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Milk fat globule\u2010epidermal growth factor 8 (MFG\u2010E8), a glycoprotein possibly secreted by macrophages in a fracture hematoma, participates in bone development. However, the role of MFG\u2010E8 in the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) is unclear. We investigated the osteogenic effect of MFG\u2010E8 in vitro and in vivo. The CCK\u20108 assay was used to assess the effect of recombinant human MFG\u2010E8 (rhMFG\u2010E8) on the viability of hBMSCs. Osteogenesis was investigated using RT\u2010PCR, Western blotting, and immunofluorescence. Alkaline phosphatase (ALP) and Alizarin red staining were used to evaluate ALP activity and mineralization, respectively. An enzyme\u2010linked immunosorbent assay was conducted to evaluate the secretory MFG\u2010E8 concentration. Knockdown and overexpression of MFG\u2010E8 in hBMSCs were established via siRNA and lentivirus vector transfection, respectively. Exogenous rhMFG\u2010E8 was used to verify the in vivo therapeutic effect in a tibia bone defect model based on radiographic analysis and histological evaluation. Endogenous and secretory MFG\u2010E8 levels increased significantly during the early osteogenic differentiation of hBMSCs. Knockdown of MFG\u2010E8 inhibited the osteogenic differentiation of hBMSCs. Overexpression of MFG\u2010E8 and rhMFG\u2010E8 protein increased the expression of osteogenesis\u2010related genes and proteins and enhanced calcium deposition. The active \u03b2\u2010catenin to total \u03b2\u2010catenin ratio and the p\u2010GSK3\u03b2 protein level were increased by MFG\u2010E8. The MFG\u2010E8\u2010induced enhanced osteogenic differentiation of hBMSCs was partially attenuated by a GSK3\u03b2\/\u03b2\u2010catenin signaling inhibitor. Recombinant MFG\u2010E8 accelerated bone healing in a rat tibial\u2010defect model. In conclusion, MFG\u2010E8 promotes the osteogenic differentiation of hBMSCs by regulating the GSK3\u03b2\/\u03b2\u2010catenin signaling pathway and so, is a potential therapeutic target.<\/jats:p>","DOI":"10.1096\/fj.202201417rrr","type":"journal-article","created":{"date-parts":[[2023,5,5]],"date-time":"2023-05-05T08:55:22Z","timestamp":1683276922000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["MFG\u2010E8 promotes osteogenic differentiation of human bone marrow mesenchymal stem cells through GSK3\u03b2\/\u03b2\u2010catenin signaling pathway"],"prefix":"10.1096","volume":"37","author":[{"given":"Jinwu","family":"Bai","sequence":"first","affiliation":[{"name":"Department of Orthopaedics The Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University  Hangzhou People's Republic of China"},{"name":"Orthopedics Research Institute, Zhejiang University  Hangzhou People's Republic of 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