Molecular mechanism of gliostatin and tenascin C in rheumatoid synoviocytes

• Project/Area Number: 18K09114
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Nagoya City University
• Principal Investigator: Yusuke Oguri 名古屋市立大学, 医薬学総合研究院(医学), 研究員 (80528969)
• Co-Investigator(Kenkyū-buntansha): 永谷 祐子 名古屋市立大学, 医薬学総合研究院(医学), 教授 (90291583) ; 川口 洋平 名古屋市立大学, 医薬学総合研究院(医学), 助教 (90766734) ; 黒柳 元 名古屋市立大学, 医薬学総合研究院(医学), 講師 (80790831)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 関節リウマチ / 滑膜細胞 / グリオスタチン / テネイシンC / 線維芽細胞様滑膜細胞 / 滑膜炎 / チミジンホスホリラーぜ

Outline of Final Research Achievements

The treatment of rheumatoid arthritis (RA) is in the era of remission, due to biological DMARDs and JAK inhibitors. However, some patients have sustained synovitis despite systemic inflammation has subsided. Further therapeutic targets need to be explored for RA, which leads to joint dysfunction and poor quality of life. Griotatin (GLS) is a protein with various physiological activities on various cells, and has inflammatory and pannus-forming effects on the synovium. Tenascin C (TNC) activates Toll-like receptor 4. We have clarified the mechanism between the molecular phases of TNC and GLS from our studies on GLS and the mechanism of action of TNC.

Academic Significance and Societal Importance of the Research Achievements

“RAの病態、関節破壊にグリオスタチンの過剰産生が関与する”という考え方は、申請者らの独創的な研究成果に基づくものである。また従来の薬物治療により臨床的寛解を得ている患者でも、少数の関節腫脹が残存し、完全寛解目標に到達できない症例が存在することが、実臨床ではよくみられる。少数の関節腫脹に対しては、外科的に滑膜切除を行なうことも有用であるが、新規治療ターゲットを探索し、薬物治療の発展によるRAの制圧は、非侵襲性治療であり、社会的ニーズが高い。本研究では、RAの病態にGLSが関与するという着想に加えて、TNCの関与を明らかにすることにより、RA完全制圧を目指せることとなる。

