Development of a novel therapeutic method for rheumatoid arthritis by targeting growth factor signaling

2011 Fiscal Year Final Research Report

• Project/Area Number: 22790929
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Kobe University
• Principal Investigator: SAEGUSA Jun 神戸大学, 医学部附属病院, 特定助教 (20514970)
• Co-Investigator(Kenkyū-buntansha): MORINOBU Akio 神戸大学, 大学院・医学研究科, 准教授 (10294216) ; KAWANO Seiji 神戸大学, 医学部附属病院, 特命准教授 (20351512)
• Project Period (FY): 2010 – 2011
• Keywords: インテグリン / 増殖因子 / 関節リウマチ

Research Abstract

FGF and IGF are of interest in the initiation and development of RA synovial hyperplasia. We recently demonstrated that FGF1 binds directly to integrin αvβ3, and that an integrin-binding-defective FGF1 mutant (FGF^R50E) cannot induce cell proliferation; this is also true for IGF1. Here we investigated how the growth factor-integrin interaction is involved in growth factor signaling. The cDNA microarray analysis showed markedly reduced EGR-1 mRNA expression in the FGF^R50E-treated RA synoviocytes, compared to wild-type FGF1-treated cells. EGR-1 mRNA and protein were rapidly induced in RA synoviocytes in response to FGF1 or IGF1, but the EGR-1 expression was significantly impaired in FGF^R50E-or IGFR^36E/R37E-treated synoviocytes. The down-regulation of EGR-1 by siRNA facilitated the apoptosis of synoviocytes treated with H2O2 or etoposide.

