • Organizer: 第89回日本整形外科学会学術集会
  • Place of Presentation: パシフィコ横浜, 横浜
  • Year and Date: 2016-05-12
• [Presentation] トファシチニブ投与RA患者の臨床像と血清グリオスタチンへの影響の検討. (2016)
  • Author(s): 川口洋平, 永谷祐子, 立松尚衛, 小林正明, 後藤英之, 野崎正浩, 小栗雄介, 浅井清文, 大塚隆信.
  • Organizer: 第60回日本リウマチ学会総会・学術集会
  • Place of Presentation: パシフィコ横浜, 横浜
  • Year and Date: 2016-04-22
• [Presentation] トファシチニブ投与RA患者の臨床像と血清グリオスタチンへの影響の検討. (2016)
  • Author(s): 川口洋平, 永谷祐子, 立松尚衛, 小林正明, 後藤英之, 野崎正浩, 小栗雄介, 浅井清文, 大塚隆信.
  • Organizer: 第60回日本リウマチ学会総会・学術集会.
  • Place of Presentation: パシフィコ横浜 (神奈川県, 横浜市)
  • Year and Date: 2016-04-21
• [Presentation] 関節リウマチ線維芽細胞様滑膜細胞においてTNF-によるグリオスタチン発現はJAK阻害剤により抑制される. (2015)
  • Author(s): 川口洋平, 永谷祐子, 立松尚衛, 小林正明, 後藤英之，野崎正浩, 青山峰芳, 浅井清文, 大塚隆信.
  • Organizer: 第30回日本整形外科基礎学術集会
  • Place of Presentation: 富山国際会議場, 富山
  • Year and Date: 2015-10-22
• [Presentation] The inhibitory effect of synthetic disease-modifying anti-rheumatic drugs and steroids on gliostatin/platelet-derived endothelial cell growth factor production in human fibroblast-like synoviocytes. (2015)
  • 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
  • Place of Presentation: Fiera Roma (Roma, Italy)
  • Year and Date: 2015-06-10 – 2015-06-13
• [Presentation] A Role For P38 Mitogen-Activated Protein Kinase (Mapk) In Gliostatin Production In Rheumatoid Fibroblast-Like Synoviocytes. (2015)
  • 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
  • Place of Presentation: Fiera Roma (Roma, Italy)
  • Year and Date: 2015-06-10 – 2015-06-13
• [Presentation] The inhibitory effect of synthetic disease-modifying anti-rheumatic drugs and steroids on gliostatin/platelet-derived endothelial cell growth factor production in human fibroblast-like synoviocytes. (2015)
  • 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 (EULAR2015)
  • Place of Presentation: Fiera Roma, Roma, Italy
  • Year and Date: 2015-06-10
  • Int'l Joint Research
• [Presentation] A Role For P38 Mitogen-Activated Protein Kinase (Mapk) In Gliostatin Production In Rheumatoid Fibroblast-Like Synoviocytes. (2015)
  • 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 (EULAR2015)
  • Place of Presentation: Fiera Roma, Roma, Italy
  • Year and Date: 2015-06-10
  • Int'l Joint Research
• [Presentation] The JAK inhibitor (Tofacitinib) inhibits TNF-induced gliostatin/thymidine phosphorylase expression in human fibroblast-like synoviocytes. (2015)
  • 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: 2015-06-08
  • Int'l Joint Research
• [Presentation] 液体クロマトグラフィー・タンデム質量分析法による関節リウマチ患者の血清中AcSDKPの検討. (2014)
  • Author(s): 立松直衛, 永谷祐子, 川口洋平, 菊池可絵, 青山峰芳, 井之上浩一, 浅井清文, 大塚隆信.
  • Organizer: 第29回日本整形外科基礎学術集会
  • Place of Presentation: 城山観光ホテル (鹿児島県、鹿児島市)
  • Year and Date: 2014-10-09 – 2014-10-10
• [Presentation] 生物学的製剤導入前後にリウマチ関節手術を考慮した症例の検討. (2014)
  • Author(s): 永谷祐子, 小林正明, 後藤英之, 野崎正浩, 井口普敬, 大塚隆信.
  • Organizer: 第123回中部日本整形外科災害外科学会
  • Place of Presentation: 名古屋国際会議場 (愛知県、名古屋市)
  • Year and Date: 2014-10-03 – 2014-10-04
• [Presentation] The importance of gliostatin as an indicator of disease activity in patients with rheumatoid arthritis. (2014)
  • Author(s): Ikuta K, Waguri-Nagaya Y, Tatematsu N, Kawaguchi Y, Kobayashi M, Aoyama M, Asai K, Otsuka T.
  • Organizer: Annual European Congress of Rheumatology
  • Place of Presentation: Le Palais des Congres de Paris (Paris, France)
  • Year and Date: 2014-06-11 – 2014-06-14
• [Presentation] Gliostatin regulates vascular endothelial growth-factor production in human fibroblast-like synoviocytes. (2014)
  • 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
  • Place of Presentation: Le Palais des Congres de Paris (Paris, France)
  • Year and Date: 2014-06-11 – 2014-06-14