Abstract
Osteoporosis is a metabolic skeletal disorder in which bone mass is depleted and bone structure is destroyed to the degree that bone becomes fragile and prone to fractures. Emerging evidence suggests that N6-methyladenosine (m6A) modification, a novel epitranscriptomic marker, has a significant role in bone development and metabolism. M6A modification not only participates in bone development, but also plays important roles as writers and erasers in the osteoporosis. M6A methyltransferase METTL3 and demethyltransferase FTO involves in the delicate process between adipogenesis differentiation and osteogenic differentiation, which is important for the pathological development of osteoporosis. Conditional knockdown of the METTL3 in bone marrow stem cells (BMSCs) could suppress PI3K-Akt signaling, limit the expression of bone formation-related genes (such as Runx2 and Osterix), restrain the expression of vascular endothelial growth factor (VEGF) and down-regulate the decreased translation efficiency of parathyroid hormone receptor-1 mRNA. Meanwhile, knockdown of the METTL3 significantly promoted the adipogenesis process and janus kinase 1 (JAK1) protein expression via an m6A-dependent way. Specifically, there was a negative correlation between METTL3 expression and porcine BMSCs adipogenesis. The evidence above suggested that the relationship between METTL3 expression and adipogenesis was inverse, and osteogenesis was positive, respectively. Similarly, FTO regulated for BMSCs fate determination during osteoporosis through the GDF11-FTO-PPARγ axis, prompting the shift of MSC lineage commitment to adipocyte and inhibiting bone formation during osteoporosis. In this systematic review, we summarize the most up-to-date evidence of m6A RNA modification in osteoporosis and highlight the potential role of m6A in prevention, treatment, and management of osteoporosis.
Highlights
Osteoporosis is a systemic skeletal disease characterized by decrease in bone mineral density (BMD) and deterioration in bone microarchitecture [1, 2]
The growth-differentiation factor 11 (GDF11)-FTO-PPARgamma axis controls the shift of osteoporotic MSC fate to adipocyte and inhibits bone formation during osteoporosis
Shen et al have reported that FTO was a regulator for bone marrow stem cells (BMSCs) fate determination during osteoporosis, with a rise in bone marrow in a growth-differentiation factor 11 (GDF11)-C/EBPα-dependent mechanism
Summary
Osteoporosis is a systemic skeletal disease characterized by decrease in bone mineral density (BMD) and deterioration in bone microarchitecture [1, 2]. First reported in 1970s, m6A modification was found to have a broad functional influence on stabilizing homeostasis closely correlated to post-transcriptional gene expression regulation, growth and development [14, 16,17,18,19,20]. It regulates the metabolic processes of most RNAs, including the pre-mRNA splicing, mRNA export, turnover, and translation of mRNA [18, 21,22,23]. The readers of the YTH domain family are effectors that decode the m6A methylation code and transform it into a functional signal in nucleus and cytoplasm
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