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

Qian Zhang, Ryan C. Riddle, Qian Yang, Clifford R. Rosen, Denis C. Guttridge, Naomi Dirckx, Marie Claude Faugere, Charles R. Farber, Thomas L. Clemens

Research output: Contribution to journalArticlepeer-review

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-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 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.

Original languageEnglish (US)
Pages (from-to)17980-17989
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number36
DOIs
StatePublished - Sep 3 2019

Keywords

  • Bone
  • DNA damage
  • Epigenetics
  • Osteoblasts
  • Osteoporosis

ASJC Scopus subject areas

  • General

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