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WTAP-mediated m6A modification of FRZB triggers the inflammatory response via the Wnt signaling pathway in osteoarthritis

Wnt信号通路 软骨 骨关节炎 癌症研究 细胞生物学 炎症 连环素 医学 信号转导 生物 化学 免疫学 病理 替代医学 解剖
作者
Xueying An,Xiaogang Wang,Zhongyang Lv,Wenshu Wu,Ziying Sun,Rui Wu,Wenjin Yan,Qing Jiang,Xingquan Xu
出处
期刊:Experimental and Molecular Medicine [Springer Nature]
卷期号:56 (1): 156-167 被引量:2
标识
DOI:10.1038/s12276-023-01135-5
摘要

Abstract Osteoarthritis (OA) is the most common form of arthritis. However, the exact pathogenesis remains unclear. Emerging evidence shows that N6-methyladenosine (m 6 A) modification may have an important role in OA pathogenesis. This study aimed to investigate the role of m 6 A writers and the underlying mechanisms in osteoarthritic cartilage. Among m 6 A methyltransferases, Wilms tumor 1-associated protein (WTAP) expression most significantly differed in clinical osteoarthritic cartilage. WTAP regulated extracellular matrix (ECM) degradation, inflammation and antioxidation in human chondrocytes. Mechanistically, the m 6 A modification and relative downstream targets in osteoarthritic cartilage were assessed by methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing, which indicated that the expression of frizzled-related protein (FRZB), a secreted Wnt antagonist, was abnormally decreased and accompanied by high m 6 A modification in osteoarthritic cartilage. In vitro dysregulated WTAP had positive effects on β-catenin expression by targeting FRZB, which finally contributed to the cartilage injury phenotype in chondrocytes. Intra-articular injection of adeno-associated virus-WTAP alleviated OA progression in a mouse model, while this protective effect could be reversed by the application of a Wnt/β-catenin activator. In summary, this study revealed that WTAP-dependent RNA m 6 A modification contributed to Wnt/β-catenin pathway activation and OA progression through post-transcriptional regulation of FRZB mRNA, thus providing a potentially effective therapeutic strategy for OA treatment.
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