Autografts are still regarded as the gold standard treatment for bone defects but they require additional surgery that causes pain for the patient. Thus, alternatives that can substitute for grafts are required. In the present study, a novel poly-GLP-1 molecule was developed using a polymeric pro-drug strategy which was found to accelerate bone healing in a mouse femoral defect model. Furthermore, the poly-GLP-1 molecule induced osteogenesis and inhibited adipogenesis in bone marrow-derived mesenchymal stem cells (BMSCs). The results demonstrate that poly-GLP-1 promoted M2 polarization of bone marrow-derived macrophages (BMDMs) and increased the levels of TGF-β1 in the bone marrow, resulting in the migration of an increased number of CD29 + Sca-1 + BMSCs to the bone surface. Finally, we found that poly-GLP-1 facilitated the migration of BMSCs due to transduction of the Smad2 signaling pathway, causing increased numbers of CD31 + Endomucin + endothelial cells in bone marrow that promoted bone formation. These results support poly-GLP-1 as a potential bone-healing agent and suggest that it may play a promising role in the clinical treatment of fracture repair.

中文翻译：

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鉴定了用于治疗股骨缺损的长效分子GLP-1R激动剂。

自体移植仍然被认为是治疗骨缺损的金标准，但是它们需要进行额外的手术，从而给患者带来痛苦。因此，需要可以替代移植物的替代物。在本研究中，使用聚合物前药策略开发了一种新型的poly-GLP-1分子，该策略在小鼠股骨缺损模型中可促进骨愈合。此外，poly-GLP-1分子在骨髓来源的间充质干细胞（BMSCs）中诱导成骨作用并抑制脂肪形成。结果表明，poly-GLP-1促进了骨髓来源的巨噬细胞（BMDM）的M2极化，并提高了骨髓中TGF-β1的水平，导致CD29 + Sca-1 + BMSCs数量增加到骨头表面。最后，我们发现，poly-GLP-1由于Smad2信号传导途径的转导而促进了BMSC的迁移，从而导致骨髓中CD31 +内切粘菌素+内皮细胞数量增加，从而促进了骨形成。这些结果支持poly-GLP-1作为潜在的骨愈合剂，并表明它可能在骨折修复的临床治疗中发挥有希望的作用。