Mir221/222 drive synovial hyperplasia and arthritis by targeting cell cycle inhibitors and chromatin remodeling components
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eLife assessment
This important manuscript used state-of-the-art techniques and employed relevant animal models to provide both convincing and solid evidence supporting the regulatory role of microRNA cluster 221/222 in rheumatoid arthritis synovial fibroblast. The findings of this work offer significant advances to current knowledge which will be interesting to a wide range audience in the rheumatology and bone research fields. However, whereas models, techniques, and analyses are solid, certain concepts related to the role of immune and bone cells are limited.
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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.
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eLife assessment
This important manuscript used state-of-the-art techniques and employed relevant animal models to provide both convincing and solid evidence supporting the regulatory role of microRNA cluster 221/222 in rheumatoid arthritis synovial fibroblast. The findings of this work offer significant advances to current knowledge which will be interesting to a wide range audience in the rheumatology and bone research fields. However, whereas models, techniques, and analyses are solid, certain concepts related to the role of immune and bone cells are limited.
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Reviewer #1 (Public Review):
The current manuscript investigates the role of microRNA cluster 221/222 (miR221/222) in rheumatoid arthritis synovial fibroblasts (RA SFs) prompted by previous evidence that this cluster is upregulated in these cells. The authors employed multiple genetic mouse models and genomic approaches demonstrating that global overexpression of miR221/222 in huTNFtg polyarthritic mice further expanded SF proliferation and exacerbated RA, whereas global deletion reduced SF proliferation and dampened RA. Mechanistically, the authors provide sufficient evidence that these effects are mediated through the regulation of cell cycle inhibitors (p27 and p57) and the epigenetic regulator Smarca1. In general, these studies offer strong evidence that miR221/222 contributes to the pathogenic mechanisms underlying SF function in …
Reviewer #1 (Public Review):
The current manuscript investigates the role of microRNA cluster 221/222 (miR221/222) in rheumatoid arthritis synovial fibroblasts (RA SFs) prompted by previous evidence that this cluster is upregulated in these cells. The authors employed multiple genetic mouse models and genomic approaches demonstrating that global overexpression of miR221/222 in huTNFtg polyarthritic mice further expanded SF proliferation and exacerbated RA, whereas global deletion reduced SF proliferation and dampened RA. Mechanistically, the authors provide sufficient evidence that these effects are mediated through the regulation of cell cycle inhibitors (p27 and p57) and the epigenetic regulator Smarca1. In general, these studies offer strong evidence that miR221/222 contributes to the pathogenic mechanisms underlying SF function in RA and provide new critical information to advance the understanding of RA pathology. However, certain important aspects are not addressed. Specifically, limited information related to the immune and inflammatory nature of this mechanism is offered, which is further complicated by limitations of using global overexpression and knockout. For example, it remains unknown to what is the extent of contribution by immune and inflammatory cells as well as what are the SF-derived effectors that propagate tissue damage and erosion
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Reviewer #2 (Public Review):
This study focuses on the role of miR221/222 in the pathogenesis of rheumatoid arthritis. Through the use of different murine models and genome-wide techniques, the authors individuate a miR221/222 elicited mechanism leading to synovial fibroblast hyperproliferation. These discoveries may provide a rationale for future targeted therapies for RA treatment.
miR-221 and miR-222 have been linked with arthritis in previous studies from this and other laboratories: miR-221 and miR-222 have been found upregulated in SFs derived from the huTNFtg mouse model and RA patients, where their expression correlates with disease activity. The novelty of the present study resides in the analysis of the role of miR-221/miR-222 in an in vivo system and provides insight into cellular and molecular mechanisms linking miR-221/222 …
Reviewer #2 (Public Review):
This study focuses on the role of miR221/222 in the pathogenesis of rheumatoid arthritis. Through the use of different murine models and genome-wide techniques, the authors individuate a miR221/222 elicited mechanism leading to synovial fibroblast hyperproliferation. These discoveries may provide a rationale for future targeted therapies for RA treatment.
miR-221 and miR-222 have been linked with arthritis in previous studies from this and other laboratories: miR-221 and miR-222 have been found upregulated in SFs derived from the huTNFtg mouse model and RA patients, where their expression correlates with disease activity. The novelty of the present study resides in the analysis of the role of miR-221/miR-222 in an in vivo system and provides insight into cellular and molecular mechanisms linking miR-221/222 to RA progression.
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Reviewer #3 (Public Review):
In this study, Roumelioti et al demonstrate the role of miR-221/222 in synovial fibroblasts (SFs) in inflammatory arthritis, applying a plethora of methods in three transgenic mouse models (huTNFtg, TgColVI-miR-221/222, huTNFtg;TgColVI-miR-221/222). miR-221/222 is upregulated in SFs, upon stimulation with TNF, both in early and established disease, while its gene is activated, as shown by scATAC-seq data. Using RNA sequencing and KEGG pathway analysis, authors showed that overexpression of miR-221 and miR-222 exacerbates arthritis, mainly due to SFs proliferation, driven by cell cycling inhibition and extracellular matrix remodeling. Although the authors suggest the potential utility of miR-221/222 targeting in inflammatory arthritis treatment, this was only examined through miR-221/222 -/- mice generation …
Reviewer #3 (Public Review):
In this study, Roumelioti et al demonstrate the role of miR-221/222 in synovial fibroblasts (SFs) in inflammatory arthritis, applying a plethora of methods in three transgenic mouse models (huTNFtg, TgColVI-miR-221/222, huTNFtg;TgColVI-miR-221/222). miR-221/222 is upregulated in SFs, upon stimulation with TNF, both in early and established disease, while its gene is activated, as shown by scATAC-seq data. Using RNA sequencing and KEGG pathway analysis, authors showed that overexpression of miR-221 and miR-222 exacerbates arthritis, mainly due to SFs proliferation, driven by cell cycling inhibition and extracellular matrix remodeling. Although the authors suggest the potential utility of miR-221/222 targeting in inflammatory arthritis treatment, this was only examined through miR-221/222 -/- mice generation and not by direct silencing of miR-221/222 by administering a miR-221/222 antagonist.
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