title: FOXO1-suppressed miR-424 regulates the proliferation and osteogenic differentiation of MSCs by targeting FGF2 under oxidative stress.
abstract: Recently, microRNAs (miRNAs) have been identified as key regulators of the proliferation and differentiation of mesenchymal stem cells (MSCs). Our previous in vivo study and other in vitro studies using miRNA microarrays suggest that miR-424 is involved in the regulation of bone formation. However, the role and mechanism of miR-424 in bone formation still remain unknown. Here, we identified that the downregulation of miR-424 mediates bone formation under oxidative stress, and we explored its underlying mechanism. Our results showed that miR-424 was significantly downregulated in an anterior lumbar interbody fusion model of pigs and in a cell model of oxidative stress induced by H2O2. The overexpression of miR-424 inhibited proliferation and osteogenic differentiation shown by a decrease in alkaline phosphatase (ALP) activity, mineralization and osteogenic markers, including RUNX2 and ALP, whereas the knockdown of miR-424 led to the opposite results. Moreover, miR-424 exerts its effects by targeting FGF2. Furthermore, we found that FOXO1 suppressed miR-424 expression and bound to its promoter region. FOXO1 enhanced proliferation and osteogenic differentiation in part through the miR-424/FGF2 pathway. These results indicated that FOXO1-suppressed miR-424 regulates both the proliferation and osteogenic differentiation of MSCs via targeting FGF2, suggesting that miR-424 might be a potential novel therapeutic strategy for promoting bone formation.
authors.affiliation: Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute /Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, P R China.|Centre for Translational Bone, Joint and Soft Tissue Research, Medical Faculty and University Centre for Orthopaedics and Trauma Surgery, University Hospital Carl Gustav Carus at Technische Universität Dresden, Dresden, 01307, Germany.
authors.forename: Liangping
authors.initials: L
authors.lastname: Li
authors.affiliation: Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute /Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, P R China.
authors.forename: Qihua
authors.initials: Q
authors.lastname: Qi
authors.affiliation: Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute /Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, P R China.
authors.forename: Jiaquan
authors.initials: J
authors.lastname: Luo
authors.affiliation: Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute /Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, P R China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Huang
authors.affiliation: Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute /Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, P R China.
authors.forename: Zemin
authors.initials: Z
authors.lastname: Ling
authors.affiliation: Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute /Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, P R China.
authors.forename: Manman
authors.initials: M
authors.lastname: Gao
authors.affiliation: Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute /Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, P R China.
authors.forename: Zhiyu
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Centre for Translational Bone, Joint and Soft Tissue Research, Medical Faculty and University Centre for Orthopaedics and Trauma Surgery, University Hospital Carl Gustav Carus at Technische Universität Dresden, Dresden, 01307, Germany.
authors.forename: Maik
authors.initials: M
authors.lastname: Stiehler
authors.affiliation: Guangdong Provincial Key Laboratory of Orthopaedics and Traumatology, Orthopaedic Research Institute /Department of Spinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, 510080, P R China.
authors.forename: Xuenong
authors.initials: X
authors.lastname: Zou
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D000071161:Forkhead Box Protein O1 / Q000378:metabolism*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D010012:Osteogenesis; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D034421:Sus scrofa; D014158:Transcription, Genetic
chemical_list: D000071161:Forkhead Box Protein O1; D035683:MicroRNAs; D017382:Reactive Oxygen Species; D016222:Fibroblast Growth Factor 2