Research Products

• [Journal Article] Podoplanin is an inflammatory protein upregulated in Th17 cells in SKG arthritic joints (2013)
  • Author(s): Miyamoto Y, Uga H, Tanaka S, Kadowaki M, Ikeda M, Saegusa J, Morinobu A, Kumagai S, Kurata H
  • Journal Title: Mol Immunol Volume: 54(2) Pages: 199-207
• [Journal Article] Mycophenolate mofetil versus intravenous cyclophosphamide for induction treatment of proliferative lupus nephritis in a Japanese population: a retrospective study (2013)
  • Author(s): Onishi A, Sugiyama D, Tsuji G, Nakazawa T, Kogata Y, Tsuda K, Naka I, Nishimura K, Misaki K, Kurimoto C, Hayashi H, Kageyama G, Saegusa J, Sugimoto T, Kawano S, Kumagai S, Morinobu A
  • Journal Title: Mod Rheumatol Volume: 23(1) Pages: 89-96
• [Journal Article] Anti TNF-α agent-induced anti-GBM antibody disease in a patient with rheumatoid arthritis (2012)
  • Author(s): Nishimura K, Saegusa J, Kawano S, Morinobu A
  • Journal Title: J Rheumatol Volume: 39(9) Pages: 1904-5
• [Journal Article] SS-A/Ro52 promotes apoptosis by regulating Bcl-2 production (2012)
  • Author(s): Jauharoh SNA, Saegusa J, Sugimoto T, Ardianto B, Kasagi S, Sugiyama D, Kurimoto C, Tokuno O, Nakamachi Y, Kumagai S, Kawano S
  • Journal Title: Biochem Biophys Res Commun Volume: 417(1) Pages: 582-7
• [Journal Article] Diagnostic Accuracy of Serum 1,3-β-D-Glucan for Pneumocystis Jiroveci Pneumonia, Invasive Candidiasis and Invasive Aspergillosis: Systematic Review and Meta-Analysis (2012)
  • Author(s): Onishi A, Sugiyama D, Kogata Y, Saegusa J, Sugimoto T, Kawano S, Morinobu A, Nishimura K, Kumagai S
  • Journal Title: J Clin Microbiol Volume: 50(1) Pages: 7-15
• [Journal Article] Galectin-3 and the skin (2011)
  • Author(s): Larsen L, Chen HY, Saegusa J, Liu FT
  • Journal Title: J Dermatol Sci Volume: 64(2) Pages: 85-91
• [Journal Article] Epidural spinal tumor and periaortitis as rare complications of Wegener's granulomatosis (2011)
  • Author(s): Kasagi S, Saegusa J, Tsuji G, Sendo S, Miura N, Hayashi H, Sugimoto T, Kawano S, Nishida K, Kakutani K, Morinobu A, Kumagai S
  • Journal Title: Mod Rheumatol Volume: 21(6) Pages: 678-83
• [Journal Article] Galectins in regulation of apoptosis (2011)
  • Author(s): Liu FT, Yang RY, Saegusa J, Chen HY, Hsu DK
  • Journal Title: Adv Exp Med Biol Volume: 705 Pages: 431-42
• [Journal Article] Histone deacetylase inhibition alters dendritic cells to assume a tolerogenic phenotype and ameliorates arthritis in SKG mice (2011)
  • Author(s): Misaki K, Morinobu A, Saegusa J, Kasagi S, Fujita M, Miyamoto Y, Matsuki F, Kumagai S
  • Journal Title: Arthritis Res Ther Volume: 13(3) Pages: R77
• [Journal Article] Nonbacterial thrombotic endocarditis associated with cancer of unknown origin complicated with thrombus in the left auricular appendage: case report. (2011)
  • Author(s): Norisada K, Tanaka H, Onishi T, Kaneko A, Tsuji T, Yamawaki K, Ryo K, Tatsumi K, Matsumoto K, Miura N, Saegusa J, Morinaga Y, Hara S, Kawai H, Hirata K
  • Journal Title: Cardiovasc Ultrasound Volume: 9 Pages: 8
• [Journal Article] Role of imaging studies in the diagnosis and evaluation of giant cell arteritis in Japanese: report of eight cases (2011)
  • Author(s): Morinobu A, Tsuji G, Kasagi S, Saegusa J, Hayashi H, Nakazawa T, Kogata Y, Misaki K, Nishimura K, Sendo S, Miura N, Kawano S, Kumagai S
  • Journal Title: Mod Rheumatol Volume: 21(4) Pages: 391-6
• [Journal Article] Plasma Platelet-derived Microparticles in Patients with Connective Tissue Diseases (2011)
  • Author(s): Oyabu C, Morinobu A, Sugiyama D, Saegusa J, Tanaka S, Morinobu S, Tsuji G, Kasagi S, Kawano S, Kumagai S
  • Journal Title: J Rheumatol Volume: 38(4) Pages: 680-4
• [Journal Article] A novel fibroblast growth factor-1 (FGF1) mutant that acts as an FGF antagonist (2010)
  • Author(s): Yamaji S, Saegusa J, Ieguchi K, Fujita M, Takada YK, Takada Y
  • Journal Title: PLoS One Volume: 5(4) Pages: e10273
• [Journal Article] T cell-binding fragment of fibrinogen can prevent autoimmunity. (2010)
  • Author(s): Takada Y, Ono Y, Saegusa J, Mitsiades C, Mitsiades N, Tsai J, He Y, Maningding E, Coleman A, Ramirez-Maverakis D, Rodriquez R, Takada Y, Maverakis E. A
  • Journal Title: J Autoimmun Volume: 34(4) Pages: 453-9
