TABLE 1.

The role of m6A in degenerative musculoskeletal diseases.

disease	m6A regulator	Cell type	Target gene/signal pathway	Roles in disease	References
OA	METTL3	ATDC5 Cell	NF- $\kappa$ B signaling	Promoting inflammatory response, collagen synthesis and degradation, and cell apoptosis in chondrocytes	Liu et al. (2019)
	METTL3	SW1353 cell	NF- $\kappa$ B signaling	Promoting inflammatory response, degradation of extracellular matrix	Sang et al. (2021)
OP	METTL3	Primary MSCs	PTH/PTH1r signaling	Impairing bone formation	Wu et al. (2018)
	METTL3	BMSCs	PI3K-AKT signaling axis	Inhibiting osteogenic differentiation	Tian et al. (2019)
	METTL3	BMSCs	JAK1/STAT5/C/EBP $\beta$ signaling axis	Suppressing the early lipid differentiation of BMSCs	Yao et al. (2019)
	METTL3	BMSCs	PremiR-320/RUNX2	Promoting OP development	Yan et al. (2020)
	METTL14	Osteoblasts	miR-103-3p	miR-103-3p can target METTL14 to inhibit osteogenic differentiation	Sun et al. (2021)
	FTO	BMSCs	GDF11- FTO - PPAR $\text{γ}$ signal pathway	Promoting differentiation of BMSCs to adipocytes	Shen et al. (2018)
	FTO	BMSCs	miR-149-3p	miR-149-3p promotes osteogenic differentiation by targeting FTO.	Li et al. (2019)
	FTO	BMSCs	miR-22-3p and MYC/PI3K/AKT signal pathway	miR-22-3p in BMSC-derived EVs can inhibit MYC/PI3K/AKT signal pathway by targeting FTO to stimulate osteogenic differentiation	Zhang et al. (2020a)
	ALKBH5	MSCs	PRMT6 mRNA	Inhibiting the osteogenic differentiation of MSCs through PRMT6	Li et al. (2021)
Sarcopenia	METTL3	C2C12 cell	MyoD mRNA	Mettl3 is required for MyoD mRNA expression in proliferative myoblasts	Kudou et al. (2017)
	METTL3	C2C12/MuSCs	-	METTL3 regulates the differentiation of MuSCs	Gheller et al. (2020)
	METTL3	MuSCs	Notch Signaling	Regulating the notch signaling pathway and controlling muscle regeneration and repair with the METTL3-m6A-YTHDF1 axis	Liang et al. (2021)
	FTO	C2C12 cell	mTOR-PGC-1α pathway	Regulating mTOR-PGC-1a-mediated intramitochondrial synthesis and muscle cell differentiation	Wang et al. (2017)
	FTO	C2C12 cell	AMPK	Reducing lipid accumulation by inhibiting the demethylase activity of FTO.	Wu et al. (2017)
Degenerative spinal diseases	METTL14	HNPCs	miR-34a-5p	METTL14 promotes he senescence of nucleus pulposus cell by increasing the expression of miR-34a-5p	Zhu et al. (2021)
	METTL3	chondrocytes	PI3K/AKT signaling	METTL3 promotes the degeneration by inhibit the protective effect of PI3K/Akt signaling pathway on endplate cartilage	Xiao et al. (2020)
	METTL3	Primary Ligament Fibroblasts	XIST/miR-302a-3p/USP8 Axis	Regulating the ossification of primary ligament fibroblasts	Yuan et al. (2021)
	ALKBH5	Ligamentum Flavum Cells	AKT pathway	Promoting ligamentum flavum cell osteogenesis by decreasing BMP2 demethylation and activating Akt signaling pathway	Wang et al. (2020b)

ALKBH5, alkB homolog 5; BMSC, bone marrow mesenchymal stem cell; FTO, fat mass and obesity-associated protein; m6A, N6-methyladenosine; METTL3, methyltransferase-like 3; METTL14, methyltransferase-like 14; OA, osteoarthritis; OP, osteoporosis. HNPCs, human nucleus pulposus cell. MuSCs, Muscle-specific adult stem cells.