title: C/EBPα regulates osteoclast lineage commitment.
abstract: Despite recent insights gained from the effects of targeted deletion of the Finkel-Biskis-Jinkins osteosarcoma oncogene (c-fos), Spleen focus-forming virus (SFFV) proviral integration 1 (PU.1), microphthalmia-associated transcription factor, NF-κB, and nuclear factor of activated cells cytoplasmic 1 (NFATc1) transcription factor genes, the mechanism underlying transcription factors specifying osteoclast (OC) lineage commitment from monocyte/macrophage remains unclear. To characterize the mechanism by which transcription factors regulate OC lineage commitment, we mapped the critical cis-regulatory element in the promoter of cathepsin K (Ctsk), which is expressed specifically in OCs, and found that CCAAT/enhancer binding protein α (C/EBPα) is the critical cis-regulatory element binding protein. Our results indicate that C/EBPα is highly expressed in pre- OCs and OCs. The combined presence of macrophage colony-stimulating factor and receptor activator of NF-κB ligand significantly induces high C/EBPα expression. Furthermore, C/EBPα(-/-) newborn mice exhibited impaired osteoclastogenesis, and a severe osteopetrotic phenotype, but unaffected monocyte/macrophage development. Impaired osteoclastogenesis of C/EBPα(-/-) mouse bone marrow cells can be rescued by c-fos overexpression. Ectopic expression of C/EBPα in mouse bone marrow cells and monocyte/macrophage cells, in the absence of receptor activator of NF-κB ligand, induces expression of receptor activator of NF-κB, c-fos, Nfatc1, and Ctsk, and it reprograms monocyte/macrophage cells to OC-like cells. Our results demonstrate that C/EBPα directly up-regulates c-fos expression. C/EBPα(+/-) mice exhibit an increase in bone density compared with C/EBPα(+/+) controls. These discoveries establish C/EBPα as the key transcriptional regulator of OC lineage commitment, providing a unique therapeutic target for diseases of excessive bone resorption, such as osteoporosis and arthritis.
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-2182, USA. wechen@uab.edu
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Guochun
authors.initials: G
authors.lastname: Zhu
authors.forename: Liang
authors.initials: L
authors.lastname: Hao
authors.forename: Mengrui
authors.initials: M
authors.lastname: Wu
authors.forename: Hongliang
authors.initials: H
authors.lastname: Ci
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Li
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D015415:Biomarkers / Q000378:metabolism; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000172:deficiency / Q000378:metabolism*; D056657:Cathepsin K / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects / Q000235:genetics; D004247:DNA / Q000378:metabolism; D005269:Femur / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009000:Monocytes / Q000166:cytology; D009929:Organ Size / Q000187:drug effects; D010010:Osteoclasts / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D010022:Osteopetrosis / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D053245:RANK Ligand / Q000494:pharmacology; D011859:Radiography; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics; D013977:Tibia / Q000000981:diagnostic imaging / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology
chemical_list: D015415:Biomarkers; D022763:CCAAT-Enhancer-Binding Protein-alpha; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; D004247:DNA; D056657:Cathepsin K; C534132:Ctsk protein, mouse