Yuan Lin, Jiang Nan, Li Yuxuan, Wang Xin, Wang Wei
Department of Health Management, The First Affiliated Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang, 110001, Liaoning, P.R. of China.
Department of Price, The First Affiliated Hospital of China Medical University, Shenyang, 110001, Liaoning, P.R. China.
Inflammation. 2025 Feb;48(1):447-463. doi: 10.1007/s10753-024-02067-6. Epub 2024 Jun 21.
Recent evidence has highlighted the functions of enhancers in modulating transcriptional machinery and affecting the development of human diseases including rheumatoid arthritis (RA). Enhancer RNAs (eRNAs) are RNA molecules transcribed from active enhancer regions. This study investigates the specific function of eRNA in gene transcription and osteoclastogenesis in RA. Regulator of G protein signaling 1 (RGS1)-associated eRNA was highly activated in osteoclasts according to bioinformatics prediction. RGS1 mRNA was increased in mice with collagen-induced arthritis as well as in M-CSF/soluble RANKL-stimulated macrophages (derived from monocytes). This was ascribed to increased RGS1 eRNA activity. Silencing of 5'-eRNA blocked the binding between forkhead box J3 (FOXJ3) and the RGS1 promoter, thus suppressing RGS1 transcription. RGS1 accelerated osteoclastogenesis through PLC-IP3R-dependent Ca response. Knockdown of either FOXJ3 or RGS1 ameliorated arthritis severity, improved pathological changes, and reduced osteoclastogenesis and bone erosion in vivo and in vitro. However, the effects of FOXJ3 silencing were negated by RGS1 overexpression. In conclusion, this study demonstrates that the RGS1 eRNA-driven transcriptional activation of the FOXJ3/RGS1 axis accelerates osteoclastogenesis through PLC-IP3R dependent Ca response in RA. The finding may offer novel insights into the role of eRNA in gene transcription and osteoclastogenesis in RA.
最近的证据突出了增强子在调节转录机制以及影响包括类风湿性关节炎（RA）在内的人类疾病发展中的作用。增强子RNA（eRNA）是从活跃增强子区域转录而来的RNA分子。本研究调查了eRNA在RA基因转录和破骨细胞生成中的具体功能。根据生物信息学预测，G蛋白信号调节因子1（RGS1）相关的eRNA在破骨细胞中高度活化。在胶原诱导性关节炎小鼠以及M-CSF/可溶性RANKL刺激的巨噬细胞（源自单核细胞）中，RGS1 mRNA增加。这归因于RGS1 eRNA活性增加。5'-eRNA的沉默阻断了叉头框J3（FOXJ3）与RGS1启动子之间的结合，从而抑制了RGS1转录。RGS1通过PLC-IP3R依赖性钙反应加速破骨细胞生成。敲低FOXJ3或RGS1可改善体内外关节炎严重程度、改善病理变化并减少破骨细胞生成和骨侵蚀。然而，RGS1过表达抵消了FOXJ3沉默的作用。总之，本研究表明，RGS1 eRNA驱动的FOXJ3/RGS1轴转录激活通过PLC-IP3R依赖性钙反应加速RA中的破骨细胞生成。这一发现可能为eRNA在RA基因转录和破骨细胞生成中的作用提供新的见解。
