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.
Elife. 2024 Sep 5;13:e84698. doi: 10.7554/eLife.84698.
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 expression is upregulated in RA SFs. Here, we demonstrate that TNF and IL-1β but not IFN-γ activated /222 gene expression in murine SFs. SF-specific overexpression of in huTNFtg mice led to further expansion of SFs and disease exacerbation, while its total ablation led to reduced SF expansion and attenuated disease. overexpression altered the SF transcriptional profile igniting pathways involved in cell cycle and ECM (extracellular matrix) regulation. Validation of targets of revealed cell cycle inhibitors and , as well as the epigenetic regulator . Single-cell ATAC-seq data analysis revealed increased /222 gene activity in pathogenic SF subclusters and transcriptional regulation by , , , , and . Our results establish an SF-specific pathogenic role of in arthritis and suggest that its therapeutic targeting in specific subpopulations could lead to novel fibroblast-targeted therapies.
miRNAs 是基因表达的精细调控因子，与从炎症到癌症等多种疾病有关。miRNA 在类风湿关节炎 (RA) 中表达失调；然而，它们在滑膜成纤维细胞 (SF) 等关键关节炎细胞中的具体作用仍不清楚。先前的研究表明，在 RA SF 中表达上调。在这里，我们证明 TNF 和 IL-1β 但不是 IFN-γ 激活了在鼠 SF 中的基因表达。在 huTNFtg 小鼠中 SF 特异性过表达导致 SF 进一步扩张和疾病恶化，而其完全缺失导致 SF 扩张减少和疾病减轻。过表达改变了 SF 的转录谱，引发了涉及细胞周期和 ECM（细胞外基质）调节的途径。对 的靶标的验证揭示了细胞周期抑制剂 和 ，以及表观遗传调节剂 。单细胞 ATAC-seq 数据分析显示，在致病 SF 亚群中基因活性增加，并由 、 、 、 、 进行转录调控。我们的研究结果确立了 在关节炎中的 SF 特异性致病作用，并表明针对其在特定亚群中的治疗可能会导致新的针对成纤维细胞的治疗方法。
