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

Autor:	Roumelioti F; Institute for Bioinnovation, Biomedical Sciences Research Centre (BSRC) 'Alexander Fleming', Vari, Greece.; Department of Pathophysiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece., Tzaferis C; Institute for Bioinnovation, Biomedical Sciences Research Centre (BSRC) 'Alexander Fleming', Vari, Greece.; Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece., Konstantopoulos D; Institute for Bioinnovation, Biomedical Sciences Research Centre (BSRC) 'Alexander Fleming', Vari, Greece., Papadopoulou D; Institute for Bioinnovation, Biomedical Sciences Research Centre (BSRC) 'Alexander Fleming', Vari, Greece.; Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece., Prados A; Institute for Bioinnovation, Biomedical Sciences Research Centre (BSRC) 'Alexander Fleming', Vari, Greece., Sakkou M; Institute for Bioinnovation, Biomedical Sciences Research Centre (BSRC) 'Alexander Fleming', Vari, Greece.; Center of New Biotechnologies & Precision Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece., Liakos A; Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center 'Alexander Fleming', Vari, Greece., Chouvardas P; Institute for Bioinnovation, Biomedical Sciences Research Centre (BSRC) 'Alexander Fleming', Vari, Greece., Meletakos T; Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center 'Alexander Fleming', Vari, Greece., Pandis Y; Institute for Bioinnovation, Biomedical Sciences Research Centre (BSRC) 'Alexander Fleming', Vari, Greece., Karagianni N; Biomedcode Hellas SA, Vari, Greece., Denis MC; Biomedcode Hellas SA, Vari, Greece., Fousteri M; Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center 'Alexander Fleming', Vari, Greece., Armaka M; Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center 'Alexander Fleming', Vari, Greece., Kollias G; Institute for Bioinnovation, Biomedical Sciences Research Centre (BSRC) 'Alexander Fleming', Vari, Greece.; Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.; Center of New Biotechnologies & Precision Medicine, National and Kapodistrian University of Athens Medical School, Athens, Greece.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2024 Sep 05; Vol. 13. Date of Electronic Publication: 2024 Sep 05.
DOI:	10.7554/eLife.84698
Abstrakt:	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. Competing Interests: FR, CT, DK, DP, AP, MS, AL, PC, TM, YP, MF, MA, GK No competing interests declared, NK, MD affiliated with Biomedcode Hellas SA. The author has no financial interests to declare (© 2024, Roumelioti et al.)
Databáze:	MEDLINE
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