The role and potential of gliostatin as a new therapeutic molecular target in rheumatoid arthritis

2023 Fiscal Year Final Research Report

• Project/Area Number: 19K18473
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56020:Orthopedics-related
• Research Institution: Nagoya City University
• Principal Investigator: Kawaguchi Yohei 名古屋市立大学, 医薬学総合研究院(医学), 助教 (90766734)
• Project Period (FY): 2019-04-01 – 2024-03-31
• Keywords: 関節リウマチ / 線維芽細胞様滑膜細胞 / グリオスタチン

Outline of Final Research Achievements

Gliostatin (GLS) is known to have angiogenic and arthritogenic activities in the pathogenesis of rheumatoid arthritis (RA). This study investigated whether GLS/TP production could be regulated by JAK/signal transducers and activators of transcription (STAT) signaling in FLSs derived from patients with RA. In cultured FLSs, GLS mRNA and protein levels were significantly induced by treatment with IFNγ and these inductions were suppressed by baricitinib treatment. Baricitinib　inhibited IFNγ-induced STAT1 phosphorylation, while JAK/STAT activation played a pivotal role in IFNγ-mediated GLS upregulation in RA. These results suggested that baricitinib suppressed IFNγ-induced GLS/TP expression by inhibiting JAK/STAT signaling, resulting in the attenuation of neovascularization, synovial inflammation, and cartilage destruction.

Free Research Field

関節リウマチ

Academic Significance and Societal Importance of the Research Achievements

既存の関節リウマチ治療では疾患活動性が制御できない関節リウマチ患者が存在する。それらの患者に対する新規治療薬の開発は急務である。我々の研究は炎症性サイトカインネットワークの下流に位置するグリオスタチンの関節破壊メカニズムを明らかとし、既存治療のnon-responderや二次無効例にグリオスタチンを治療ターゲットとしたRA治療が探索できる。さらに副作用で既存の薬剤が使用できない患者に対し新たな治療を提供することが本研究の社会的意義である。