Alcohol-induced inhibition of bone formation and neovascularization contributes to the failure of fracture healing via the miR-19a-3p/FOXF2 axis
Aims: Alcoholism is a well-known detrimental factor in fracture healing. However, the underlying mechanism of alcohol-inhibited fracture healing remains poorly understood. Methods: MicroRNA (miR) sequencing was performed on bone mesenchymal stem cells (BMSCs). The effects of alcohol and miR-19a-3p o...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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The British Editorial Society of Bone & Joint Surgery
2022-06-01
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| Series: | Bone & Joint Research |
| Subjects: | |
| Online Access: | https://online.boneandjoint.org.uk/doi/epdf/10.1302/2046-3758.116.BJR-2021-0596.R1 |
| _version_ | 1811324272625319936 |
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| author | Daoyu Zhu Haoyu Fang Hongping Yu Pei Liu Qianhao Yang Pengbo Luo Changqing Zhang Youshui Gao Yi-Xuan Chen |
| author_facet | Daoyu Zhu Haoyu Fang Hongping Yu Pei Liu Qianhao Yang Pengbo Luo Changqing Zhang Youshui Gao Yi-Xuan Chen |
| author_sort | Daoyu Zhu |
| collection | DOAJ |
| description | Aims: Alcoholism is a well-known detrimental factor in fracture healing. However, the underlying mechanism of alcohol-inhibited fracture healing remains poorly understood. Methods: MicroRNA (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. Results: miR-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. Conclusion: This 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. Cite this article: Bone Joint Res 2022;11(6):386–397. |
| first_indexed | 2024-04-13T14:11:22Z |
| format | Article |
| id | doaj.art-d9803a2ec55a4afa97444d6342a0d6b9 |
| institution | Directory Open Access Journal |
| issn | 2046-3758 |
| language | English |
| last_indexed | 2024-04-13T14:11:22Z |
| publishDate | 2022-06-01 |
| publisher | The British Editorial Society of Bone & Joint Surgery |
| record_format | Article |
| series | Bone & Joint Research |
| spelling | doaj.art-d9803a2ec55a4afa97444d6342a0d6b92022-12-22T02:43:47ZengThe British Editorial Society of Bone & Joint SurgeryBone & Joint Research2046-37582022-06-0111638639710.1302/2046-3758.116.BJR-2021-0596.R1Alcohol-induced inhibition of bone formation and neovascularization contributes to the failure of fracture healing via the miR-19a-3p/FOXF2 axisDaoyu Zhu0Haoyu Fang1Hongping Yu2Pei Liu3Qianhao Yang4Pengbo Luo5Changqing Zhang6Youshui Gao7Yi-Xuan Chen8Department of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, ChinaDepartment of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, ChinaDepartment of Orthopedic Surgery, The First Affiliated Hospital of Xiamen University, Xiamen, ChinaDepartment of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, ChinaDepartment of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, ChinaDepartment of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, ChinaDepartment of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, ChinaDepartment of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, ChinaDepartment of Orthopedic Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, ChinaAims: Alcoholism is a well-known detrimental factor in fracture healing. However, the underlying mechanism of alcohol-inhibited fracture healing remains poorly understood. Methods: MicroRNA (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. Results: miR-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. Conclusion: This 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. Cite this article: Bone Joint Res 2022;11(6):386–397.https://online.boneandjoint.org.uk/doi/epdf/10.1302/2046-3758.116.BJR-2021-0596.R1microrna-19a-3pforkhead box f2alcoholbone fractureosteogenesisvascularizationbone fracture healingbone formationbmscsmesenchymal stem cellsendothelial cellsmouse modelveinluciferase reporter assaystainingmicrorna |
| spellingShingle | Daoyu Zhu Haoyu Fang Hongping Yu Pei Liu Qianhao Yang Pengbo Luo Changqing Zhang Youshui Gao Yi-Xuan Chen 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 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 |
| title | Alcohol-induced inhibition of bone formation and neovascularization contributes to the failure of fracture healing via the miR-19a-3p/FOXF2 axis |
| title_full | Alcohol-induced inhibition of bone formation and neovascularization contributes to the failure of fracture healing via the miR-19a-3p/FOXF2 axis |
| title_fullStr | Alcohol-induced inhibition of bone formation and neovascularization contributes to the failure of fracture healing via the miR-19a-3p/FOXF2 axis |
| title_full_unstemmed | Alcohol-induced inhibition of bone formation and neovascularization contributes to the failure of fracture healing via the miR-19a-3p/FOXF2 axis |
| title_short | Alcohol-induced inhibition of bone formation and neovascularization contributes to the failure of fracture healing via the miR-19a-3p/FOXF2 axis |
| title_sort | alcohol induced inhibition of bone formation and neovascularization contributes to the failure of fracture healing via the mir 19a 3p foxf2 axis |
| topic | 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 |
| url | https://online.boneandjoint.org.uk/doi/epdf/10.1302/2046-3758.116.BJR-2021-0596.R1 |
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