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

  • Bone Res. 2023 Aug 16;11(1):45. doi: 10.1038/s41413-023-00279-4.
Zhe Ruan  #  1  2 ,  Hao Yin  #  1  2  3  4 ,  Teng-Fei Wan  1  2  3  4 ,  Zhi-Rou Lin  5 ,  Shu-Shan Zhao  1 ,  Hai-Tao Long  1 ,  Cheng Long  1 ,  Zhao-Hui Li  1 ,  Yu-Qi Liu  1 ,  Hao Luo  1 ,  Liang Cheng  1 ,  Can Chen  1 ,  Min Zeng  1 ,  Zhang-Yuan Lin  1 ,  Rui-Bo Zhao  1 ,  Chun-Yuan Chen  1  2  3  4  6 ,  Zhen-Xing Wang  1  2  3  4  6 ,  Zheng-Zhao Liu  1  2  3  4  6 ,  Jia Cao  1  2  3  4  6 ,  Yi-Yi Wang  1  2  3  4 ,  Ling Jin  1  2  3  4 ,  Yi-Wei Liu  1  2  3  4 ,  Guo-Qiang Zhu  1  2  3  4 ,  Jing-Tao Zou  1  2  3  4 ,  Jiang-Shan Gong  1  2  3  4 ,  Yi Luo  1  2  3  4 ,  Yin Hu  5 ,  Yong Zhu  7 ,  Hui Xie  8  9  10  11  12
Affiliations
  • 1. Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
  • 2. Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
  • 3. Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China.
  • 4. Angmedicine Research Center of Central South University, Changsha, Hunan, 410008, China.
  • 5. The First Affiliated Hospital, Department of Metabolism and Endocrinology, Hengyang Medical School, University of South China, Hengyang, Hunan, 421001, China.
  • 6. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
  • 7. Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. [email protected].
  • 8. Department of Orthopedics, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. [email protected].
  • 9. Movement System Injury and Repair Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. [email protected].
  • 10. Hunan Key Laboratory of Angmedicine, Changsha, Hunan, 410008, China. [email protected].
  • 11. Angmedicine Research Center of Central South University, Changsha, Hunan, 410008, China. [email protected].
  • 12. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China. [email protected].
  • # Contributed equally.
PMID: 37587136 DOI: 10.1038/s41413-023-00279-4
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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