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 () 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 in bone, we characterized the phenotype of mice lacking globally ( ) or selectively in osteoblasts ( ). 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 revealed changes in transcripts of and other genes in the DNA repair pathway containing consensus m6A motifs required for demethylation by KO osteoblasts were more susceptible to genotoxic agents (UV and HO) and exhibited increased rates of apoptosis. Importantly, forced expression of or inhibition of NF-κB signaling normalized the DNA damage and apoptotic rates in KO osteoblasts. Furthermore, increased metabolic stress induced in mice by feeding a high-fat diet induced greater DNA damage in osteoblast of 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.