N6-Methyladenosine in Cell-Fate Determination of BMSCs: From Mechanism to Applications

The methylation of adenosine base at the nitrogen-6 position is referred to as "N6-methyladenosine (m⁶A)" and is one of the most prevalent epigenetic modifications in eukaryotic mRNA and noncoding RNA (ncRNA). Various m⁶A complex components known as "writers," "erasers," and "readers" are involved in the function of m⁶A. Numerous studies have demonstrated that m⁶A plays a crucial role in facilitating communication between different cell types, hence influencing the progression of diverse physiological and pathological phenomena. In recent years, a multitude of functions and molecular pathways linked to m⁶A have been identified in the osteogenic, adipogenic, and chondrogenic differentiation of bone mesenchymal stem cells (BMSCs). Nevertheless, a comprehensive summary of these findings has yet to be provided. In this review, we primarily examined the m⁶A alteration of transcripts associated with transcription factors (TFs), as well as other crucial genes and pathways that are involved in the differentiation of BMSCs. Meanwhile, the mutual interactive network between m⁶A modification, miRNAs, and lncRNAs was intensively elucidated. In the last section, given the beneficial effect of m⁶A modification in osteogenesis and chondrogenesis of BMSCs, we expounded upon the potential utility of m⁶A-related therapeutic interventions in the identification and management of human musculoskeletal disorders manifesting bone and cartilage destruction, such as osteoporosis, osteomyelitis, osteoarthritis, and bone defect.