2. Academic Validation
  3. METTL14 upregulates TCF1 through m6A mRNA methylation to stimulate osteogenic activity in osteoporosis

METTL14 upregulates TCF1 through m6A mRNA methylation to stimulate osteogenic activity in osteoporosis

  • Hum Cell. 2022 Nov 19. doi: 10.1007/s13577-022-00825-y.
Xuepeng Wang # 1,  Chunchun Zou # 2,  Maoqiang Li 1,  Changju Hou 1,  Wu Jiang 1,  Zhenyu Bian 1,  Liulong Zhu 3
Affiliations

Affiliations

  • 1 Department of Orthopedics Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 261 Huansha Road, Hangzhou, 310006, Zhejiang, People's Republic of China.
  • 2 Department of Obstetrics and Gynecology, Hangzhou Third People's Hospital, Hangzhou, 310009, Zhejiang, People's Republic of China.
  • 3 Department of Orthopedics Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, 261 Huansha Road, Hangzhou, 310006, Zhejiang, People's Republic of China. drzhuliulong@126.com.
  • # Contributed equally.
PMID: 36401086 DOI: 10.1007/s13577-022-00825-y
Abstract

Alteration of N6-methyladenosine (m6A) is closely linked to spanning biological processes including osteoporosis (OP) development. This research focuses on the function of methyltransferase like 14 (METTL14) in bone turnover and its interaction with T cell factor 1 (TCF1). A mouse model of OP was established by ovariectomy (OVX). The bone mass parameters were evaluated by micro-CT analysis. Mouse MC3T3-E1 cells and mouse bone marrow macrophages (BMMs) were induced for osteogenic or osteoclastic differentiation, respectively, for in vitro experiments. The osteogenesis or osteoclasis activity was analyzed by measuring the biomarkers such as OPG, ALP, NFATC1, CTSK, RANKL, and TRAP. RT-qPCR and IHC assays identified reduced METTL14 expression in bone tissues of osteoporotic patients and ovariectomized mice. Artificial METTL14 overexpression increased bone mass of mice and promoted osteogenesis whereas suppressed osteoclasis both in vivo and in vitro. METTL14 promoted TCF1 expression through m6A mRNA methylation, and TCF1 increased the osteogenic activity by elevating the protein level of RUNX2, a key molecule linked to bone formation. In rescue experiments, TCF1 restored the RUNX2 level and osteogenic activity of cells suppressed by METTL14 silencing. In summary, this research demonstrates that METTL14 plays a protective role against OP by promoting the TCF1/RUNX2 axis.

Keywords

METTL14; Osteogenic differentiation; Osteoporosis; RUNX2; TCF1; m6A RNA methylation.

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