Mir221/222 drive synovial hyperplasia and arthritis by targeting cell cycle inhibitors and chromatin remodeling components

Elife. 2024 Sep 5:13:e84698. doi: 10.7554/eLife.84698.

Abstract

miRNAs constitute fine-tuners of gene expression and are implicated in a variety of diseases spanning from inflammation to cancer. miRNA expression is deregulated in rheumatoid arthritis (RA); however, their specific role in key arthritogenic cells such as the synovial fibroblast (SF) remains elusive. Previous studies have shown that Mir221/222 expression is upregulated in RA SFs. Here, we demonstrate that TNF and IL-1β but not IFN-γ activated Mir221/222 gene expression in murine SFs. SF-specific overexpression of Mir221/222 in huTNFtg mice led to further expansion of SFs and disease exacerbation, while its total ablation led to reduced SF expansion and attenuated disease. Mir221/222 overexpression altered the SF transcriptional profile igniting pathways involved in cell cycle and ECM (extracellular matrix) regulation. Validation of targets of Mir221/222 revealed cell cycle inhibitors Cdkn1b and Cdkn1c, as well as the epigenetic regulator Smarca1. Single-cell ATAC-seq data analysis revealed increased Mir221/222 gene activity in pathogenic SF subclusters and transcriptional regulation by Rela, Relb, Junb, Bach1, and Nfe2l2. Our results establish an SF-specific pathogenic role of Mir221/222 in arthritis and suggest that its therapeutic targeting in specific subpopulations could lead to novel fibroblast-targeted therapies.

Keywords: cell proliferation; expansion; immunology; inflammation; miRNAs; mouse; rheumatoid arthritis; sc-ATAC seq; synovial fibroblasts.

MeSH terms

  • Animals
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / metabolism
  • Arthritis, Rheumatoid / pathology
  • Chromatin Assembly and Disassembly
  • Fibroblasts / metabolism
  • Gene Expression Regulation
  • Mice
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Synovial Membrane / metabolism
  • Synovial Membrane / pathology

Substances

  • MicroRNAs
  • MIRN221 microRNA, mouse
  • MIRN222 microRNA, mouse

Associated data

  • GEO/GSE210887