文献类型： 外文期刊

作者： Yuan, Yue ¹ ; Mu, Nan ³ ; Li, Yan ¹ ; Gu, Jintao ³ ; Chu, Chu ³ ; Yu, Xiaobo ¹ ; Kang, Jiefang ¹ ; Li, Tao ¹ ; Yan, Yaping ¹ ; Zhang, Hai ⁵ ; Liu, Yan ⁶ ; Xu, Hua ⁷ ; Wang, Changli ⁸ ; Zhang, Dawei ⁹ ; Sun, Qiang ⁹ ; Zhang, Wei ³ ; Zheng, Zhaohui ¹⁰ ; Feng, Guodong ¹¹ ; Xue, Xiaochang ¹ ;

作者机构： 1.Shaanxi Normal Univ, Key Lab Med Resources & Nat Pharmaceut Chem, Natl Engn Lab Resource Dev Endangered Crude Drugs, Coll Life Sci,Minist Educ, Xian, Peoples R China

2.Southwest Med Univ, Affiliated Hosp, Lab Neurol Dis & Brain Funct, Luzhou, Peoples R China

3.Air Force Med Univ, Biotechnol Ctr, Sch Pharm, State Key Lab Canc Biol, Xian, Peoples R China

4.Air Force Med Univ, Sch Basic Med, Dept Physiol & Pathophysiol, Xian, Peoples R China

5.Air Force Med Univ, Natl Translat Sci Ctr Mol Med, Dept Cell Biol, Xian, Peoples R China

6.Chinese Acad Agr Sci, Changchun Vet Res Inst, State Key Lab Pathogen & Biosecur, Key Lab Jilin Prov Zoonosis Prevent & Control, Changchun, Peoples R China

7.Shaanxi Blood Ctr, Xian, Peoples R China

8.Air Force Mil Med Univ, Hosp 986, Dept Urol, Xian, Peoples R China

9.Air Force Med Univ, Xijing Hosp, Dept Orthoped, Xian, Peoples R China

10.Air Force Med Univ, Xijing Hosp, Dept Clin Immunol, Xian, Peoples R China

11.Fudan Univ, Dept Neurol, Zhongshan Hosp, Shanghai, Peoples R China

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

页码：

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.