Epitranscriptomic Regulation of Bone Metabolism: Emerging Roles of N6‐Methyladenosine (m6A) Modification in Skeletal Homeostasis

ABSTRACT

N6‐methyladenosine (m6A) is the most abundant internal chemical modification of eukaryotic RNA and a central mechanism of epitranscriptomic gene regulation. Although m6A was first characterized in messenger RNA (mRNA), it is also deposited on ribosomal RNA (rRNA), circular RNA, and other RNA species, where it regulates RNA stability, decay, splicing, nuclear export, translational efficiency, and ribosome function. m6A‐mediated gene regulation has attracted increasing attention as a mechanism that contributes to development, differentiation, metabolism, and disease. Its relevance is also becoming evident in skeletal biology and bone metabolism. METTL3‐mediated m6A modification of mRNA regulates the balance between osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells and contributes to the maintenance of bone mass, while METTL5‐mediated m6A modification of 18S rRNA supports bone formation through OSER1‐dependent antioxidant regulation. m6A modification has also been implicated in osteoclast differentiation and bone‐resorbing activity, acting through mRNA decay, nuclear export, and transcription factor regulation. In this review, we summarize the basic concepts of m6A modification and discuss its emerging roles in the regulation of bone metabolism, with particular focus on osteoblasts, osteoclasts, osteocytes, and bone marrow mesenchymal stem cells. We also consider the implications of m6A‐mediated epitranscriptomic regulation for oral and skeletal biology.