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

• Published in: The FASEB journal Vol. 39; no. 14; p. e70876
• Main Authors: Yuan, Yue, Mu, Nan, Li, Yan, Gu, Jintao, Chu, Chu, Yu, Xiaobo, Kang, Jiefang, Li, Tao, Yan, Yaping, Zhang, Hai, Liu, Yan, Xu, Hua, Wang, Changli, Zhang, Dawei, Sun, Qiang, Zhang, Wei, Zheng, Zhaohui, Feng, Guodong, Xue, Xiaochang
• Format: Journal Article
• Language: English
• Published: United States 31.07.2025
• Subjects: Animals; Arthritis, Experimental - metabolism; Arthritis, Experimental - pathology; Arthritis, Rheumatoid - genetics; Arthritis, Rheumatoid - metabolism; Arthritis, Rheumatoid - pathology; Cartilage - metabolism; Cartilage - pathology; Female; Humans; Inflammation - metabolism; Inflammation - pathology; Male; Mice; MicroRNAs - genetics; MicroRNAs - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; Osteoarthritis - metabolism; Signal Transduction; Synovial Membrane - metabolism; Synovial Membrane - pathology; Synoviocytes - metabolism; Synoviocytes - pathology; Tumor Necrosis Factor-alpha - metabolism; YY1 Transcription Factor - genetics; YY1 Transcription Factor - metabolism; miR‐103a‐3p; mitogen‐activated protein kinase kinase kinase 7; tumor necrosis factor alpha; Dickkopf‐related protein 1; rheumatoid arthritis
• ISSN: 1530-6860
• DOI: 10.1096/fj.202501452R

Tumor necrosis factor alpha (TNF-α) 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-α/IL-1β in RA fibroblast-like synoviocytes (FLSs) through an NF-κB-dependent manner via the de novo produced transcription factor Yin Yang 1 (YY1). In addition, downregulation of miR-103a-3p in FLSs promoted NF-κB 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-α 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.