Analysis of epigenetic structure responsible for inflammatory mediator production from rheumatoid arthritis synovial fibroblast

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02846
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: The University of Tokyo
• Principal Investigator: FUJIO KEISHI 東京大学, 医学部附属病院, 教授 (70401114)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 関節リウマチ / 遺伝素因 / エピゲノム修飾

Outline of Final Research Achievements

Synovial fibroblasts (SFs) contribute to the induction and persistence of synovitis in rheumatoid arthritis (RA) by highly expressing inflammatory mediators represented by IL-6. In this research, the applicant was the first in the world to catalog the relationship between gene expression of inflammatory mediators from SFs and chromatin structural changes and disease susceptibility polymorphisms. Moreover, through integrated functional genome analysis, it was clarified that chromatin structural changes in SFs under a complex inflammatory environment are associated with RA susceptibility and high expression of IL-6. The applicant also identified a transcription factor complex crucial for this pathological structure formation and clarified that its constituent, MTF1, is involved in arthritis formation.

Free Research Field

アレルギー・リウマチ学

Academic Significance and Societal Importance of the Research Achievements

近年登場した生物学的製剤や分子標的薬により、RAの治療は大きく発展したが、これら薬剤の効果が十分に得られない患者の存在や、全身的な免疫抑制が原因の重篤な有害事象が、治療を行う上で臨床的課題となっている。本研究では、関節局所に存在し、炎症や骨軟骨破壊を担うSFsに着目することで、統合的機能ゲノム解析によりRAの遺伝素因と関連する新たな創薬標的を同定した。本知見は、既存の薬剤とは全く異なる経路を介した、より全身的な免疫抑制作用の少ない治療開発につながる可能性を内包している。