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Metformin accelerates bone fracture healing by promoting type H vessel formation through inhibition of YAP1/TAZ expression
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 s...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10432554/ https://www.ncbi.nlm.nih.gov/pubmed/37587136 http://dx.doi.org/10.1038/s41413-023-00279-4 |
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author | Ruan, Zhe Yin, Hao Wan, Teng-Fei Lin, Zhi-Rou Zhao, Shu-Shan Long, Hai-Tao Long, Cheng Li, Zhao-Hui Liu, Yu-Qi Luo, Hao Cheng, Liang Chen, Can Zeng, Min Lin, Zhang-Yuan Zhao, Rui-Bo Chen, Chun-Yuan Wang, Zhen-Xing Liu, Zheng-Zhao Cao, Jia Wang, Yi-Yi Jin, Ling Liu, Yi-Wei Zhu, Guo-Qiang Zou, Jing-Tao Gong, Jiang-Shan Luo, Yi Hu, Yin Zhu, Yong Xie, Hui |
author_facet | Ruan, Zhe Yin, Hao Wan, Teng-Fei Lin, Zhi-Rou Zhao, Shu-Shan Long, Hai-Tao Long, Cheng Li, Zhao-Hui Liu, Yu-Qi Luo, Hao Cheng, Liang Chen, Can Zeng, Min Lin, Zhang-Yuan Zhao, Rui-Bo Chen, Chun-Yuan Wang, Zhen-Xing Liu, Zheng-Zhao Cao, Jia Wang, Yi-Yi Jin, Ling Liu, Yi-Wei Zhu, Guo-Qiang Zou, Jing-Tao Gong, Jiang-Shan Luo, Yi Hu, Yin Zhu, Yong Xie, Hui |
author_sort | Ruan, Zhe |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-10432554 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-104325542023-08-18 Metformin accelerates bone fracture healing by promoting type H vessel formation through inhibition of YAP1/TAZ expression Ruan, Zhe Yin, Hao Wan, Teng-Fei Lin, Zhi-Rou Zhao, Shu-Shan Long, Hai-Tao Long, Cheng Li, Zhao-Hui Liu, Yu-Qi Luo, Hao Cheng, Liang Chen, Can Zeng, Min Lin, Zhang-Yuan Zhao, Rui-Bo Chen, Chun-Yuan Wang, Zhen-Xing Liu, Zheng-Zhao Cao, Jia Wang, Yi-Yi Jin, Ling Liu, Yi-Wei Zhu, Guo-Qiang Zou, Jing-Tao Gong, Jiang-Shan Luo, Yi Hu, Yin Zhu, Yong Xie, Hui Bone Res Article 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. Nature Publishing Group UK 2023-08-16 /pmc/articles/PMC10432554/ /pubmed/37587136 http://dx.doi.org/10.1038/s41413-023-00279-4 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Ruan, Zhe Yin, Hao Wan, Teng-Fei Lin, Zhi-Rou Zhao, Shu-Shan Long, Hai-Tao Long, Cheng Li, Zhao-Hui Liu, Yu-Qi Luo, Hao Cheng, Liang Chen, Can Zeng, Min Lin, Zhang-Yuan Zhao, Rui-Bo Chen, Chun-Yuan Wang, Zhen-Xing Liu, Zheng-Zhao Cao, Jia Wang, Yi-Yi Jin, Ling Liu, Yi-Wei Zhu, Guo-Qiang Zou, Jing-Tao Gong, Jiang-Shan Luo, Yi Hu, Yin Zhu, Yong Xie, Hui Metformin accelerates bone fracture healing by promoting type H vessel formation through inhibition of YAP1/TAZ expression |
title | Metformin accelerates bone fracture healing by promoting type H vessel formation through inhibition of YAP1/TAZ expression |
title_full | Metformin accelerates bone fracture healing by promoting type H vessel formation through inhibition of YAP1/TAZ expression |
title_fullStr | Metformin accelerates bone fracture healing by promoting type H vessel formation through inhibition of YAP1/TAZ expression |
title_full_unstemmed | Metformin accelerates bone fracture healing by promoting type H vessel formation through inhibition of YAP1/TAZ expression |
title_short | Metformin accelerates bone fracture healing by promoting type H vessel formation through inhibition of YAP1/TAZ expression |
title_sort | metformin accelerates bone fracture healing by promoting type h vessel formation through inhibition of yap1/taz expression |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10432554/ https://www.ncbi.nlm.nih.gov/pubmed/37587136 http://dx.doi.org/10.1038/s41413-023-00279-4 |
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