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WTAP-mediated m 6 A modification of FRZB triggers the inflammatory response via the Wnt signaling pathway in osteoarthritis.
Experimental & Molecular Medicine 2024 January 5
Osteoarthritis (OA) is the most common form of arthritis. However, the exact pathogenesis remains unclear. Emerging evidence shows that N6-methyladenosine (m6 A) modification may have an important role in OA pathogenesis. This study aimed to investigate the role of m6 A writers and the underlying mechanisms in osteoarthritic cartilage. Among m6 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 m6 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 m6 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 m6 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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