title: FOXO1 inhibits osteoclastogenesis partially by antagnozing MYC.
abstract: FOXO transcription factors especially FOXO1 have profound roles in bone development and remodeling. The regulation of cells of the osteoblast lineage by FOXOs is suggested to be stage-specific or context dependent. Intriguingly, recent studies on the role played by FOXOs in osteoclastogenesis reached different conclusion. Bartell et al. showed that FOXOs restrained osteoclastogenesis and bone resorption partially by upregulation of the H2O2-inactivating enzyme catalase. Wang et al. demonstrated that FOXO1 activated osteoclast formation. In the present study, we confirmed the results of Bartell et al. that FOXO1 expression was reduced upon stimulation of RANKL; FOXO1 inhibition promoted and FOXO1 activation repressed, osteoclast differentiation and activity; the inhibitory effect of FOXO1 on osteoclastogenesis was partially mediated by ROS since treatment with ROS scavengers cancelled the effect of FOXO1 inhibition on osteoclastogenesis. We further investigated the mechanisms responsible for repressed osteoclastogenesis by FOXO1. We found that FOXO1 inhibition modulated MAPKs, NF-κB and AP-1. Finally, we proved that the inhibitory effect of FOXO1 on osteoclast formation was partially mediated by MYC suppression by showing that MYC repression almost totally abrogated the effect of FOXO1 inhibition on osteoclastogenesis. To conclude, our study confirmed FOXO1 as a cell-autonomous inhibitor of osteoclastogenesis.
authors.affiliation: Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Tan
authors.affiliation: Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Hanfeng
authors.initials: H
authors.lastname: Guan
authors.affiliation: Cancer Center of Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Linka
authors.initials: L
authors.lastname: Xie
authors.affiliation: Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Baoguo
authors.initials: B
authors.lastname: Mi
authors.affiliation: Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Zhong
authors.initials: Z
authors.lastname: Fang
authors.affiliation: Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Orthopaedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Li
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology; D053245:RANK Ligand / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C553926:5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D016166:Free Radical Scavengers; C489428:Myc protein, mouse; D016328:NF-kappa B; D016271:Proto-Oncogene Proteins c-myc; D015363:Quinolones; D053245:RANK Ligand; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D020928:Mitogen-Activated Protein Kinases