title: TNF-α-induced NF-κB activation upregulates microRNA-150-3p and inhibits osteogenesis of mesenchymal stem cells by targeting β-catenin.
abstract: Although systemic or local inflammation, commonly featured by cytokine activation, is implicated in patients with bone loss, the underlying mechanisms are still elusive. As microRNAs (miR), a class of small non-coding RNAs involved in essential physiological processes, have been found in bone cells, we aimed to investigate the role of miR for modulating osteogenesis in inflammatory milieu using human bone marrow mesenchymal stem cells (hBM-MSCs). Induced by proinflammatory cytokine TNF-α, miR-150-3p was identified as a key player in suppressing osteogenic differentiation through downregulating β-catenin, a transcriptional co-activator promoting bone formation. TNF-α treatment increased the levels of miR-150-3p, which directly targeted the 3'-UTR of β-catenin mRNA and in turn repressed its expression. In addition, we observed that miR-150-3p expression was increased by TNF-α via IKK-dependent NF-κB signalling. There are three putative NF-κB binding sites in the promoter region of miR-150, and we identified -686 region as the major NF-κB binding site for stimulation of miR-150 expression by TNF-α. Finally, the osteogenic differentiation of hBM-MSCs was inhibited by either miR-150-3p overexpression or TNF-α treatment, which was prevented by anti-miR-150-3p oligonucleotides. Taken together, our data suggested that miR-150-3p integrated inflammation signalling and osteogenic differentiation and may contribute to the inhibition effects of inflammation on bone formation, thus expanding the pathophysiological functions of microRNAs in bone diseases.
authors.affiliation: Department of Orthopaedic Surgery, Shanghai Jiao Tong University affiliated Sixth People's Hospital, Shanghai, People's Republic of China Department of Emergency, the first affiliated hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China.
authors.forename: Nan
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Orthopaedic Surgery, Shanghai Jiao Tong University affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
authors.forename: Zubin
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Department of Orthopaedics and Traumatology, Lui Che Woo Institute of Innovative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong SAR, People's Republic of China.
authors.forename: Tianyi
authors.initials: T
authors.lastname: Wu
authors.affiliation: Department of Orthopaedic Surgery, Shanghai Jiao Tong University affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Department of Orthopaedic Surgery, Shanghai Jiao Tong University affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
authors.forename: Peipei
authors.initials: P
authors.lastname: Yin
authors.affiliation: Department of Orthopaedic Surgery, Shanghai Jiao Tong University affiliated Sixth People's Hospital, Shanghai, People's Republic of China.
authors.forename: Chenhao
authors.initials: C
authors.lastname: Pan
authors.affiliation: Department of Orthopaedic Surgery, Shanghai Jiao Tong University affiliated Sixth People's Hospital, Shanghai, People's Republic of China yuxw@sjtu.edu.cn.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Yu
mesh_terms: D002454:Cell Differentiation; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000276:immunology; D016328:NF-kappa B / Q000276:immunology*; D010006:Osteoblasts / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D010012:Osteogenesis; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*; D015854:Up-Regulation; D051176:beta Catenin / Q000235:genetics / Q000276:immunology*
chemical_list: D035683:MicroRNAs; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; C533097:MIR150, human
keywords: TNF-α; mesenchymal stem cells; microRNA; osteogenesis; β-catenin