Metformin accelerates bone fracture healing by promoting type H vessel formation through inhibition of YAP1/TAZ expression

作者：Zhe Ruan, Hao Yin, Tengfei Wan, Zhi-Rou Lin, Shushan Zhao, Haitao Long, Cheng Long, Zhaohui Li, Yu-Qi Liu, Hao Luo, Liang Cheng, Can Chen, Min Zeng, Zhangyuan Lin, Ruibo Zhao, Chun‐Yuan Chen, Zhen‐Xing Wang, Zhengzhao Liu, Jia Cao, Yiyi Wang, Ling Jin, Yi-Wei Liu, Guo‐Qiang Zhu, Jingtao Zou, Jiang-Shan Gong, Yi Luo, Yin Hu, Yong Zhu, Hui Xie · 发表于：Bone Research · 年份：2023 · DOI：10.1038/s41413-023-00279-4 · 被引用次数：59 · 研究领域：Hippo pathway signaling and YAP/TAZ、Fibroblast Growth Factor Research、Cancer, Hypoxia, and Metabolism

Due 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.