METTL14 Regulates Osteogenesis of Bone Marrow Mesenchymal Stem Cells via Inducing Autophagy Through m6A/IGF2BPs/Beclin-1 Signal Axis

作者：He, Mingyu; Lei, Hong; He, Xiaoqi; Liu, Ying; Wang, Ao; Ren, Zijing; Liu, Xiaoyan; Yan, Gege; Wang, Wenbo; Wang, Yang; Li, Guanghui; Wang, Tong; Pu, Jiaying; Shen, Zhihua; Wang, Yanquan; Xie, Jiajie; Du, Weijie; Yuan, Ye^*; Yang, Lei^*

来源：2022, 11(9): 987-1001.

DOI：10.1093/stcltm/szac049

• m(6)A RNA methylation
• bone marrow mesenchymal stem cells
• METTL14
• autophagy
• osteogenic differentiation

The development of osteoporosis is often accompanied by autophagy disturbance, which also causes new osteoblast defects from bone marrow mesenchymal stem cells (BMSCs). However, the underlying molecular mechanisms are still not fully understood. Methyltransferase-like 14 (METTL14) is the main enzyme for N-6-methyladenosine (m(6)A), the most prevalent internal modification in mammalian mRNAs, and it has been implicated in many bioprocesses. Herein, we demonstrate that METTL14 plays a critical role in autophagy induction and hinders osteoporosis process whose expression is decreased both in human osteoporosis bone tissue and ovariectomy (OVX) mice. In vivo, METTL14(+/-) knockdown mice exhibit elevated bone loss and impaired autophagy similar to the OVX mice, while overexpression of METTL14 significantly promotes bone formation and inhibits the progression of osteoporosis caused by OVX surgery. In vitro, METTL14 overexpression significantly enhances the osteogenic differentiation ability of BMSCs through regulating the expression of beclin-1 depending on m(6)A modification and inducing autophagy; the opposite is true with METTL14 silencing. Subsequently, m(6)A-binding proteins IGF2BP1/2/3 recognize m(6)A-methylated beclin-1 mRNA and promote its translation via mediating RNA stabilization. Furthermore, METTL14 negatively regulates osteoclast differentiation. Collectively, our study reveals the METTL14/IGF2BPs/beclin-1 signal axis in BMSCs osteogenic differentiation and highlights the critical roles of METTL14-mediated m(6)A modification in osteoporosis.

• 单位
  y; 中国医学科学院; 1; 哈尔滨医科大学