RNA N6‐methyladenosine demethylase FTO inhibits glucocorticoid‐induced osteoblast differentiation and function in bone marrow mesenchymal stem cells

Abstract

AbstractExcess glucocorticoids (GCs) have been reported as key factors that impair osteoblast (OB) differentiation and function. However, the role of RNA N6‐methyladenosine (m6A) in this process has not yet been elucidated. In this study, we report that both the mRNA and protein expression of fat mass and obesity‐associated gene (FTO), a key m6A demethylase, were dose‐dependently downregulated during OB differentiation by dexamethasone (DEX) in bone marrow mesenchymal stem cells (BMSCs), and FTO was gradually increased during OB differentiation. Meanwhile, FTO knockdown suppressed OB differentiation and mineralization, whereas overexpression of wide‐type FTO, but not mutant FTO (mutated m6A demethylase active site), reversed DEX‐induced osteogenesis impairment. Interfering with FTO inhibited proliferation and the expression of Ki67 and Pcna in BMSCs during OB differentiation, whereas forced expression of wide‐type FTO improved DEX‐induced inhibition of BMSCs proliferation. Moreover, FTO knockdown reduced the mRNA stability of the OB marker genes Alpl and Col1a1, and FTO‐modulated OB differentiation via YTHDF1 and YTHDF2. In conclusion, our results suggest that FTO inhibits the GCs‐induced OB differentiation and function of BMSCs.