title: TNF-α Inhibits FoxO1 by Upregulating miR-705 to Aggravate Oxidative Damage in Bone Marrow-Derived Mesenchymal Stem Cells during Osteoporosis.
abstract: Decline of antioxidant defense after estrogen deficiency leads to oxidative damage in bone marrow-derived mesenchymal stem cells (BMMSCs), resulting a defect of bone formation in osteoporosis. Forkhead box O1 (FoxO1) protein is crucial for defending physiological oxidative damage in bone. But whether FoxO1 is involved in the oxidative damage during osteoporosis is largely unknown. In this study, we found that FoxO1 protein accumulation was decreased in BMMSCs of ovariectomized mice. The decrease of FoxO1 resulted in the suppression of manganese superoxide dismutase (Sod2) and catalase (Cat) expression and accumulation of reactive oxygen species (ROS), inhibiting the osteogenic differentiation of BMMSCs. The decline of FoxO1 protein was caused by tumor necrosis factor-alpha (TNF-α) accumulated after estrogen deficiency. Mechanistically, TNF-α activated NF-κB pathway to promote microRNA-705 expression, which function as a repressor of FoxO1 through post-transcriptional regulation. Inhibition of NF-κB pathway or knockdown of miR-705 largely prevented the decline of FoxO1-mediated antioxidant defense caused by TNF-α and ameliorated the oxidative damage in osteoporotic BMMSCs. Moreover, the accumulated ROS further activated NF-κB pathway with TNF-α, which formed a feed-forward loop to persistently inhibiting FoxO1 protein accumulation in BMMSCs. In conclusion, our study revealed that the decline of FoxO1 is an important etiology factor of osteoporosis and unclosed a novel mechanism of FoxO1 regulation by TNF-α. These findings suggested a close correlation between inflammation and oxidative stress in stem cell dysfunction during degenerative bone diseases.
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.|State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.|Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Li
authors.initials: L
authors.lastname: Liao
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.|Department of Orthodontics, Stomatology Hospital of Xi'an Jiaotong University College of Medicine, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Su
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.|Department of Prosthetics, School of Stomatology, ZunYi Medical College, ZunYi, Guizhou, People's Republic of China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.|Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Chenghu
authors.initials: C
authors.lastname: Hu
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.|State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.|Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Bei
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Dermatology, Tangdu Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Yajie
authors.initials: Y
authors.lastname: Lv
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.|State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.|Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shuai
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.|State Key Laboratory of Military Stomatology, Department of Oral Histology and Pathology, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.|Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Huan
authors.initials: H
authors.lastname: Jing
authors.affiliation: Department of Otolaryngology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Deng
authors.affiliation: State Key Laboratory of Military Stomatology, Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.|Research and Development Center for Tissue Engineering, Fourth Military Medical University, Xi'an, Shaanxi, People's Republic of China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jin
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D002374:Catalase / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics*; D004967:Estrogens / Q000172:deficiency; D000071161:Forkhead Box Protein O1 / Q000096:biosynthesis / Q000235:genetics*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D010012:Osteogenesis / Q000235:genetics; D010024:Osteoporosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy; D018384:Oxidative Stress / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics*; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D002374:Catalase; D004967:Estrogens; D000071161:Forkhead Box Protein O1; D035683:MicroRNAs; D017382:Reactive Oxygen Species; D013482:Superoxide Dismutase; D014409:Tumor Necrosis Factor-alpha; D000099156:Superoxide Dismutase 2; C000613310:MIRN705 microRNA, mouse
keywords: Differentiation; Mesenchymal stem cells; Osteoporosis; Stem cell-microenvironment; miRNA