title: FOXO1 mediates RANKL-induced osteoclast formation and activity.
abstract: We have previously shown that the transcription factor FOXO1 is elevated in conditions with high levels of bone resorption. To investigate the role of FOXO1 in the formation of osteoclasts, we examined mice with lineage-specific deletion of FOXO1 in osteoclast precursors and by knockdown of FOXO1 with small interfering RNA. The receptor activator for NF-κB ligand (RANKL), a principal bone-resorbing factor, induced FOXO1 expression and nuclear localization 2 d after stimulation in bone marrow macrophages and RAW264.7 osteoclast precursors. RANKL-induced osteoclast formation and osteoclast activity was reduced in half in vivo and in vitro with lineage-specific FOXO1 deletion (LyzM.Cre(+)FOXO1(L/L)) compared with matched controls (LyzM.Cre(-)FOXO1(L/L)). Similar results were obtained by knockdown of FOXO1 in RAW264.7 cells. Moreover, FOXO1-mediated osteoclast formation was linked to regulation of NFATc1 nuclear localization and expression as well as a number of downstream factors, including dendritic cell-specific transmembrane protein, ATP6vod2, cathepsin K, and integrin αv. Lastly, FOXO1 deletion reduced M-CSF-induced RANK expression and migration of osteoclast precursors. In the present study, we provide evidence that FOXO1 plays a direct role in osteoclast formation by mediating the effect of RANKL on NFATc1 and several downstream effectors. This is likely to be significant because FOXO1 and RANKL are elevated in osteolytic conditions.
authors.affiliation: Department of Implantology, School of Stomatology, Jilin University, Changchun 130021, China; Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Yu
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Guangyu
authors.initials: G
authors.lastname: Dong
authors.affiliation: Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Hyeran Helen
authors.initials: HH
authors.lastname: Jeon
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Mohamad
authors.initials: M
authors.lastname: Elazizi
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Lan B
authors.initials: LB
authors.lastname: La
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Alhassan
authors.initials: A
authors.lastname: Hameedaldeen
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104; School and Hospital of Stomatology, Peking University, Beijing 100081, China; and.
authors.forename: E
authors.initials: E
authors.lastname: Xiao
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Chen
authors.initials: C
authors.lastname: Tian
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104;
authors.forename: Sarah
authors.initials: S
authors.lastname: Alsadun
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.affiliation: Department of Periodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104; dtgraves@dental.upenn.edu.
authors.forename: Dana T
authors.initials: DT
authors.lastname: Graves
mesh_terms: D000818:Animals; D015153:Blotting, Western; D056657:Cathepsin K / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D039482:Integrin alpha5 / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D050778:NFATC Transcription Factors / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D053245:RANK Ligand / Q000494:pharmacology*; D034622:RNA Interference; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D039482:Integrin alpha5; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; D016173:Macrophage Colony-Stimulating Factor; D056657:Cathepsin K