Metformin accelerates bone fracture healing by promoting type H vessel formation through inhibition of YAP1/TAZ expression
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Published:2023-08-16
Issue:1
Volume:11
Page:
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ISSN:2095-6231
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Container-title:Bone Research
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language:en
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Short-container-title:Bone Res
Author:
Ruan Zhe, Yin Hao, Wan Teng-Fei, Lin Zhi-Rou, Zhao Shu-Shan, Long Hai-Tao, Long Cheng, Li Zhao-Hui, Liu Yu-QiORCID, Luo Hao, Cheng Liang, Chen Can, Zeng Min, Lin Zhang-Yuan, Zhao Rui-Bo, Chen Chun-Yuan, Wang Zhen-XingORCID, Liu Zheng-ZhaoORCID, Cao Jia, Wang Yi-Yi, Jin Ling, Liu Yi-Wei, Zhu Guo-Qiang, Zou Jing-Tao, Gong Jiang-Shan, Luo Yi, Hu Yin, Zhu YongORCID, Xie HuiORCID
Abstract
AbstractDue to increasing morbidity worldwide, fractures are becoming an emerging public health concern. This study aimed to investigate the effect of metformin on the healing of osteoporotic as well as normal fractures. Type H vessels have recently been identified as a bone-specific vascular subtype that supports osteogenesis. Here, we show that metformin accelerated fracture healing in both osteoporotic and normal mice. Moreover, metformin promoted angiogenesis in vitro under hypoxia as well as type H vessel formation throughout fracture healing. Mechanistically, metformin increased the expression of HIF-1α, an important positive regulator of type H vessel formation, by inhibiting the expression of YAP1/TAZ in calluses and hypoxia-cultured human microvascular endothelial cells (HMECs). The results of HIF-1α or YAP1/TAZ interference in hypoxia-cultured HMECs using siRNA further suggested that the enhancement of HIF-1α and its target genes by metformin is primarily through YAP1/TAZ inhibition. Finally, overexpression of YAP1/TAZ partially counteracted the effect of metformin in promoting type H vessel-induced angiogenesis-osteogenesis coupling during fracture repair. In summary, our findings suggest that metformin has the potential to be a therapeutic agent for fractures by promoting type H vessel formation through YAP1/TAZ inhibition.
Funder
National Natural Science Foundation of China Natural Science Foundation of Hunan Province Independent Exploration and Innovation Project of Central South University
Publisher
Springer Science and Business Media LLC
Subject
Physiology,Histology,Endocrinology, Diabetes and Metabolism
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