Abstract
N6-methyladenosine (m6A) is an important modification of eukaryotic mRNA. Since the first discovery of the corresponding demethylase and the subsequent identification of m6A as a dynamic modification, the function and mechanism of m6A in mammalian gene regulation have been extensively investigated. “Writer”, “eraser” and “reader” proteins are key proteins involved in the dynamic regulation of m6A modifications, through the anchoring, removal, and interpretation of m6A modifications, respectively. Remarkably, such dynamic modifications can regulate the progression of many diseases by affecting RNA splicing, translation, export and degradation. Emerging evidence has identified the relationship between m6A modifications and degenerative musculoskeletal diseases, such as osteoarthritis, osteoporosis, sarcopenia and degenerative spinal disorders. Here, we have comprehensively summarized the evidence of the pathogenesis of m6A modifications in degenerative musculoskeletal diseases. Moreover, the potential molecular mechanisms, regulatory functions and clinical implications of m6A modifications are thoroughly discussed. Our review may provide potential prospects for addressing key issues in further studies.
Highlights
Emerging evidence has shown that methylation modifications have regulatory effects on the RNA of eukaryotic cells, and the common modifications include N1-methyladenosine (m1A), N6methyladenosine (m6A), 5-methylcytosine (m5C), 7-methylguanosine (m7G), m1G, m2G, m6G, etc. (Shi et al, 2020). m6A is the most common of these modifications, accounting for the largest proportion, and approximately 20–40% of all transcripts encoded in mammalian cells are m6Amethylated (Frye et al, 2018)
Promoting OP development miR-103-3p can target METTL14 to inhibit osteogenic differentiation Promoting differentiation of BMSCs to adipocytes miR-149-3p promotes osteogenic differentiation by targeting fat mass and obesity-associated protein (FTO). miR-22-3p in BMSC-derived EVs can inhibit MYC/PI3K/AKT signal pathway by targeting FTO to stimulate osteogenic differentiation Inhibiting the osteogenic differentiation of MSCs through PRMT6 Mettl3 is required for MyoD mRNA expression in proliferative myoblasts METTL3 regulates the differentiation of MuSCs
METTL14 promotes he senescence of nucleus pulposus cell by increasing the expression of miR-34a-5p METTL3 promotes the degeneration by inhibit the protective effect of PI3K/Akt signaling pathway on endplate cartilage Regulating the ossification of primary ligament fibroblasts
Summary
Emerging evidence has shown that methylation modifications have regulatory effects on the RNA of eukaryotic cells, and the common modifications include N1-methyladenosine (m1A), N6methyladenosine (m6A), 5-methylcytosine (m5C), 7-methylguanosine (m7G), m1G, m2G, m6G, etc. (Shi et al, 2020). m6A is the most common of these modifications, accounting for the largest proportion, and approximately 20–40% of all transcripts encoded in mammalian cells are m6Amethylated (Frye et al, 2018). MiR-22-3p in BMSC-derived EVs can inhibit MYC/PI3K/AKT signal pathway by targeting FTO to stimulate osteogenic differentiation Inhibiting the osteogenic differentiation of MSCs through PRMT6 Mettl3 is required for MyoD mRNA expression in proliferative myoblasts METTL3 regulates the differentiation of MuSCs Regulating the notch signaling pathway and controlling muscle regeneration and repair with the METTL3-m6A-YTHDF1 axis Regulating mTOR-PGC-1a-mediated intramitochondrial synthesis and muscle cell differentiation Reducing lipid accumulation by inhibiting the demethylase activity of FTO.
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