The study investigates the role of microRNAs miR-221 and miR-222 in the pathogenesis of rheumatoid arthritis (RA) using a TNF-driven mouse model. The key findings are:
miR-221 and miR-222 are upregulated in synovial fibroblasts (SFs) from arthritic mice, with expression levels correlating with disease progression. This upregulation is mediated by the TNF/TNFR1 axis, independent of IL-1β signaling.
Transgenic overexpression of miR-221/222 in mesenchymal cells, including SFs, exacerbates arthritis in the TNF-driven mouse model. This is accompanied by enhanced expansion of SF populations, both in the lining and sublining layers of the synovium.
Transcriptional profiling of SFs overexpressing miR-221/222 reveals activation of cell cycle-related pathways and repression of extracellular matrix (ECM) remodeling pathways. miR-221/222 directly target cell cycle inhibitors p27 and p57, as well as the chromatin remodeling component Smarca1.
Genetic ablation of miR-221/222 in the arthritic mice leads to amelioration of disease, decreased SF expansion, and partial de-repression of their target genes.
Single-cell ATAC-seq analysis shows increased chromatin accessibility and gene activity of the miR-221/222 locus in the pathogenic and expanding intermediate and lining compartments of SFs in arthritis.
In summary, the study establishes a key pathogenic role for miR-221/222 in promoting synovial fibroblast proliferation and expansion, thereby exacerbating arthritis in a TNF-driven mouse model. Targeting these microRNAs could inform the development of novel fibroblast-directed therapies for rheumatoid arthritis.
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by Roumelioti,F... at www.biorxiv.org 07-22-2022
https://www.biorxiv.org/content/10.1101/2022.07.22.500939v1Deeper Inquiries