Oral Presentation 1st Asia Pacific Herbert Fleisch Workshop 2025

ERα signaling in synovial fibroblasts inhibits inflammation, hyperplasia and bone erosion in an inflammatory arthritis female mice model.   (#17)

Noritaka Saeki 1 2 , Yuuki Imai 1 3
  1. Division of Integrative Pathophysiology, Proteo-Science Center (PROS), Ehime University, Toon, Ehime, Japan
  2. Research Coordination and Technical Development Office, Ehime University, Matsuyama, Ehime, Japan
  3. Department of Pathophysiology, Ehime University Graduate School of Medicine, Toon, Ehime, Japan

The patients with rheumatoid arthritis show sex differences in prevalence and pathogenesis via sex steroid hormones. However, the molecular mechanisms of sex steroid hormones and their receptors in synovial fibroblasts (SFs) underlying inflammatory arthritis remain unknown. RT-qPCR analysis found that the highest expression of ERα in SFs derived from serum-transfer arthritis (STA) mice among sex steroid hormone receptors (ERα, ERβ, Gpr30, Ar, Pgr). To reveal the pathophysiological function of ERα in SF, we established SF-specific ERα knockout mice (cKO) and littermate control mice (Ctrl). Hind paw swelling was enhanced in female cKO compared to Ctrl but not in male mice. Histological analysis also indicated severe pathogenesis in cKO compared to Ctrl. To understand the difference in gene expression profile between Ctrl-SF and cKO-SF, lining (Thy1low) and interstitial (Thy1high) SF were isolated by FACS from Ctrl and cKO mice, respectively, and bulk RNA-seq analysis was performed. Gene ontology analysis using highly expressed genes in cKO compared to Ctrl had significant enrichment in the terms “inflammation response” for lining SFs and “mitotic cell cycle” for interstitial SFs. Xenium Prime 5K analysis found one lining SF cluster and four interstitial SF clusters in arthritis tissue. The proportion of Mmp13 high interstitial SF cluster was higher in cKO than in Ctrl. Collectively, these data suggested that ERα signaling in SFs inhibits inflammation, hyperplasia and bone erosion in synovium with arthritis.