@article{9045746edb964955ad5a49ea1a05718a,
title = "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 (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 (FtoKO) or selectively in osteoblasts (FtoOc 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-{\^e}B 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 FtoOc 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.",
keywords = "Bone, DNA damage, Epigenetics, Osteoblasts, Osteoporosis",
author = "Qian Zhang and Riddle, {Ryan C.} and Qian Yang and Rosen, {Clifford R.} and Guttridge, {Denis C.} and Naomi Dirckx and Faugere, {Marie Claude} and Farber, {Charles R.} and Clemens, {Thomas L.}",
note = "Funding Information: To more precisely define the role of FTO in bone, we created both global and osteoblast-specific Fto KO models and compared their phenotypes. A side-by-side comparison of both models revealed reductions in bone mass that strongly support an osteoblast intrinsic role for FTO in preserving bone formation during adulthood. This conclusion is supported by several additional lines of evidence. First, Fto was expressed at relatively high levels in osteoblasts of WT mice. Second, osteoblast precursors lacking Fto differentiated poorly and demonstrated increased rates of apoptosis. Moreover, loss of Fto in osteoblast lineage cells reduced the ability of mesenchymal colonies to form osteoblasts (CFU-Ob) while increasing the numbers of adipocyte precursors. Finally and most importantly, the decreased trabecular bone in mice lacking Fto was associated with decreased bone formation by resident osteoblasts and fewer surviving osteocytes. These results indicate that FTO is required for the maintenance of osteoblast lineage cell precursors and their subsequent ability to differentiate and form bone. These alterations in mouse bone are compatible with the skeletal changes associated with age-related bone loss in humans, including a decline in the rate of bone formation and an increase in bone marrow adiposity (39–42). Publisher Copyright: {\textcopyright} 2019 National Academy of Sciences. All rights reserved.",
year = "2019",
month = sep,
day = "3",
doi = "10.1073/pnas.1905489116",
language = "English (US)",
volume = "116",
pages = "17980--17989",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "36",
}