Analysis of DIP2C as a novel regulator for epithelial-mesenchymal transition of rheumatoid arthritis synovium and a potential therapeutic target

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08905
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Kyoto University
• Principal Investigator: Tanaka Masao 京都大学, 医学研究科, 特定准教授 (10332719)
• Co-Investigator(Kenkyū-buntansha): 高橋 智聡 金沢大学, がん進展制御研究所, 教授 (50283619) ; 杉本 直俊 金沢大学, 医学系, 准教授 (80272954)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 関節リウマチ / DIP2 / 上皮間葉転移 / 関節滑膜 / 可塑性 / エピジェネシス

Outline of Final Research Achievements

In rheumatoid arthritis (RA), DIP2C is an important molecule involved in the abnormal proliferation of synovium, which is comparable to epithelial-mesenchymal transition, EMT. Domain structure analysis of DIP2C disclosed that it has two regulatory mechanisms for epigenesis and metabolism. The former was located in the SNAI1/2 binding site and the latter in the acetyl-CoA activating site. Synovial cell ChIP-seq data analysis revealed activating histone modifications of the IL-6 gene H3K4me3 and H3K27ac in RA, which are absent in osteoarthritis, and that IL-6 production is altered to be autonomous rather than induced. These epigenetic changes were also observed in the loci for EMT markers SNAI1 and COL1A1, indicating that the EMT changes were linked to dysregulation of cytokine production.

Free Research Field

リウマチ学、免疫学

Academic Significance and Societal Importance of the Research Achievements

今世紀に入って分子標的薬が導入され，関節リウマチ（RA）は制御できる疾患となったが，未だに半数近くの患者が寛解を得ていない．治療抵抗性の患者は，経時的に治療反応性が低下する傾向を示し，何らかの非可逆的な形質の変化が背景にあると思われる．本研究の仮説ではそれが滑膜EMTであり，サイトカイン産生異常との連動が判明したことは仮説の正しさを示唆している．RA滑膜の非可逆的な変化を可逆的に戻せば，治療反応性を取り戻せるかもしれない．滑膜EMTの分子機構を解明することにより，RA滑膜が正常滑膜に戻る可塑性を回復する方法がわかれば，新規治療アプローチとして難治性のRA患者にも福音をもたらすことが期待される．