Elucidation of the pathogenesis of systemic sclerosis and development of novel therapeutic strategy focusing on PDE

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K17456
• 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 Women's Medical University
• Principal Investigator: Tomoaki Higuchi 東京女子医科大学, 医学部, 寄附部門講師 (80836966)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 強皮症

Outline of Final Research Achievements

We conducted a study based on the idea that inhibiting phosphodiesterase (PDE) could lead to the improvement of the "three pathological abnormalities" in systemic sclerosis: 1) autoimmunity/inflammation, 2) fibrosis, and 3) vascular change. We particularly focused on one of the PDE isozymes, PDE4, and investigated the antifibrotic effects of apremilast, a PDE4 inhibitor, on systemic sclerosis skin fibroblasts and a scleroderma model mouse. When apremilast was added to cultured systemic sclerosis skin fibroblasts, it inhibited the production of type I collagen. Furthermore, administering apremilast to bleomycin-induced model mice was able to suppress the progression of skin sclerosis.

Free Research Field

リウマチ性疾患

Academic Significance and Societal Importance of the Research Achievements

本研究の結果、PDE4阻害薬が強皮症の病態である線維化の進行を抑制しうることが、強皮症皮膚線維芽細胞を用いた検討でも実証された。さらに、強皮症マウスモデルを用いた検証でも、PDE4阻害が皮膚線維化進展を抑制するだけでなく、強皮症の病態である、自己免疫異常や炎症を制御しうることが示された。これらの結果は、これまで標準治療が確立されていない強皮症に対し、PDE4阻害薬が革新的治療法となるポテンシャルを有することを示唆し、新規治療法の開発につながることが期待される。