Analysis of bone remodeling using iPS cells derived from the patients with phagocyte signal transduction defects

• Project/Area Number: 25870468
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics; Immunology
• Research Institution: Hiroshima University
• Principal Investigator: TSUMURA Miyuki 広島大学, 医歯薬保健学研究院(医), 研究員 (80646274)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 食細胞異常 / 骨髄炎 / 破骨細胞 / IFN-γ / STAT1 / IFN-γR1 / 骨リモデリング / 原発性免疫不全症 / iPS細胞

Outline of Final Research Achievements

The loss-of-function formed IFN-γR1 and STAT1 deficiency presents mendelian susceptibility to mycobacterial diseases (MSMD). Osteomyelitis is a bone infection by bacteria and other microorganism, and is one of clinical features presented in more than 80% of patients with MSMD. Osteoclasts, bone-resorbing multinuclear cells, are derived from myeloid/ monocyte lineage. IFN-γ is known to strongly suppress osteoclast formation in mice. However, the mechanism and the function of IFN-γ still remains unclear. In this study, we analyzed the formation of osteoclasts and the function of osteoclast using the mononuclear phagocytes of IFN-γR1 and STAT1 deficient patients. Our results strongly show the augmented osteoclast formation and their function in patients with MSMD through the deficiency to IFN-γ-STAT1 signal. The IFN-γ-STAT1 signal transduction system in mononuclear phagocytes may play an important role in the presentation of multiple bone lesions in MSMD patients.

Research Products

• [Journal Article] Simple diagnosis of STAT1 gain-of-function alleles in patients with chronic mucocutaneous candidiasis. (2014)
  • Author(s): Mizoguchi Y, Tsumura M, Okada S, Hirata O, Minegishi S, Imai K, Hyakuna N, Muramatsu H, Kojima S, Ozaki Y, Imai T, Takeda S, Okazaki T, Ito T, Yasunaga S, Takihara Y, Bryant VL, Kong XF, Cypowyj S, Boisson-Dupuis S, Puel A, Casanova JL, Morio T, Kobayashi M.
  • Journal Title: J. Leukoc. Biol. Volume: 95 Issue: 4 Pages: 667-76
  • DOI: 10.1189/jlb.0513250
  • Peer Reviewed / Open Access
• [Journal Article] Naïve and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells. (2013)
  • Author(s): Deenick EK, Avery DT, Chan A, Berglud LJ, Ives ML, Bustamante J, Boisson-Dupuis S, Tsumura M, Kobayashi M, Arkwright PD, Averbuch D, Engelhard D, Roesler J, Peake J, Wong M, Adelstein S, Choo S, Smart JM, French MA, Fulcher DA, Cook MC, Picard C, Durandy A, Klein C, Holland SM, Uzel G, Casanova JL, Ma CS, Tangye SG
  • Journal Title: Journal of Experimental Medicine Volume: 210 Issue: 12 Pages: 2739-2753
  • DOI: 10.1084/jem.20130323
  • Peer Reviewed
• [Journal Article] Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8(+) T-cell memory formation and function. (2013)
  • Author(s): Ives ML, Ma CS, Palendira U,Chan A, Bustamante J, Boisson-Dupuis S, Arkwright PD, Engelhard D, Averbuch D, Magdorf K, Roesler J, Peake J, Wong M, Adelstein S, Choo S, Smart JM, Frnch MA, Fulcher DA, Cook MC, Picard C, Durandy A, Tsumura M, Kobayashi M, Uzel G, Casanova JL, Tangye SG, Deenick EK
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: 132 Issue: 2 Pages: 400-411
  • DOI: 10.1016/j.jaci.2013.05.029
  • Peer Reviewed
• [Journal Article] Heterozygosity for the Y701C STAT1 mutation in a multiplex kindred with multifocal osteomyelitis (2013)
  • Author(s): Hirata, O.
  • Journal Title: Haematologica Volume: 98 Issue: 10 Pages: 1641-1649
  • DOI: 10.3324/haematol.2013.083741
  • Peer Reviewed
• [Presentation] 本邦３家系のSTAT1異常症における臨床症状と機能解析 (2014)
  • Author(s): 津村弥来, 平田修, 香川礼子, 岡田賢, 小林正夫
  • Organizer: 日本血液学会
  • Place of Presentation: 大阪国際会議場（大阪府大阪市北区）
  • Year and Date: 2014-10-31