The m6A methyltransferase METTL3 cooperates with demethylase ALKBH5 to regulate osteogenic differentiation through NF-κB signaling
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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.
KeywordsMETTL3 M6A methylation Osteogenesis NF-κB signaling ALKBH5
Mesenchymal stem cells
Menstrual blood-derived mesenchymal stem cells
This work was supported by grants from the National Natural Science Foundation of China (31502045) and Xinxiang Medical University Foundation (300-505307).
JL, MC, and XZ are responsible for designing the project. JY and LS performed most of the experiments. YL contributed to data analysis. XZ wrote the draft of this manuscript. All authors take part in discussions.
Compliance with ethical standards
Conflict of interest
The authors declare that there is no conflict of interest.
The MenSCs used in this study were obtained with the informed consent of the donors. All experiments in this manuscript meet the “Declaration of Helsinki” and were approved by the Ethics Committee of Xinxiang Medical University.
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