Epigenetic transcriptional regulation of skeletal aging: The emerging role of m6A methylation.

Bone plays critical roles in providing mechanical support, maintaining mineral homeostasis, and facilitating hematopoiesis. However, its structure and function progressively deteriorate with age. Although peak bone mass is achieved in early adulthood, aging is associated with decreased bone density, increased marrow adiposity, and accelerated bone turnover, collectively elevating the risk of fractures and osteoporosis (OP). With the growing elderly population worldwide, the socioeconomic burden of skeletal disorders-particularly OP-has intensified, highlighting the urgent need to elucidate their underlying molecular mechanisms for improved clinical management. Emerging evidence indicates that RNA modifications, especially N6-methyladenosine (m6A) methylation, serve as critical regulators of bone metabolism and aging. This review explores the mechanisms by which m6A methylation influences bone aging and its impact on key bone cells, including bone marrow-derived mesenchymal stem cells, osteoblasts, and osteoclasts, as well as its role in the pathogenesis of skeletal-related diseases. Deeper insights into these processes may open new perspectives and offer novel therapeutic avenues for the prevention and treatment of bone aging-related disorders. The translational potential of this article: The exploration of m6A methylation in skeletal aging transcends fundamental scientific discovery, holding significant promise for translating these findings into clinical applications. Understanding this novel regulatory layer opens up new avenues for diagnosing, preventing, and treating age-related skeletal disorders, most notably OP and sarcopenia. The translational potential can be envisioned across several key areas: (1) The dynamic and reversible nature of m6A methylation makes it an ideal candidate for biomarker development; (2) The "writers," "erasers," and "readers" of m6A represent a entirely new class of druggable targets for combating skeletal aging; (3) This research can provide a mechanistic basis for the action of existing drugs and inform their better use.