WTAP-mediated m6A modification of FRZB triggers the inflammatory response via the Wnt signaling pathway in osteoarthritis
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Osteoarthritis (OA) is the most common form of arthritis. However, the exact pathogenesis remains unclear. Emerging evidence shows that N6-methyladenosine (m6A) modification may have an important role in OA pathogenesis. This study aimed to investigate the role of m6A writers and the underlying mechanisms in osteoarthritic cartilage. Among m6A 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 m6A 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 m6A 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 m6A 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.
Abstract
Osteoarthritis (OA) is the most common form of arthritis. However, the exact pathogenesis remains unclear. Emerging evidence shows that N6-methyladenosine (m6A) modification may have an important role in OA pathogenesis. This study aimed to investigate the role of m6A writers and the underlying mechanisms in osteoarthritic cartilage. Among m6A 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 m6A 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 m6A 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 m6A 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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