TNF-α Promotes Synovial Inflammation and Cartilage Bone Destruction in Rheumatoid Arthritis via NF-κB/YY1/miR-103a-3p Axis

文献类型： 外文期刊

第一作者： Yuan, Yue

作者： Yuan, Yue;Li, Yan;Yu, Xiaobo;Kang, Jiefang;Li, Tao;Yan, Yaping;Xue, Xiaochang;Yuan, Yue;Xue, Xiaochang;Mu, Nan;Gu, Jintao;Chu, Chu;Zhang, Wei;Mu, Nan;Zhang, Hai;Liu, Yan;Xu, Hua;Wang, Changli;Zhang, Dawei;Sun, Qiang;Zheng, Zhaohui;Feng, Guodong

作者机构：

关键词： Dickkopf-related protein 1; miR-103a-3p; mitogen-activated protein kinase kinase kinase 7; rheumatoid arthritis; tumor necrosis factor alpha

期刊名称：FASEB JOURNAL （ 影响因子：4.2； 五年影响因子：4.5 ）

ISSN： 0892-6638

年卷期： 2025 年 39 卷 14 期

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收录情况： SCI

摘要： Tumor necrosis factor alpha (TNF-alpha) plays important roles in inflammation and bone destruction in rheumatoid arthritis (RA), but the detailed mechanism is still not fully elucidated. Here, we found that the levels of microRNA (miR)-103a-3p were decreased markedly in the inflamed synovial tissues of patients with RA compared with osteoarthritis (OA) or healthy control subjects. Further studies uncovered that miR-103a-3p was significantly downregulated by TNF-alpha/IL-1 beta in RA fibroblast-like synoviocytes (FLSs) through an NF-kappa B-dependent manner via the de novo produced transcription factor Yin Yang 1 (YY1). In addition, downregulation of miR-103a-3p in FLSs promoted NF-kappa B signaling pathway activation, inflammatory cytokines secretion, and bone marrow-derived monocytes (BMMs) cells differentiation into osteoclasts, whereas ectopic expression of miR-103a-3p had the opposite effects. Notably, miR-103a-3p was downregulated thousands of times in the sera of RA patients and CIA mice, while the blockade of TNF-alpha with infliximab greatly recovered its levels in RA patients in sustained remission. Consistently, rescue of miR-103a-3p expression by an agomiR potently ameliorated inflammatory responses and bone erosion in CIA mice. Mechanistically, mitogen-activated protein kinase kinase kinase 7 (MAP3K7) and Dickkopf-related protein 1 (DKK1) were identified as the direct targets of miR-103a-3p, by which it exerts the effects on synovial inflammation and cartilage bone destruction. Taken together, miR-103a-3p mediates TNF-triggered synovial inflammation and joint bone destruction via targeting MAP3K7 and DKK1; it thus serves as a candidate target for RA treatment.

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