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Upregulation of miR-221/222 Promotes Synovial Fibroblast Expansion and Exacerbates Arthritis in a TNF-Driven Mouse Model


Core Concepts
Overexpression of miR-221/222 in synovial fibroblasts leads to their enhanced proliferation and expansion, contributing to the exacerbation of arthritis in a TNF-driven mouse model. Genetic ablation of miR-221/222 ameliorates arthritis by inhibiting fibroblast expansion.
Abstract
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.
Stats
Synovial hyperplasia score was decreased in huTNFtg;miR-221/222-/- mice compared to huTNFtg mice. Cartilage destruction score was decreased in huTNFtg;miR-221/222-/- mice compared to huTNFtg mice. Number of osteoclasts was decreased in huTNFtg;miR-221/222-/- mice compared to huTNFtg mice. Bone volume fraction was decreased in TgColVI-miR-221/222 mice compared to WT mice. Trabecular thickness was decreased in TgColVI-miR-221/222 mice compared to WT mice. Trabecular separation was increased in TgColVI-miR-221/222 mice compared to WT mice.
Quotes
"Overexpression of miR-221/222 in mesenchymal cells, including SFs, exacerbates arthritis in the TNF-driven mouse model." "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."

Deeper Inquiries

How do the transcriptional regulators Nrf2 and Bach1 identified in the study modulate the expression of miR-221/222 in the context of arthritis, and could they serve as additional therapeutic targets?

In the study, the transcriptional regulators Nrf2 and Bach1 were found to be enriched in the regulatory regions associated with the miR-221/222 locus. These transcription factors may positively regulate the activity of miR-221/222 in arthritis, leading to the expansion of pathogenic synovial fibroblast clusters. Nrf2, also known as Nfe2l2, is a key transcription factor that regulates the expression of antioxidant response element (ARE)-dependent genes and plays a crucial role in cellular defense against oxidative stress. Bach1, on the other hand, is a transcriptional repressor that regulates heme oxygenase-1 (HO-1) expression and is involved in the response to oxidative stress. In the context of arthritis, Nrf2 and Bach1 may modulate the expression of miR-221/222 by directly binding to regulatory regions of the miR-221/222 locus and influencing their transcriptional activity. These transcription factors could serve as potential therapeutic targets for modulating the expression of miR-221/222 and regulating the pathogenic expansion of synovial fibroblasts in arthritis. Targeting Nrf2 and Bach1 could potentially offer a novel approach to controlling the aberrant proliferation and activation of fibroblasts in rheumatoid arthritis, thereby mitigating disease progression.

How might other microRNAs or epigenetic mechanisms be involved in the regulation of synovial fibroblast proliferation and activation in rheumatoid arthritis, and how could they be targeted in combination with miR-221/222?

In addition to miR-221/222, several other microRNAs and epigenetic mechanisms have been implicated in the regulation of synovial fibroblast proliferation and activation in rheumatoid arthritis. MicroRNAs such as miR-146a and miR-155 have been shown to play important roles in modulating inflammatory responses and immune cell functions in arthritis. These microRNAs can target key signaling pathways involved in fibroblast activation and proliferation, thereby influencing disease pathogenesis. Targeting these microRNAs in combination with miR-221/222 could offer a comprehensive approach to modulating the behavior of synovial fibroblasts in rheumatoid arthritis. By simultaneously targeting multiple microRNAs that regulate different aspects of fibroblast function, it may be possible to achieve a more robust and effective therapeutic outcome. Epigenetic mechanisms such as DNA methylation and histone modifications also play a role in regulating gene expression in synovial fibroblasts and could be targeted in combination with microRNA-based therapies to achieve synergistic effects in controlling fibroblast proliferation and activation.

Given the potential role of miR-221/222 in bone homeostasis suggested by the study, how might their dysregulation contribute to the bone erosion and remodeling observed in rheumatoid arthritis, and could targeting these microRNAs have broader implications for musculoskeletal diseases?

The dysregulation of miR-221/222 in rheumatoid arthritis may contribute to bone erosion and remodeling through its effects on synovial fibroblast behavior and the production of factors that influence bone homeostasis. Synovial fibroblasts are known to play a role in bone erosion by secreting matrix metalloproteinases and other factors that promote osteoclast activation and bone resorption. By promoting the proliferation and activation of synovial fibroblasts, miR-221/222 may indirectly contribute to the destruction of bone tissue in arthritis. Targeting miR-221/222 could have broader implications for musculoskeletal diseases beyond rheumatoid arthritis. Since these microRNAs have been implicated in cell proliferation, survival, and migration, their dysregulation could impact various aspects of bone homeostasis and tissue remodeling in different musculoskeletal conditions. By modulating the expression of miR-221/222, it may be possible to regulate the behavior of fibroblasts and other cell types involved in bone remodeling, offering a potential therapeutic strategy for a range of musculoskeletal disorders characterized by aberrant tissue turnover and destruction.
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