Identification of a prolonged action molecular GLP-1R agonist for the treatment of femoral defects
Identification of a prolonged action molecular GLP-1R agonist for the treatment of femoral defects
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鉴定用于治疗股骨缺损的长效分子 GLP-1R 激动剂
DOI：
10.1039/c9bm01426h
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发表时间：
2020
影响因子：
6.6
通讯作者：
Guo Zheng
中科院分区：
文献类型：
--
作者：
Wan Ning;Li Xuanchen;Sh Lei;Li Yanwu;Gu Shuo;Li Wenwen;Li Xiaokang;Men Jingru;Ma Xue;Guo Zheng
自体移植仍然被认为是骨缺损的金标准治疗方法，但它们需要额外的手术，给患者带来痛苦。因此，需要可以替代移植物的替代品。在本研究中，利用聚合前药策略开发了一种新型聚 GLP-1 分子，该分子被发现可以加速小鼠股骨缺损模型中的骨愈合。此外，聚 GLP-1 分子还可诱导骨髓间充质干细胞 (BMSC) 中的骨生成并抑制脂肪生成。结果表明，聚 GLP-1 促进骨髓源性巨噬细胞 (BMDM) 的 M2 极化，并增加骨髓中 TGF-β1 的水平，导致更多数量的 CD29 + Sca-1 + BMSC 迁移到骨表面。最后，我们发现poly-GLP-1通过Smad2信号通路的转导促进BMSCs的迁移，导致骨髓中CD31 + Endomucin +内皮细胞数量增加，从而促进骨形成。这些结果支持聚-GLP-1作为一种潜在的骨愈合剂，并表明它可能在骨折修复的临床治疗中发挥有前景的作用。
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.