• [Presentation] Regulatory and pro-inflammatory properties of CD4+ T-cell subsets defined by CD45RA, CCR7, CD27, and CD28 in patients with rheumatoid arthritis. (2012)
  • Author(s): Matsuki F, Saegusa J, Miyamoto Y, Misaki K, Kumagai S, Morinobu A
  • Organizer: The 12th meeting of the Asian Society of Clinical Pathology and Laboratory Medicine (アジア臨床病理・臨床検査医学会)
  • Place of Presentation: Kyoto
  • Year and Date: 20121126-1201
• [Presentation] Serum Metabolomics As a Novel Diagnostic Approach for Systemic Lupus Erythematosus (2012)
  • Author(s): Saegusa J, Irino Y, Yoshida M, Tanaka S, Kogata Y, Kageyama G, Kawano S, Tsuji G, Kumagai S, Morinobu A
  • Organizer: American College of Rheumatology 76th Annual ScientificMeeting(アメリカリウマチ学会)
  • Place of Presentation: Washington DC
  • Year and Date: 20121109-14
• [Presentation] Early Growth Response-1 (EGR-1) Controls Synoviocyte Apoptosis, and Its Expression Is Regulated by the Direct Binding of Fibroblast Growth Factor-1 (FGF1) or Insulin-Like Growth Factor-1 (IGF1) to Integrin αvβ3 (2012)
  • Author(s): Tanaka S, Saegusa J, Kawano S, Takada Y, Kumagai S, Morinobu A
  • Organizer: American College of Rheumatology 76thAnnual Scientific Meeting(アメリカリウマチ学会)
  • Place of Presentation: Washington DC
  • Year and Date: 20121109-14
• [Presentation] The Sjogren's Syndrome-Related Autoantigen Ro52 Is a Pro-Apoptotic Molecule Upon Oxidative Stress (2011)
  • Author(s): Jauharoh SN, Kawano S, Saegusa J, Sugimoto T, Sugiyama D, Tokuno O, Kurimoto C, Nobuhara Y, Nakamachi Y, Ardianto B, Kumagai S
  • Organizer: American College of Rheumatology 75th Annual ScientificMeeting(アメリカリウマチ学会)
  • Place of Presentation: Chicago
  • Year and Date: 20111105-09
• [Presentation] Induces CD8a Positive Tolerogenic Dendritic Cells, Regulatory T Cells in SKG Mice, and Ameliorates the Severe Arthritis (2011)
  • Author(s): Misaki K, Morinobu A, Saegusa J, Kasagi S, Fujita M, Miyamoto Y, Matsuki F, Kumagai S. Trichostatin A
  • Organizer: American College of Rheumatology 75th Annual ScientificMeeting(アメリカリウマチ学会)
  • Place of Presentation: Chicago
  • Year and Date: 20111105-09
• [Presentation] インテグリンと増殖因子受容体の"two-receptor" model. 日本リウマチ学会カレントシンポジウム4 若手研究者が語るリウマチ性疾患の病態とシグナル伝達 (2011)
  • Author(s): 三枝 淳
  • Organizer: 第55回日本リウマチ学会総会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 20110000
• [Presentation] Histone Deacetylase Inhibitor (HDAi) Ameliorates Chronic Arthritis in SKG Mice by Altering Conventional Dendritic Cells (cDCs) Phenotype into Tolerogenic DCs (2010)
  • Author(s): Misaki K, Morinobu A, Saegusa J, Miyamoto Y, Kasagi S, Kumagai S
  • Organizer: American College of Rheumatology 74th Annual ScientificMeeting(アメリカリウマチ学会)
  • Place of Presentation: Atlanta
  • Year and Date: 20101107-11
• [Presentation] Galectin-3 is critical for the development of the allergic inflammatory response in a mouse model of atopic dermatitis (2010)
  • Author(s): Saegusa J, Morinobu A, Kawano S, Kumagai S, Hsu DK, Chen HY, Yu L, Liu FT
  • Organizer: International Congress of Immunology(国際免疫学会)
  • Place of Presentation: Kobe
  • Year and Date: 20100000
• [Presentation] THE PROINFLAMMATORY ACTION OF PHOSPHOLIPASE A2 GROUP IIA IS MEDIATED THROUGH INTERACTION WITH INTEGRINS (ALPHA)v(BETA)3 AND (ALPHA)4(BETA)1 (2010)
  • Author(s): Saegusa J, Morinobu A, Kawano S, Takada Y, Kumagai S
  • Organizer: Annual European Congress of Rheumatology, EULAR(欧州リウマチ学会)
  • Place of Presentation: Rome
  • Year and Date: 20100000
• [Presentation] HISTONE DEACETYLASE INHIBITOR (HDAI) AMELIORATES CHRONIC ARTHRITIS IN SKG MICE BY ALTERING CONVENTIONAL DENDRITIC CELLS (CDCS) PHENOTYPE INTO TOLEROGENIC DCS. (2010)
  • Author(s): Misaki K, Morinobu A, Saegusa J, Miyamoto Y, Kasagi S, Kumagai S
  • Organizer: Annual European Congress of Rheumatology, EULAR(欧州リウマチ学会)
  • Place of Presentation: Rome
  • Year and Date: 20100000
• [Presentation] Saegusa J, Fujita M, Morinobu A, Misaki K, Kawano S, Kumagai S (2010)
  • Author(s): Saegusa J, Fujita M, Morinobu A, Misaki K, Kawano S, Kumagai S
  • Organizer: Annual general Assembly and Scientific Meeting of Japan College of Rheumatology(日本リウマチ学会総会・学術集会国際ワークショップ)
  • Place of Presentation: Kobe
  • Year and Date: 20100000