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

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 <i>Mir221/222</i> expression is upregulated in RA SFs. Here, we demonstrate that TNF and IL-1β but not IFN-γ activated <i>Mir221</i>/222 gene expression in murine SFs. SF-specific overexpression of <i>Mir221/222</i> in huTNFtg mice led to further expansion of SFs and disease exacerbation, while its total ablation led to reduced SF expansion and attenuated disease. <i>Mir221/222</i> overexpression altered the SF transcriptional profile igniting pathways involved in cell cycle and ECM (extracellular matrix) regulation. Validation of targets of <i>Mir221/222</i> revealed cell cycle inhibitors <i>Cdkn1b</i> and <i>Cdkn1c</i>, as well as the epigenetic regulator <i>Smarca1</i>. Single-cell ATAC-seq data analysis revealed increased <i>Mir221</i>/222 gene activity in pathogenic SF subclusters and transcriptional regulation by <i>Rela</i>, <i>Relb</i>, <i>Junb</i>, <i>Bach1</i>, and <i>Nfe2l2</i>. Our results establish an SF-specific pathogenic role of <i>Mir221/222</i> in arthritis and suggest that its therapeutic targeting in specific subpopulations could lead to novel fibroblast-targeted therapies.