The RNA demethylase FTO is required for maintenance of bone mass and functions to protect osteoblasts from genotoxic damage

The fat mass and obesity-associated gene (FTO) encodes an m6A RNA demethylase that controls mRNA processing and has been linked to both obesity and bone mineral density in humans by genome-wide association studies. To examine the role of FTO in bone, we characterized the phenotype of mice lacking Fto globally (Fto^KO) or selectively in osteoblasts (Fto^{Oc KO}). Both mouse models developed age-related reductions in bone volume in both the trabecular and cortical compartments. RNA profiling in osteoblasts following acute disruption of Fto revealed changes in transcripts of Hspa1a and other genes in the DNA repair pathway containing consensus m6A motifs required for demethylation by Fto. Fto KO osteoblasts were more susceptible to genotoxic agents (UV and H₂O₂) and exhibited increased rates of apoptosis. Importantly, forced expression of Hspa1a or inhibition of NF-êB signaling normalized the DNA damage and apoptotic rates in Fto KO osteoblasts. Furthermore, increased metabolic stress induced in mice by feeding a high-fat diet induced greater DNA damage in osteoblast of Fto^{Oc KO} mice compared to controls. These data suggest that FTO functions intrinsically in osteoblasts through Hspa1a-NF-κB signaling to enhance the stability of mRNA of proteins that function to protect cells from genotoxic damage.