Novel therapeutic strategy of polymyositis targeting muscle fiber death

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K23839
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0803:Pathology, infection/immunology, and related fields
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Kamiya Mari 東京医科歯科大学, 医学部附属病院, 特任助教 (20844377)
• Project Period (FY): 2019-08-30 – 2021-03-31
• Keywords: 炎症性筋疾患 / 細胞死

Outline of Final Research Achievements

We clarified that the pattern of cell death of muscle fibers in polymyositis (PM) is FAS ligand-dependent necroptosis, while that of satellite cells and myoblasts is perforin 1/granzyme B-dependent apoptosis, using human muscle biopsy specimens of PM patients and models of PM in vitro and in vivo. While apoptosis is an anti-inflammatory cell death, necroptosis is known as one of inflammatory forms of cell death, as necroptotic cells release inflammatory mediators such as damaged molecular patterns (DAMPs) and cytokines. Treatment with a necroptosis inhibitor ameliorated myositis-induced muscle weakness as well as muscle cell death and inflammation in the muscles in murine model of PM. Thus, targeting necroptosis in muscle cells is a promising strategy for treating PM providing an alternative to current therapies directed at leukocytes.

Free Research Field

膠原病・リウマチ内科学

Academic Significance and Societal Importance of the Research Achievements

多発性筋炎(PM)の既存治療は副腎皮質ステロイド薬や免疫抑制薬であるが、これらは免疫細胞を標的とした治療であり、感染症を合併するほどの免疫抑制状態を誘導してすら筋炎を抑制できない例や、筋炎抑制に長期間を要し筋力低下が更に進行する例が存在することが臨床的問題であり、PMに対する免疫抑制療法の限界と考えざるを得ない。
我々は本研究において、筋の細胞死の制御が、PMの新たな治療戦略として期待されることを示した。
筋の細胞死を直接の標的とする治療は、既存治療とは全く異なる仕組みを介した治療であり、既存の治療で炎症が抑制できない症例や、治療開始後も筋力低下が更に進行する症例への有効性が期待できる。