GLP-1RA Promotes Osteogenic Differentiation of Jaw Bone Marrow Mesenchymal Stem Cells by Modulating CREB/YAP/STAT3/BRD4-Mediated Proliferation and Stemness for Osteoporosis Treatment

OBJECTIVE: To investigate the molecular mechanisms underlying the role of jaw bone marrow mesenchymal stem cells (JBMMSCs) in treating rat mandibular osteoporosis under semaglutide intervention. METHODS: Osteoporosis samples from rats were obtained from the GEO database for bioinformatics analysis. JBMMSCs were isolated from rat mandibles and characterized by flow cytometry. Osteoporosis models were established in rats, and hematoxylin and eosin (HE) staining was used to detect the therapeutic efficacy of semaglutide on osteoporosis after intervention with JBMMSCs. In vitro, CCK-8, colony formation, and scratch assays were used to determine the optimal concentration of semaglutide for osteogenic induction in JBMMSCs, which were then injected via the tail vein for osteoporosis treatment. Western blotting was employed to assess the expression of osteogenesis- and adipogenesis-related proteins. Additionally, ALP, ARS, and Oil Red O staining were performed to evaluate the osteogenic and adipogenic differentiation potential of JBMMSCs. Finally, protein levels of p-CREB, YAP, BRD4, OCT4, SOX2, c-Myc, Cyclin D1, p-STAT3, TET3, SHP2, p-SMAD1/5, β-Catenin, RUNX2, and DLX5 were detected to explore the molecular mechanisms by which semaglutide improves osteoporosis through JBMMSCs. RESULTS: HE staining revealed a significant alleviation of osteoporosis in rats following JBMMSC intervention with semaglutide. Immunofluorescence analysis showed increased expression of stemness proteins in JBMMSCs. CCK-8 and colony formation assays confirmed that semaglutide enhanced the proliferation and stemness of JBMMSCs. Western blot analysis indicated that semaglutide preserved the stemness of JBMMSCs through the CREB/YAP/BRD4 axis and mediated osteogenic and adipogenic differentiation via the BMP2/STAT3/TET3/SHP2 axis, ultimately improving osteoporosis. Rescue experiments further supported these findings. CONCLUSION: GLP-1RA promotes the osteogenic differentiation of JBMMSCs by modulating the CREB/YAP/STAT3/BRD4 pathway, which enhances cellular proliferation and stemness, ultimately offering a potential therapeutic strategy for osteoporosis treatment.