Alcohol-induced inhibition of bone formation and neovascularization contributes to the failure of fracture healing via the miR-19a-3p/FOXF2 axis

Bone & Joint Research

article

Daoyu Zhu¹  Haoyu Fang¹  Hongping Yu²  Pei Liu¹  Qianhao Yang¹  Pengbo Luo¹  Changqing Zhang¹  Youshui Gao¹  Yi-Xuan Chen¹ 

[1] Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital;Department of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University

关键词: MicroRNA-19a-3p;    Forkhead box F2;    Alcohol;    Bone fracture;    Osteogenesis;    Vascularization;    bone fracture healing;    bone formation;    BMSCs;    mesenchymal stem cells;    endothelial cells;    mouse model;    vein;    luciferase reporter assay;    staining;    MicroRNA;   

DOI  :  10.1302/2046-3758.116.BJR-2021-0596.R1

学科分类：骨科学

来源: British Editorial Society Of Bone And Joint Surgery

【 摘 要 】

AimsAlcoholism is a well-known detrimental factor in fracture healing. However, the underlying mechanism of alcohol-inhibited fracture healing remains poorly understood.MethodsMicroRNA (miR) sequencing was performed on bone mesenchymal stem cells (BMSCs). The effects of alcohol and miR-19a-3p on vascularization and osteogenic differentiation were analyzed in vitro using BMSCs and human umbilical vein endothelial cells (HUVECs). An in vivo alcohol-fed mouse model of femur fracture healing was also established, and radiological and histomorphometric analyses were used to evaluate the role of miR-19a-3p. The binding of miR-19a-3p to forkhead box F2 (FOXF2) was analyzed using a luciferase reporter assay.ResultsmiR-19a-3p was identified as one of the key regulators in the osteogenic differentiation of BMSCs, and was found to be downregulated in the alcohol-fed mouse model of fracture healing. In vitro, miR-19a-3p expression was downregulated after ethanol administration in both BMSCs and HUVECs. Vascularization and osteogenic differentiation were independently suppressed by ethanol and reversed by miR-19a-3p. In addition, the luciferase reporter assay showed that FOXF2 is the direct binding target of miR-19a-3p. In vivo, miR-19a-3p agomir stimulated callus transformation and improved the alcohol-impaired fracture healing.ConclusionThis study is the first to demonstrate that the miR-19a-3p/FOXF2 axis has a pivotal role in alcohol-impaired fracture healing, and may be a potential therapeutic target.

【 授权许可】

CC BY-NC