A metabolic approach for discovering therapeutic target in rheumatoid arthritis synovial fibroblast

• Project/Area Number: 15K09525
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Kobe University
• Principal Investigator: Saegusa Jun 神戸大学, 医学部附属病院, 講師 (20514970)
• Co-Investigator(Kenkyū-buntansha): 森信 暁雄 神戸大学, 医学研究科, 准教授 (10294216) ; 河野 誠司 神戸大学, 医学部附属病院, 特命教授 (20351512)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 関節リウマチ / グルタミン代謝 / 滑膜細胞 / 解糖系 / メタボロミクス / グルタミナーゼ１ / グルタミノリシス / 代謝

Outline of Final Research Achievements

Fibroblast-like synoviocytes from rheumatoid arthritis patients (RA-FLS) exhibit several tumor cell-like characteristics; however, the role of glucose and glutamine metabolism in the aberrant proliferation of these cells is unclear. We evaluated the role of these metabolic pathways in RA-FLS and in mouse model of RA.
GLS1 expression was increased in RA-FLS. RA-FLS proliferation was reduced under glutamine-deprived, but not glucose-deprived, conditions. Cell growth of RA-FLS was inhibited by GLS1 siRNA or GLS1 inhibitor treatment. Treating RA-FLS with either IL-17 or PDGF resulted in increased GLS1 levels. GLS1 inhibitor ameliorated the arthritis and decreased the number of Ki-67-positive synovial cells in SKG mice. Our results suggested that glutamine metabolism is involved in the pathogenesis of RA and that GLS1 plays an important role in regulating RA-FLS proliferation, and may be a novel therapeutic target for RA.

