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Original Article | Open Access

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

Zhe Ruan1,2,, Hao Yin1,2,3,4,, Teng-Fei Wan1,2,3,4, Zhi-Rou Lin5, Shu-Shan Zhao1, Hai-Tao Long1, Cheng Long1, Zhao-Hui Li1, Yu-Qi Liu1, Hao Luo1, Liang Cheng1, Can Chen1, Min Zeng1, Zhang-Yuan Lin1, Rui-Bo Zhao1, Chun-Yuan Chen1,2,3,4,6, Zhen-Xing Wang1,2,3,4,6, Zheng-Zhao Liu1,2,3,4,6, Jia Cao1,2,3,4,6, Yi-Yi Wang1,2,3,4, Ling Jin1,2,3,4, Yi-Wei Liu1,2,3,4, Guo-Qiang Zhu1,2,3,4, Jing-Tao Zou1,2,3,4, Jiang-Shan Gong1,2,3,4, Yi Luo1,2,3,4, Yin Hu5, Yong Zhu1 ( ), Hui Xie1,2,3,4,6 ( )
Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China
Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China
Angmedicine Research Center of Central South University, Changsha, Hunan, 410008, China
The First Affiliated Hospital, Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China

These authors contributed equally: Zhe Ruan, Hao Yin

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Abstract

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.

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Bone Research
Volume 11,
December 2023
Article number: 45
DOI: 10.1038/s41413-023-00279-4
Cite this article:
Ruan Z, Yin H, Wan T-F, et al. Metformin accelerates bone fracture healing by promoting type H vessel formation through inhibition of YAP1/TAZ expression. Bone Research, 2023, 11: 45. https://doi.org/10.1038/s41413-023-00279-4

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Received: 18 July 2022
Revised: 04 June 2023
Accepted: 26 June 2023
Published: 16 August 2023
© The Author(s) 2023

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