二甲双胍通过抑制YAP1/TAZ表达促进H型血管形成,从而加速骨折愈合。

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING
Zhe Ruan, Hao Yin, Teng-Fei Wan, Zhi-Rou Lin, Shu-Shan Zhao, Hai-Tao Long, Cheng Long, Zhao-Hui Li, Yu-Qi Liu, Hao Luo, Liang Cheng, Can Chen, Min Zeng, Zhang-Yuan Lin, Rui-Bo Zhao, Chun-Yuan Chen, Zhen-Xing Wang, Zheng-Zhao Liu, Jia Cao, Yi-Yi Wang, Ling Jin, Yi-Wei Liu, Guo-Qiang Zhu, Jing-Tao Zou, Jiang-Shan Gong, Yi Luo, Yin Hu, Yong Zhu, Hui Xie
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引用次数: 0

摘要

由于世界范围内发病率的增加,骨折正在成为一个新兴的公共卫生问题。本研究旨在探讨二甲双胍对骨质疏松性骨折及正常骨折愈合的影响。H型血管最近被确定为支持成骨的骨特异性血管亚型。在这里,我们发现二甲双胍加速了骨质疏松和正常小鼠的骨折愈合。此外,二甲双胍促进体外缺氧条件下的血管生成以及骨折愈合过程中H型血管的形成。机制上,二甲双胍通过抑制YAP1/TAZ在愈伤组织和缺氧培养的人微血管内皮细胞(HMECs)中的表达,增加HIF-1α的表达,HIF-1α是H型血管形成的重要正调节因子。利用siRNA对缺氧培养hmec进行HIF-1α或YAP1/TAZ干扰的结果进一步表明,二甲双胍主要通过抑制YAP1/TAZ来增强HIF-1α及其靶基因。最后,YAP1/TAZ的过表达部分抵消了二甲双胍在骨折修复过程中促进H型血管诱导的血管生成-成骨耦合的作用。总之,我们的研究结果表明,二甲双胍通过抑制YAP1/TAZ促进H型血管形成,具有成为骨折治疗剂的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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

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 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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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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