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Research Paper|Volume 13, Issue 17|pp 21134—21141

RNA N6-methyladenosine demethylase FTO promotes osteoporosis through demethylating Runx2 mRNA and inhibiting osteogenic differentiation

Jing Wang1,2, Qiang Fu3, Jian Yang2, Jin-Long Liu4, Shu-Ming Hou2, Xing Huang2, Jia-Shi Cao2, Tie-Long Liu2, Kun-Zheng Wang1
  • 1Department of Orthopedics, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China
  • 2Spinal Tumor Center, Chang Zheng Hospital, Second Military Medical University, Shanghai, China
  • 3Department of Orthopedic Trauma Surgery, Second Military Medical University, Shanghai, China
  • 4Department of Biotechnology and Pathology, School of Medical Technology, Shanghai University of Medicine and Health Sciences, Shanghai, China
* Equal contribution
# Co-first authors
Received: February 13, 2020Accepted: December 16, 2020Published: September 8, 2021
https://doi.org/10.18632/aging.203377

Copyright: © 2021 Wang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

As a systemic disease, osteoporosis (OP) results in bone density loss and fracture risk, particularly in the hip and vertebrae. However, the underlying molecular mechanisms of OP development have not been fully illustrated. N6-Methyladenosine (m6A) is the most abundant modification of mRNAs, which is involved in many of pathological processes in aging disease. However, its role and regulatory mechanism in OP remains unknown. Here, we aimed to investigate the roles of m6A and its demethylase FTO in OP development. The results showed that m6A methylated RNA level was up-regulated in the bone marrow mesenchymal stem cells (BMSCs) from patients with OP. The level of N6-methyladenosine demethylase FTO was consistently decreased in the BMSCs from patients with OP. Functionally, lentivirus-mediated FTO overexpression in normal BMSCs to compromised osteogenic potential. Mechanism analysis further suggested that FTO overexpression decreased the m6A methylated and total level of runt related transcription factor 2 (Runx2) mRNA, subsequently inhibited osteogenic differentiation. We found that FTO inhibition could effectively improve the bone formation in ovariectomized osteoporotic mice in vivo. Together, these results reveal that RNA N6-methyladenosine demethylase FTO promotes osteoporosis through demethylating runx2 mRNA and inhibiting osteogenic differentiation.