Research Products

• [Journal Article] Glutaminase 1 plays a key role in the cell growth of fibroblast-like synoviocytes in rheumatoid arthritis. (2017)
  • Author(s): Takahashi S, Saegusa J, Sendo S, Okano T, Akashi K, Irino Y, Morinobu A
  • Journal Title: Arthritis Res Ther. Volume: 19 Issue: 1 Pages: 76-76
  • DOI: 10.1186/s13075-017-1283-3
  • NAID: 120006318800
  • Peer Reviewed / Open Access
• [Journal Article] 3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation. (2017)
  • Author(s): Okano T, Saegusa J, Nishimura K, Takahashi S, Sendo S, Ueda Y, Morinobu A.
  • Journal Title: Sci Rep. Volume: 7 Issue: 1 Pages: 42412-42412
  • DOI: 10.1038/srep42412
  • NAID: 120006624239
  • Peer Reviewed / Open Access
• [Journal Article] CD11b+ Gr1dim tolerogenic dendritic cell-like cells are expanded in interstitial lung disease in SKG mice. (2017)
  • Author(s): Sendo S, Saegusa J, Okano T, Takahashi S, Akashi K, Morinobu A.
  • Journal Title: Arthritis Rheumatol. Volume: 69 Issue: 12 Pages: 2314-27
  • DOI: 10.1002/art.40231
  • NAID: 120006621623
  • Peer Reviewed
• [Journal Article] Direct binding to integrins and loss of disulfide linkage in IL-1beta are involved in the agonistic action of IL-1beta. (2017)
  • Author(s): Takada YK, Yu J, Fujita M, Saegusa J, Wu CY, Takada Y.
  • Journal Title: J Biol Chem. Volume: 292 Issue: 49 Pages: 20067-75
  • DOI: 10.1074/jbc.m117.818302
  • Peer Reviewed
• [Journal Article] Knockout of endothelin type B receptor signaling attenuates bleomycin-induced skin sclerosis in mice. (2016)
  • Author(s): Akashi K, Saegusa J, Sendo S, Nishimura K, Okano T, Yagi K, Yanagisawa M, Emoto N, Morinobu A.
  • Journal Title: Arthritis Res Ther. Volume: 18 Issue: 1 Pages: 113-113
  • DOI: 10.1186/s13075-016-1011-4
  • NAID: 120007135444
  • Peer Reviewed / Open Access
• [Journal Article] Expression and Functions of Immediate Early Response Gene X-1 (IEX-1) in Rheumatoid Arthritis Synovial Fibroblasts. (2016)
  • Author(s): Morinobu A, Tanaka S, Nishimura K, Takahashi S, Kageyama G, Miura Y, Kurosaka M, Saegusa J, Kumagai S.
  • Journal Title: PLoS One Volume: 11 Issue: 10 Pages: e0164350-e0164350
  • DOI: 10.1371/journal.pone.0164350
  • NAID: 120005898575
  • Peer Reviewed / Open Access
• [Journal Article] メタボロームに着目した膠原病の新規治療法および診断法の開発 (2016)
  • Author(s): 三枝淳, 蔭山豪一, 森信暁雄
  • Journal Title: アレルギーの臨床 Volume: 36 Pages: 1292-1297
• [Journal Article] Tofacitinib facilitates the expansion of myeloid-derived suppressor cells and ameliorates arthritis in SKG mice. (2015)
  • Author(s): Nishimura K, Saegusa J, Matsuki F, Akashi K, Kageyama G, Morinobu A
  • Journal Title: Arthritis Rheumatol Volume: 67 Issue: 4 Pages: 893-902
  • DOI: 10.1002/art.39007
  • Peer Reviewed
• [Journal Article] MicroRNA-124 inhibits the progression of adjuvant-induced arthritis in rats. (2015)
  • Author(s): Nakamachi Y, Ohnuma K, Uto K, Noguchi Y, Saegusa J, Kawano S
  • Journal Title: Ann Rheum Dis Volume: 印刷中 Issue: 3 Pages: 601-608
  • DOI: 10.1136/annrheumdis-2014-206417
  • Peer Reviewed / Open Access
• [Journal Article] Metabolomics analysis of saliva from patients with primary Sjogren's syndrome. (2015)
  • Author(s): Kageyama G, Saegusa J, Irino Y, Tanaka S, Tsuda K, Takahashi S, Sendo S, Morinobu A.
  • Journal Title: Clinical & Experimental Immunology Volume: 182(2) Issue: 2 Pages: 149-153
  • DOI: 10.1111/cei.12683
  • Peer Reviewed
• [Journal Article] 自己免疫疾患のメタボローム解析の未来～新規バイオマーカーの同定と病態解明を目指して～ (2015)
  • Author(s): 三枝淳, 河野誠司, 森信暁雄
  • Journal Title: 臨床病理 Volume: 63(4) Pages: 498-505
• [Journal Article] メタボロームに着目した膠原病の新規治療法および診断法の開発 (2015)
  • Author(s): 三枝淳, 蔭山豪一, 森信暁雄
  • Journal Title: BIO Clinica Volume: 30(11) Pages: 1110-1115
• [Presentation] Glutamine metabolism plays a key role in the cell growth of fibroblast-like synoviocytes in rheumatoid arthritis. (2017)
  • Author(s): Takahashi S, Saegusa J, Yamada H, Ichise Y, Naka I, Okano T, Akashi K, Sendo S, Ueda Y, Onishi A, Morinobu A.
  • Organizer: The 18th Annual European Congress of Rheumatology - EULAR 2017
  • Int'l Joint Research
• [Presentation] CD11b+Cr1dim tolerogenic dendritic cell-like cells are expanded in interstitial lung disease in SKG mice. (2017)
  • Author(s): Sendo S, Saegusa J, Ichise Y, Yamada H, Naka I, Okano T, Takahashi S, Ueda Y, Akashi K, Onishi A, Morinobu A.
  • Organizer: The 18th Annual European Congress of Rheumatology - EULAR 2017
  • Int'l Joint Research
• [Presentation] 3-bromopyruvate ameliorate autoimmune arthritis by modulating Th17/Treg cell differentiation and suppressing dendritic cell activation) (2017)
