Fani Roumelioti, Christos Tzaferis, Dimitris Konstantopoulos, Dimitra Papadopoulou, Alejandro Prados, Maria Sakkou, Anastasios Liakos, Panagiotis Chouvardas, Theodore Meletakos, Yiannis Pandis, Niki Karagianni, Maria C Denis, Maria Fousteri, Maria Armaka, George Kollias
{"title":"Mir221/222 通过靶向细胞周期抑制剂和染色质重塑成分驱动滑膜增生和关节炎","authors":"Fani Roumelioti, Christos Tzaferis, Dimitris Konstantopoulos, Dimitra Papadopoulou, Alejandro Prados, Maria Sakkou, Anastasios Liakos, Panagiotis Chouvardas, Theodore Meletakos, Yiannis Pandis, Niki Karagianni, Maria C Denis, Maria Fousteri, Maria Armaka, George Kollias","doi":"https://doi.org/10.7554/elife.84698","DOIUrl":null,"url":null,"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.","PeriodicalId":11640,"journal":{"name":"eLife","volume":null,"pages":null},"PeriodicalIF":6.4000,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Mir221/222 drive synovial hyperplasia and arthritis by targeting cell cycle inhibitors and chromatin remodeling components\",\"authors\":\"Fani Roumelioti, Christos Tzaferis, Dimitris Konstantopoulos, Dimitra Papadopoulou, Alejandro Prados, Maria Sakkou, Anastasios Liakos, Panagiotis Chouvardas, Theodore Meletakos, Yiannis Pandis, Niki Karagianni, Maria C Denis, Maria Fousteri, Maria Armaka, George Kollias\",\"doi\":\"https://doi.org/10.7554/elife.84698\",\"DOIUrl\":null,\"url\":null,\"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.\",\"PeriodicalId\":11640,\"journal\":{\"name\":\"eLife\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.4000,\"publicationDate\":\"2024-09-05\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"eLife\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/https://doi.org/10.7554/elife.84698\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"eLife","FirstCategoryId":"99","ListUrlMain":"https://doi.org/https://doi.org/10.7554/elife.84698","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOLOGY","Score":null,"Total":0}
Mir221/222 drive synovial hyperplasia and arthritis by targeting cell cycle inhibitors and chromatin remodeling components
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.
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