Targeting synovial fibroblasts for the treatment of rheumatoid arthritis by CDK4/6 inhibition

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17884
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54020:Connective tissue disease and allergy-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Hosoya Tadashi 東京医科歯科大学, 大学院医歯学総合研究科, 講師 (60737104)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 滑膜線維芽細胞 / CDK4/6 / 関節リウマチ / AP-1

Outline of Final Research Achievements

We identified that a small part of inflammatory gene transcription, including was impaired in the absence of CDK4/6 activity by attenuating the AP-1 transcriptional activity. Since the target AP-1 component was protected from ubiquitine-proteasome dependent degradation when CDK4/6 were active, the inhibition of CDK4/6 resulted in the down-regulation of the baseline expression and its induction in RASFs.
We hypothesized that the inhibition of CDK4/6 attenuated cytokine responsiveness in the RASFs by enhancing degradation. Furthermore, we confirmed that the inhibition of CDK4/6 resulted in selective gene suppression sharing specific AP-1 motifs in their promoter by the RNA-seq analysis.

Free Research Field

関節リウマチ、膠原病、免疫学

Academic Significance and Societal Importance of the Research Achievements

関節リウマチ(RA)は代表的な炎症性疾患であり、炎症を標的にした治療は患者の予後を大きく改善するに至ったが、関節炎を完全にコントロールできる患者は一部で感染症などの合併症が問題になる。
滑膜線維芽細胞を標的としたいくつかの治療戦略は現在のRA治療を補補完と期待され、臨床応用が現在試みられているが、本研究で注目したCDK4/6はリウマチ関節の滑膜線維芽細胞の特徴である過剰な細胞増殖とサイトカイン産生という両面を抑制する、理想的な治療になりうる。