Hyaluronate modulates gliostatin expression in rheumatoid fibroblast-like synoviocytes

• Project/Area Number: 17K11020
• 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, 医薬学総合研究院(医学), 高度医療教育研究センター教授 (90291583)
• Co-Investigator(Kenkyū-buntansha): 浅井 清文 名古屋市立大学, 医薬学総合研究院(医学), 教授 (70212462) ; 野崎 正浩 名古屋市立大学, 医薬学総合研究院(医学), 講師 (00509309)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥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 / チミジンホシホリラーゼ / ヒアルロン酸 / チミジンホスホリラーゼ

Outline of Final Research Achievements

The treatment of rheumatoid arthritis (RA) is in the era of remission. However, some patients have sustained local synovitis despite systemic inflammation has subsided. We have reported that gliostatin is closely involved in the development of RA.
Intra-articular injection of high molecular weight hyaluronic acid (HMW-HA) is widely used as a local treatment for osteoarthritis (OA) and RA, however the mechanism of action on synoviocytes is still unclear . In this study, we used cultured synoviocytes to clarify the mechanism by which HMW-HA controls angiogenic factors such as gliostatin and vascular endothelial cell growth factor, and to effectively and safely prevent synovitis and joint destruction. The significance of topical treatment with HMW-HA was found.

Academic Significance and Societal Importance of the Research Achievements

“関節リウマチの病態、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。生物学的製剤やメトトレキサートを使用しているにも関わらず、少数の関節腫脹が残存し、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外科的に滑膜切除を行なうことも有用であるが、関節内注射療法の方がより侵襲性が低い。
炎症性サイトカインネットワークの下流に位置するグリオスタチン産生を高分子ヒアルロン酸により制御できれば、薬物治療不応性の関節炎に対しても、有効かつ安全な局所治療が可能となる。

Research Products

• [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] 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
• [Journal Article] The janus kinase inhibitor tofacitinib inhibits TNFα-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: 印刷中
  • 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
  • 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
  • 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
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
  • Peer Reviewed
• [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
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] 関節リウマチ患者におけるフレイルの背景要因に関する検討. (2020)
  • Author(s): 小嶋雅代、佐竹昭介、松井康素、渡邉美貴、鈴木貞夫、野口泰三、村田千代栄、斉藤民、小嶋俊久、永谷祐子、尾島俊之、近藤克則
  • Organizer: 第30回日本疫学会学術総会
• [Presentation] 外側型変形性膝関節症に対する単顆型人工膝関節置換術の1例. (2020)
  • Author(s): 佐野嘉紀, 永谷祐子.
  • Organizer: 第50回日本人工関節学会
• [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] ACL 損傷においてramp lesion が膝不安定性にもたらす影響 - Inertial sensorによるpivot shift test の定量評価- (2019)
  • Author(s): 野崎正浩，小林真, 安間三四郎, 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] Ramp lesionの鏡視所見と術前MRI評価との比較. (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] 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3例 (2019)
  • Author(s): 上用祐士, 川口洋平, 小林真, 三井裕人, 黒柳元, 野崎正浩, 村上英樹, 永谷祐子.
  • Organizer: 第31回中部リウマチ学会
• [Presentation] 皮膚筋炎に合併した肘部難治性皮膚潰瘍に洗浄液周期的自動注入機能付き陰圧創傷治療システムが有効であった1例 (2019)
  • Author(s): 川口洋平, 永谷祐子, 上用祐士, 小林真, 三井裕人, 黒柳元, 野崎正浩, 村上英樹.
  • Organizer: 第31回中部リウマチ学会
• [Presentation] 高齢関節リウマチ患者の「健康とくらしの調査」 (2019)
  • Author(s): 小嶋雅代, 永谷祐子, 高橋伸典, 祖父江康司, 西梅剛, 鈴木望人, 野崎正浩, 三井裕人, 川口洋平, 黒柳元, 小嶋俊久.
  • Organizer: 第34回日本臨床リウマチ学会
• [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
• [Presentation] トシリズマブを使用した関節リウマチ患者血清ちゅうグリオスタチンの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, 小林正明, 立松尚衞, 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
• [Presentation] The inhibitory effects of tacrolimus on gliostatin production in RA synoviocytes. (2017)
  • Author(s): Ikuta K, Waguri-Nagaya Y, Kawaguchi Y , Tatematsu N, Kobayashi M, Goto H, Nozaki M, Aoyama M, Asai K, Otsuka T.
  • Organizer: Annual European Congress of Rheumatology (EULAR2017)
  • Int'l Joint Research
• [Presentation] Quantitative Evaluation of the Biomechanical Function of the Anterolateral structure using an inertial sensor (2017)
  • 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
  • Int'l Joint Research