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

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.

WTAP: A Game-changer in Osteoarthritis Cartilage Degradation

This research examined the function of an RNA alteration known as WTAP in osteoarthritis (OA - a condition which breaks down the joints). Presently, treatments are limited due to insufficient understanding of the root causes of the disease. The study discovered that WTAP, an enzyme (a substance that speeds up chemical reactions in the body) that changes RNA, was increased in cartilage affected by OA and played a role in the advancement of the disease. This was accomplished through a process known as methylation, influencing the expression of FRZB, a protein that blocks a signaling pathway linked with cartilage growth and joint health. By inhibiting FRZB, WTAP activates this harmful pathway, resulting in cartilage breakdown. The study suggests that focusing on WTAP could be a potential treatment approach for OA.

This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.