C/EBPα regulates osteoclast lineage commitment

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-04, Vol.110 (18), p.7294-7299
• Main Authors: Chen, Wei, Zhu, Guochun, Hao, Liang, Wu, Mengrui, Ci, Hongliang, Li, Yi-Ping
• Format: Article
• Language: English
• Subjects: Animals; Animals, Newborn; Base Sequence; Binding sites; Biological Sciences; Biomarkers - metabolism; Bones; Cathepsin K - metabolism; CCAAT-Enhancer-Binding Protein-alpha - deficiency; CCAAT-Enhancer-Binding Protein-alpha - metabolism; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Line; Cell Lineage - drug effects; Cell Lineage - genetics; Cell lines; DNA - metabolism; Femur - diagnostic imaging; Femur - drug effects; Femur - pathology; Femur - physiopathology; Gene expression regulation; Gene Expression Regulation - drug effects; Genes; Giant cells; Macrophages; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Mice; Mice, Knockout; Molecular Sequence Data; Monocytes - cytology; Organ Size - drug effects; Osteoclasts; Osteoclasts - drug effects; Osteoclasts - enzymology; Osteoclasts - metabolism; Osteoclasts - pathology; Osteogenesis - drug effects; Osteogenesis - genetics; Osteopetrosis; Osteopetrosis - diagnostic imaging; Osteopetrosis - pathology; Osteopetrosis - physiopathology; Phenotype; Promoter Regions, Genetic - genetics; Proto-Oncogene Proteins c-fos - metabolism; Radiography; RANK Ligand - pharmacology; Regulatory Sequences, Nucleic Acid - genetics; Tibia - diagnostic imaging; Tibia - drug effects; Tibia - pathology; Tibia - physiopathology; Transcription factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1211383110

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.