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. 2025 Aug 12;38(5):141.
doi: 10.1007/s13577-025-01271-2.

Bone marrow mesenchymal stem cell-derived exosomal METTL14 promotes the osteogenic differentiation of MC3T3-E1 cells by regulating BMP2 in bone fracture recovery

Min Liu #  1 , Zhenye Guo #  1 , Xiaoyan Shi  1 , Zhengquan Dong  1 , Huyun Qiao  1 , Dong Wang  1 , Yonghong Zhang  2
Affiliations

Bone marrow mesenchymal stem cell-derived exosomal METTL14 promotes the osteogenic differentiation of MC3T3-E1 cells by regulating BMP2 in bone fracture recovery

Min Liu et al. Hum Cell. .

Abstract

Bone fracture healing is a complex physiologic process that aims at restoring the damaged bone to its pre-injury state and cellular composition. Exosomes secreted by bone marrow mesenchymal stem cells (BMSCs) are emerging as a promising strategy to promote bone regeneration due to exosomal bioactive cargos. Furthermore, N6-Methyladenosine (m6A) methylation affects osteoblastic differentiation and bone remodeling. This study is designed to clarify the role and mechanism of BMSC-derived exosomal Methyltransferase-like 14 (METTL14) in osteogenesis. METTL14 and bone morphogenetic protein 2 (BMP2) levels were detected by RT-qPCR. METTL14, exosome-specific markers, BMP2, and IGF2BP1 protein levels were determined using Western blot. Cell viability, proliferation, and apoptosis were examined using MTT, EdU, and flow cytometry. The degree of osteogenic differentiation was verified by the Alizarin Red S staining assay and ALP activity assay. The interaction between METTL14 and BMP2 was analyzed using methylated RNA immunoprecipitation (MeRIP)-qPCR and RIP assays. METTL14 and BMP2 levels were decreased in delayed fracture healing (DFH), a common complication after fracture surgery. METTL14 upregulation expedited MC3T3-E1 cell viability, proliferation, and repressed apoptosis. METTL14 promotes osteogenic differentiation of MC3T3-E1 cells by enhancing ALP activity and mineralized formation. After co-culturing BMSC-derived exosomes and MC3T3-E1 cells, BMSC-derived exosomal METTL14 expedited the osteoblast activity. Mechanistically, METTL14 stabilized BMP2 mRNA through the m6A-IGF2BP1-dependent mechanism. These findings indicated that BMSC-derived exosomes encapsulate METTL14 and transport it into MC3T3-E1 cells, and the transported METTL14 could accelerate the osteogenesis by regulating the stability of BMP2 mRNA, which provided a potentially effective therapeutic strategy for bone regeneration.

Keywords: BMP2; BMSC-derived exosomes; IGF2BP1; METTL14; Osteogenic differentiation.

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Conflict of interest statement

Declarations. Ethical approval and consent to participate: The present study was approved by the ethical review committee of The Second Hospital of Shanxi Medical University with approval No. 20240316. Written informed consent was obtained from all enrolled patients. Human rights statements and informed consent: The research has been carried out in accordance with the World Medical Association Declaration of Helsinki, and all subjects provided written informed consent. Animal studies: Animal studies were performed in compliance with the ARRIVE guidelines and the Basel Declaration. All animals received humane care according to the National Institutes of Health (USA) guidelines. Consent for publication: Patients agree to participate in this work.

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