Unraveling the Role of N6-Methylation Modification: From Bone Biology to Osteoporosis

Abstract

N6-methyladenosine (m6A) is the most abundant and reversible epitranscriptomic modification in eukaryotes, playing a pivotal role in regulating various RNA metabolic processes, including splicing, nuclear export, translation and degradation. Emerging evidence indicates that m6A modification is indispensable in biological processes of bone cells such as proliferation, differentiation and apoptosis. Given its pivotal influence on osteoblastogenesis and osteoclastogenesis, m6A modification, particularly via METTL3, has attracted considerable attention in osteoporosis (OP). In this review, we probe the function of m6A modification in intramembranous and endochondral ossification. Furthermore, we summarize the regulatory role of m6A modification in various biological processes in osteoblasts, osteoclasts and osteocytes, focusing on its potential signaling pathways in osteoblast and osteoclast differentiation. Specifically, m6A modulates osteoblast differentiation predominantly through signaling pathways such as Wnt/β-catenin, PI3K/AKT, and BMP/Smad. Concurrently, it regulates osteoclast differentiation and maturation via the RANKL/RANK pathway and its downstream signaling mechanisms. We also discuss recent discoveries that m6A modification regulates OP and further explore its potential clinical value in diagnosing and treating OP. Collectively, m6A modification serves as a crucial regulatory factor in bone metabolism, and a comprehensive understanding of the molecular mechanisms of m6A modification in bone biology is expected to provide new targets for treating OP.

Keywords: N6-methyladenosine; bone cells; bone development; m6A modification; osteoporosis.

Figure 1

Components and regulatory mechanisms of m6A modification. The regulation of m6A modification depends on the coordination of m6A methyltransferases ("Writers"), m6A demethylases ("Erasers") and m6A-binding proteins ("Readers"). They collectively regulate various RNA biological processes, including splicing, nuclear export, translation, and degradation. (Created with BioRender.com.)

Figure 2

The pathways involved in the regulation of osteoblast and osteoclast differentiation by m6A modification. m6A regulators are involved in osteoblast differentiation via Wnt/β-catenin, BMP/Smad, PI3K/AKT, and other potential signaling pathways, while regulating osteoclast differentiation via RANKL/RANK and its downstream pathways. In addition, under pathological conditions such as aging, AGE and LPS, m6A regulators also affect bone-resorbing osteoclasts and bone-forming osteoblasts through relevant pathways. (Created with BioRender.com.)