Development of new therapeutic strategies targeting rheumatoid arthritis-associated fibroblast subset

• Project/Area Number: 16K09889
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Mizoguchi Fumitaka 東京医科歯科大学, 大学院医歯学総合研究科, 助教 (60510360)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 関節リウマチ / 線維芽細胞 / 滑膜組織 / 滑膜線維芽細胞 / トランスクリプトミクス / 病理学 / 免疫学

Outline of Final Research Achievements

We have reported that synovial fibroblasts consist of three major subsets with distinct functions. One fibroblast subset, characterized by CD34-THY1+, is expanded in patients with rheumatoid arthritis (RA) compared to those with osteoarthritis. These fibroblasts are proliferative, express high level of proteinases and RANKL, a crucial cytokine for osteoclastogenesis, and have a phenotype characteristic of invasive cells, indicating the pathogenic roles in RA. CD34+ subset is characterized by the high expression of inflammatory cytokines.
To identify candidate target genes for the development of fibroblast-targeting therapy, we focused on the differentially expressed transcription factors (TFs) across fibroblast subsets. We performed in vitro assays using siRNAs to knock down the expression of the TFs, and found new TFs to regulate the fibroblast functions.

Academic Significance and Societal Importance of the Research Achievements

本研究により、RA関連滑膜線維芽細胞サブセットの機能や増生を抑えることを作用機序とする、新たな治療戦略の開発へとつながることが期待される。このような治療は既存の治療薬によっても改善が得られない患者や、合併症のために治療が困難な患者への選択肢として、RA診療の抱える課題の克服へとつながることが期待される。
更に、線維芽細胞は間質性肺炎や肝硬変、慢性腎不全など数多くの炎症性疾患や慢性の臓器障害をきたす疾患において重要な役割を担うことが知られており、線維芽細胞による疾患制御という新たな領域を切り開く成果になると考えられる。

Research Products

• [Int'l Joint Research] Brigham and Women's Hospital/Harvard Medical School/Hospital for Special Surgery(米国)
• [Int'l Joint Research] Brigham and Women's Hospital/Harvard Medical School/Broad Institute(米国)
• [Int'l Joint Research] Hospital for Special Surgery(米国)
• [Int'l Joint Research] Queen Elizabeth Hospital/University of Birmingham(英国)
• [Int'l Joint Research] Harvard Medical School/Brigham and Women's Hospital/Hospital for Special Surgery(米国)
• [Int'l Joint Research] Broad Institute(米国)
• [Int'l Joint Research] University of Birmingham/Queen Elizabeth Hospital(英国)
• [Journal Article] Methods for high-dimensional analysis of cells dissociated from cryopreserved synovial tissue (2018)
  • Author(s): Donlin LT, Rao DA, Wei K, Slowikowski K, McGeachy MJ, Turner JD, Meednu N, Mizoguchi F, Gutierrez-Arcelus M, Lieb DJ, Keegan J, Muskat K, Hillman J, Rozo C, Ricker E, Eisenhaure TM, Li S, Browne EP, Chicoine A, Sutherby D, Noma A; Accelerating Medicines Partnership RA/SLE Network, et al.
  • Journal Title: Arthritis Research & Therapy Volume: 20 Issue: 1 Pages: 139-139
  • DOI: 10.1186/s13075-018-1631-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Functionally distinct disease-associated fibroblast subsets in rheumatoid arthritis (2018)
  • Author(s): Mizoguchi F, Slowikowski K, Wei K, Marshall JL, Rao DA, Chang SK, Nguyen HN, Noss EH, Turner JD, Earp BE, Blazar PE, Wright J, Simmons BP, Donlin LT, Kalliolias GD, Goodman SM, Bykerk VP, Ivashkiv LB, Lederer JA, Hacohen N, Nigrovic PA, Filer A, Buckley CD, Raychaudhuri S, Brenner MB
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 789-789
  • DOI: 10.1038/s41467-018-02892-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] シングルセル解析による線維芽細胞亜群の同定と関節リウマチの病態解析 (2018)
  • Author(s): 溝口史高
  • Organizer: 第46回日本臨床免疫学会総会
  • Invited
• [Presentation] 関節リウマチの病態を担う新規線維芽細胞サブセットの同定 (2017)
  • Author(s): 溝口史高
  • Organizer: 日本臨床免疫学会Midwinter Seminar XI
  • Place of Presentation: ANAインターコンチネンタル万座ビーチホテル（恩納村、沖縄）
  • Year and Date: 2017-02-22
• [Presentation] 関節リウマチ滑膜病理の脱構築による病態解析 (2017)
  • Author(s): 溝口史高
  • Organizer: 第４回JCRベーシックリサーチカンファレンス
  • Invited
• [Presentation] IL6を高産生する線維芽細胞サブセットを制御する転写因子の同定 (2017)
  • Author(s): 溝口史高、小宮陽仁、上阪等
  • Organizer: 第45回臨床免疫学会総会
• [Presentation] シングルセル解析による線維芽細胞サブセットの同定と関節リウマチの病態解析 (2017)
  • Author(s): 溝口史高
  • Organizer: 第35回日本骨代謝学会学術集会
  • Invited
• [Presentation] 単一細胞解析による関節リウマチの病態を担う線維芽細胞サブセットの同定 (2017)
  • Author(s): 溝口史高
  • Organizer: 第61回日本リウマチ学会総会・学術集会
  • Invited
• [Presentation] 関節リウマチの病態を担う新規線維芽細胞サブセットの同定 (2016)
  • Author(s): 溝口史高
  • Organizer: 第15回リウマチ膠原病・よつやセミナー
  • Place of Presentation: ベルサール西新宿（新宿、東京）
  • Year and Date: 2016-09-24
  • Invited
• [Presentation] シングルセル解析による関節リウマチの病態を担う線維芽細胞サブセットの同定 (2016)
  • Author(s): 溝口史高
  • Organizer: Rising Star Symposium, 第44回臨床免疫学会総会
  • Place of Presentation: 京王プラザホテル（新宿、東京）
  • Year and Date: 2016-09-08
  • Invited
• [Presentation] Single cell transcriptomics and protein expression analysis define disease-specific fibroblast subsets in rheumatoid arthritis joint tissue (2016)
  • Author(s): Fumitaka Mizoguchi, Kamil Slowikowski, Soumya Raychaudhuri, Michael B Brenner
  • Organizer: 第２回日本骨免疫学会
  • Place of Presentation: ホテルモントレ沖縄スパ＆リゾート（恩納村、沖縄）
  • Year and Date: 2016-07-06