  • Author(s): Okano Takaichi, Saegusa Jun, Nishimura Keisuke, Ueda Yo, Sendo Sho, Takahashi Soshi, Nishida Miwa, Akashi Kengo, Onishi Akira, Morinobu Akio
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Presentation] CD11b+Gr1dimTolerogenic Dendritic Cell-Like Cells are Expanded in Interstitial Lung Disease of SKG Mice (2017)
  • Author(s): Sendo Sho, Saegusa Jun, Ichise Yoshihide, Yamada Hirotaka, Naka Ikuko, Okano Takaichi, Takahashi Soshi, Ueda Yo, Akashi Kengo, Onishi Akira, Kogata Yoshinori, Morinobu Akio
  • Organizer: 第61回日本リウマチ学会総会・学術集会
• [Presentation] CD11b+Gr1dim tolerogenic dendritic cell-like cells suppress the progression of interstitial lung disease in SKG mice. (2017)
  • Author(s): Sendo S, Saegusa J, Yamada H, Ichise Y, Naka I, Ueda Y, Okano T, Takahashi S, Akashi K, Onishi A, Morinobu A.
  • Organizer: American College of Rheumatology 81 th Annual Scientific Meeting
  • Int'l Joint Research
• [Presentation] Glutamine metabolism plays a crucial role in the pathogenesis of rheumatoid arthritis. (2016)
  • Author(s): Takahashi S, Saegusa J, Naka I, Tsuda K, Okano T, Akashi K, Sendo S, Ueda Y, Onishi A, Kogata Y, Morinobu A.
  • Organizer: American College of Rheumatology 80th Annual Scientific Meeting
  • Place of Presentation: ワシントンDC、米国
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] CD11b+Gr1dim cells, which are induced by GM-CSF produced by Th17 and group3 innate lymphoid cell, may facilitate the progression of pneumonitis in SKG mice. (2016)
  • Author(s): Sendo S, Saegusa J, Okano T, Takahashi S, Morinobu A.
  • Organizer: American College of Rheumatology 80th Annual Scientific Meeting
  • Place of Presentation: ワシントンDC、米国
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Dual effect of 3-bromopyruvate on both Th17 and Treg cell differentiation and dendritic cell activation ameliorates autoimmune arthritis in mice. (2016)
  • Author(s): Okano T, Saegusa J, Nishimura K, Ueda Y, Sendo S, Takahashi S, Akashi K, Onishi A, Morinobu A.
  • Organizer: American College of Rheumatology 80th Annual Scientific Meeting
  • Place of Presentation: ワシントンDC、米国
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Knockout of endothelin type B receptor signaling attenuates bleomycin-induced skin sclerosis in mice. (2016)
  • Author(s): Akashi K, Saegusa J, Sendo S, Nishimura K, Tsuda K, Naka I, Okano T, Takahashi S, Nishida M, Ueda Y, Morinobu A.
  • Organizer: The 17th Annual European Congress of Rheumatology - EULAR 2016
  • Place of Presentation: イギリス ロンドン
  • Year and Date: 2016-06-11
  • Int'l Joint Research
• [Presentation] 3-bromopyruvate ameliorates autoimmune arthritis by exerting a dual effect on both Th17 and Treg cell differentiation and dendritic cell activation. (2016)
  • Author(s): Okano T, Saegusa J, Nishimura K, Takahashi S, Sendo S, Ueda Y, Onishi A, Morinobu A.
  • Organizer: The 17th Annual European Congress of Rheumatology - EULAR 2016
  • Place of Presentation: イギリス ロンドン
  • Year and Date: 2016-06-09
  • Int'l Joint Research
• [Presentation] Knockout of endothelin type B receptor signaling attenuates bleomycin-induced skin sclerosis in mice. (2016)
  • Author(s): Akashi K, Saegusa J, Sendo S, Nishimura K, Tsuda K, Naka I, Okano T, Takahashi S, Nishida M, Ueda Y, Morinobu A.
  • Organizer: The 17th Annual European Congress of Rheumatology
  • Place of Presentation: ロンドン、英国
  • Year and Date: 2016-06-08
  • Int'l Joint Research
• [Presentation] 3-bromopyruvate ameliorates autoimmune arthritis by exerting a dual effect on both Th17 and Treg cell differentiation and dendritic cell activation. (2016)
  • Author(s): Okano T, Saegusa J, Nishimura K, Takahashi S, Sendo S, Ueda Y, Onishi A, Morinobu A.
  • Organizer: The 17th Annual European Congress of Rheumatology
  • Place of Presentation: ロンドン、英国
  • Year and Date: 2016-06-08
  • Int'l Joint Research
• [Presentation] Taurine as a biomarker for prediction of response to biologic therapy in rheumatoid arthritis. (2015)
  • Author(s): Takahashi S, Saegusa J, Naka I, Tsuda K, Okano T, Akashi K, Nishida M, Nishimura K, Sendo S, Ueda Y, Onishi A, Kogata Y, Kageyama G, Morinobu A.
  • Organizer: American College of Rheumatology 79th Annual Scientific Meeting,
  • Place of Presentation: アメリカ サンフランシスコ
  • Year and Date: 2015-11-08
  • Int'l Joint Research
• [Presentation] MicroRNA-124 inhibits progression of adjuvant-induced arthritis in rats. (2015)
  • Author(s): Nakamachi Y, Ohnuma K, Uto K, Noguchi Y, Saegusa J, Kawano S.
  • Organizer: The 16th Annual European Congress of Rheumatology - EULAR 2015
  • Place of Presentation: イタリア ローマ
  • Year and Date: 2015-06-11
  • Int'l Joint Research