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

Abstract

The fat mass and obesity-associated gene (<i>FTO</i>) 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 <i>FTO</i> in bone, we characterized the phenotype of mice lacking <i>Fto</i> globally (<i>Fto</i>^<i>KO</i> ) or selectively in osteoblasts (<i>Fto</i>^<i>Oc</i>^<i>KO</i> ). 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 <i>Fto</i> revealed changes in transcripts of <i>Hspa1a</i> and other genes in the DNA repair pathway containing consensus m6A motifs required for demethylation by <i>Fto</i><i>Fto</i> KO osteoblasts were more susceptible to genotoxic agents (UV and H₂O₂) and exhibited increased rates of apoptosis. Importantly, forced expression of <i>Hspa1a</i> or inhibition of NF-κB signaling normalized the DNA damage and apoptotic rates in <i>Fto</i> KO osteoblasts. Furthermore, increased metabolic stress induced in mice by feeding a high-fat diet induced greater DNA damage in osteoblast of <i>Fto</i>^{<i>Oc KO</i>} 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.