School of Psychology, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
Stem Cell and Biotherapy Engineering Research Center of Henan, College of Life Science and Technology, Xinxiang Medical University, Xinxiang, 453003, Henan, China.
Mol Cell Biochem. 2020 Jan;463(1-2):203-210. doi: 10.1007/s11010-019-03641-5. Epub 2019 Oct 23.
As a m6A methylation modifier, METTL3 is functionally involved in various biological processes. Nevertheless, the role of METTL3 in osteogenesis is not determined up to date. In the current study, METTL3 is identified as a crucial regulator in the progression of osteogenic differentiation. Loss of METTL3 significantly augments calcium deposition and enhances alkaline phosphatase activity of mesenchymal stem cells, uncovering an inhibitory role of METTL3 in osteogenesis. More importantly, the underlying molecular basis by which METTL3 regulates osteogenesis is illustrated. We find that METTL3 positively regulates expression of MYD88, a critical upstream regulator of NF-κB signaling, by facilitating m6A methylation modification to MYD88-RNA, subsequently inducing the activation of NF-κB which is widely regarded as a repressor of osteogenesis and therefore suppressing osteogenic progression. Moreover, the METTL3-mediated m6A methylation is found to be dynamically reversed by the demethylase ALKBH5. In summary, this study highlights the functional importance of METTL3 in osteogenic differentiation and METTL3 may serve as a promising molecular target in regenerative medicine, as well as in the field of bone tissue engineering.
作为 m6A 甲基化修饰酶，METTL3 参与多种生物学过程。然而，METTL3 在成骨中的作用尚未确定。在本研究中，METTL3 被鉴定为成骨分化过程中的关键调控因子。METTL3 的缺失显著增加了间充质干细胞的钙沉积和碱性磷酸酶活性，揭示了 METTL3 在成骨中的抑制作用。更重要的是，阐明了 METTL3 调节成骨作用的潜在分子基础。我们发现，METTL3 通过促进 MYD88-RNA 的 m6A 甲基化修饰，正向调节 NF-κB 信号通路的关键上游调控因子 MYD88 的表达，从而诱导 NF-κB 的激活，NF-κB 被广泛认为是成骨的抑制因子，因此抑制成骨进程。此外，发现去甲基化酶 ALKBH5 可使 METTL3 介导的 m6A 甲基化发生动态逆转。总之，本研究强调了 METTL3 在成骨分化中的功能重要性，METTL3 可能成为再生医学以及骨组织工程领域有前途的分子靶点。