Research Products

• [Journal Article] N-acetyl-seryl-aspartyl-lysyl-proline: A new potential serum biomarker of rheumatoid arthritis (2021)
  • Author(s): Yusuke Oguri, Yohei Kawaguchi , Naoe Tatematsu, Yuji Joyo, Ken Mizuguchi, Hiroki Yonezu, Hideki Okamoto, Masahiro Nozaki, Makoto Kobayashi, Gen Kuroyanagi, Hisaki Aiba, Kiyofumi Asai, Koichi Inoue, Hideki Murakami, Yuko Waguri-Nagaya
  • Journal Title: Medical Mass Spectrometry Volume: 5 Pages: 28-37
  • NAID: 130008062713
  • Peer Reviewed / Open Access
• [Journal Article] バイク事故による橈骨遠位端骨折に合併した月状骨脱臼の1例 (2021)
  • Author(s): 加藤 明裕, 福田 誠, 川口 洋平, 五島 隆宏, 松嶋 麻子
  • Journal Title: 日本救急医学会雑誌 Volume: 32 Pages: 73-79
  • Peer Reviewed
• [Journal Article] 臼蓋巨大骨欠損に対するBuerch-Schneider anti-protrusio cageの治療経験 (2020)
  • Author(s): 佐野 嘉紀, 永谷 祐子, 小栗 雄介
  • Journal Title: 東海関節 Volume: 12 Pages: 47-53
  • Peer Reviewed
• [Journal Article] 気胸、細菌性肺炎を繰り返し治療に難渋した間質性肺疾患合併RAの1例 (2020)
  • Author(s): 小栗 雄介, 川口 洋平, 黒柳 元, 上用 祐士, 野崎 正浩, 小林 真, 永谷 祐子
  • Journal Title: 中部リウマチ Volume: 50 Pages: 9-12
  • Peer Reviewed
• [Journal Article] 重度不安定性を呈する肘関節脱臼骨折における,尺骨鈎状突起骨折・前方軟部組織再建の意義 (2020)
  • Author(s): 早川 和男, 遠藤 浩二郎, 川口 洋平, 岡本 秀貴
  • Journal Title: 日本手外科学会雑誌 Volume: 37 Pages: 113-117
  • Peer Reviewed
• [Journal Article] Depression, physical function, and disease activity associated with frailty in patients with rheumatoid arthritis (2020)
  • Author(s): Kojima Masayo、Kojima Toshihisa、Waguri-Nagaya Yuko、Takahashi Nobunori、Asai Shuji、Sobue Yasumori、Nishiume Tsuyoshi、Suzuki Mochihito、Mitsui Hiroto、Kawaguchi Yohei、Kuroyanagi Gen、Yasuoka Mikako、Watanabe Miki、Suzuki Sadao、Arai Hidenori
  • Journal Title: Modern Rheumatology Volume: 2 Issue: 5 Pages: 1-8
  • DOI: 10.1080/14397595.2020.1838402
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Pyogenic tenosynovitis of the wrist due to Corynebacterium striatum in a patient with dermatomyositis. A case report. (2020)
  • Author(s): Kawaguchi Y, Okamoto H, Endo K, Iwata H, Joyo Y, Nozaki, M, Tamechika S, Waguri-Nagaya Y, Murakami H.
  • Journal Title: Medicine Volume: 99 Issue: 3 Pages: e18761-e18761
  • DOI: 10.1097/md.0000000000018761
  • Peer Reviewed / Open Access
• [Journal Article] Incretin accelerates platelet-derived growth factor-BB-induced osteoblast migration via protein kinase A: The upregulation of p38 MAP kinase. (2020)
  • Author(s): Kawabata T, Tokuda H, Kuroyanagi G, Fujita K, Sakai G, Kim W, Matsushima-Nishiwaki R, Iida H, Yata KI, Wang S, Mizoguchi A, Otsuka T, Kozawa O.
  • Journal Title: Sci Rep Volume: 10 Issue: 1 Pages: 2341-2341
  • DOI: 10.1038/s41598-020-59392-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Anterolateral ligament reconstruction as an augmented procedure for double-bundle anterior cruciate ligament reconstruction restores rotational stability: Quantitative evaluation of the pivot shift test using an inertial sensor. (2020)
  • Author(s): Yasuma S, Nozaki M, Murase A, Kobayashi M, Kawanishi Y, Fukushima H, Takenaga T, Yoshida M, Kuroyanagi G, Kawaguchi Y, Nagaya Y, Murakami H.
  • Journal Title: Knee Volume: S0968-0160 Issue: 2 Pages: 30053-3
  • DOI: 10.1016/j.knee.2020.02.015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Enhancement by HSP90 inhibitor of PGD2-stimulated HSP27 induction in osteoblasts: Suppression of SAPK/JNK and p38 MAP kinase. (2019)
  • Author(s): Kim W, Tokuda H, Kawabata T, Fujita K, Sakai G, Nakashima D, Tachi J, Kuroyanagi G, Matsushima-Nishiwaki R, Tanabe K, Otsuka T, Iida H, Kozawa O.
  • Journal Title: Prostaglandins Other Lipid Mediat Volume: 143 Pages: 106327-106327
  • DOI: 10.1016/j.prostaglandins.2019.03.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] IL6 receptor blockade preserves articular cartilage and increases bone volume following ischemic osteonecrosis in immature mice (2019)
  • Author(s): Kamiya N.、Kuroyanagi G.、Aruwajoye O.、Kim H.K.W.
  • Journal Title: Osteoarthritis and Cartilage Volume: 27 Issue: 2 Pages: 326-335
  • DOI: 10.1016/j.joca.2018.10.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Treatment of aneurysmal bone cysts using endoscopic curettage (2018)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Treatment of simple bone cysts using endoscopic curettage: a case series analysis (2018)
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] The Janus kinase inhibitor tofacitinib inhibits TNF-α-induced gliostatin expression in rheumatoid fibroblast-like synoviocytes (2018)
  • 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
  • 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
  • Peer Reviewed
• [Presentation] グリオスタチン産生からみた滑膜細胞に対するバリシチニブの新規作用 (2020)
  • Author(s): 上用 祐士, 川口 洋平, 黒柳 元, 浅井 清文, 永谷 祐子
  • Organizer: 第64回日本リウマチ学会
• [Presentation] リウマチ滑膜細胞においてバリシチニブはSTAT1のリン酸化阻害でGLS産生を抑制する (2020)
  • Author(s): 上用 祐士, 川口 洋平, 黒柳 元, 小林 真, 野崎 正浩, 浅井 清文, 永谷 祐子, 村上 英樹
  • Organizer: 日本整形外科学会基礎学術集会
• [Presentation] Novel anti-angiogenic effects of tofacitinib in fibroblast-like synoviocytes derived from patients with RA. (2019)
  • Author(s): Kawaguchi Y, Oguri Y, Nozaki M, Asai K, Waguri-Nagaya Y.
  • Organizer: Annual European Congress of Rheumatology EULAR 2019
  • Int'l Joint Research
• [Presentation] The JAK inhibitor (baricitinib) inhibits IFNγ-induced gliostatin expression in human fibroblast-like synoviocytes. (2019)
  • Author(s): Joyo Y, Kawaguchi Y, Oguri Y, Nozaki M, Asai K, Waguri-Nagaya Y.
  • Organizer: Annual European Congress of Rheumatology EULAR 2019
  • Int'l Joint Research
• [Presentation] 生物学的製剤導入時の胸部CT検査で悪性腫瘍が発見された関節リウマチの2例 (2019)
  • Author(s): 上用祐士, 川口洋平, 小栗雄介, 三井裕人, 黒柳元, 永谷祐子.
  • Organizer: 第63回日本リウマチ学会総会・学術集会.
• [Presentation] Inertial sensorを用いたpivot shift test の定量評価.ACL再建術前、time zero, 抜釘時の比較- (2019)
  • Author(s): 安間三四郎, 野崎正浩，小林真, 川西佑典, 永谷祐子，吉田雅人, 三井裕人，黒柳元, 井口普敬.
  • Organizer: 第92回日本整形外科学会学術集会
• [Presentation] Circulating gliostatin correlates with serological feature and response to IL-6 inhibitor therapy in patients with RA. (2018)
  • Author(s): Oguri Y, Kawaguchi Y, Nozaki M, Asai K, Waguri-Nagaya Y
  • Organizer: 39th SICOT Orthopaedic World Congress 2018
  • 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
  • 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