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• The polypeptide OP 3-4 promoted bone regeneration of mandibular defect. • OP 3-4 improved osteogenic differentiation of bone marrow mesenchymal stem cells. • OP 3-4 promoted osteogenic differentiation by AKT/GSK3β/β-catenin pathway. The aims of this study were to explore: (ⅰ) the effect of the polypeptide OP 3-4 on bone regeneration in vivo ; (ⅱ) the effect of OP 3-4 on osteogenic differentiation of bone marrow mesenchymal stem cells in vitro ; and (ⅲ) the potential mechanism of OP 3-4 in promoting osteogenic differentiation of bone marrow mesenchymal stem cells. 30 Wistar rats (8-week, male) were randomly divided into Control group (n = 5), Hydrogel group (n = 5), and Hydrogel loaded OP 3-4 group (n = 5). Hematoxylin and eosin staining was used to evaluate the level of bone regeneration in mandibular defect. Immunohistochemistry staining was used to evaluate the expression of alkaline phosphatase, runt-related transcription factor 2, and type Ⅰ collagen. Flow cytometry was applied to identify the phenotype of bone marrow mesenchymal stem cells. Furthermore, LY294002, the inhibitor of protein kinase B, was applied to verify the role of OP 3-4 in promoting osteogenic differentiation via protein kinase B/glycogen synthase kinase 3β/β-catenin pathway through western blot. OP 3-4 promoted bone regeneration of rat mandibular defect. The expression of osteogenic differentiation related markers were increased after adding OP 3-4 to bone marrow mesenchymal stem cells. OP 3-4 promoted osteogenic differentiation of bone marrow mesenchymal stem cells via protein kinase B/glycogen synthase kinase 3β/β-catenin pathway. OP 3-4 could promote bone regeneration of mandibular defect and improve osteogenic differentiation through protein kinase B/glycogen synthase kinase 3β/β-catenin pathway. [ABSTRACT FROM AUTHOR]

Background: The incidence of diabetic osteoporosis is increasing. This article evaluates the effect of combination treatment with the hypoglycemic drug exendin-4 (Ex-4) and the vitamin D analog eldecalcitol (ED-71) on improving diabetic osteoporosis and explores the relevant mechanism of action. Method: Micro-CT, HE staining, immunohistochemistry, qPCR and ELISA were used to evaluate the impact of Ex-4 and ED-71 on bone formation and macrophage polarization in a mouse model of diabetic osteoporosis in vivo. Immunofluorescence, flow cytometry and qPCR were used to characterize the polarization type of macrophages treated with Ex-4 and ED-71 in vitro. A co-culture system of BMSCs and macrophages was established. Subsequently, crystal violet staining, alkaline phosphatase staining and alizarin red staining were used to evaluate the migration and osteogenesis differentiation of BMSCs. Results: Ex-4 combined with ED-71 significantly reduced blood glucose levels and enhanced bone formation in mice with diabetic osteoporosis. In addition, Ex-4 synergized with ED-71 to induce the polarization of macrophages into M2 through the PI3K/AKT pathway. Macrophages treated with the combination of Ex-4 and ED-71 can significantly induce the osteogenic differentiation of BMSCs. Conclusion: Ex-4 synergized with ED-71 to reduce blood glucose levels significantly. And this combination therapy can synergistically induce osteogenic differentiation of BMSCs by promoting M2 macrophages polarization, thereby improving diabetic osteoporosis. Therefore, the combination of Ex-4 and ED-71 may be a new strategy for the treatment of diabetic osteoporosis. [ABSTRACT FROM AUTHOR]