C/EBP[alpha] regulates osteoclast lineage commitment

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-04, Vol.110 (18), p.7294
• Main Authors: Chen, Wei, Zhu, Guochun, Hao, Liang, Wu, Mengrui, Ci, Hongliang, Li, Yi-Ping
• Format: Article
• Language: English
• Subjects: Binding sites; Cytoplasm; Gene expression; Ligands; Proteins; Rodents; Viruses
• ISSN: 0027-8424; 1091-6490

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-KB, 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-KB 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-KB ligand, induces expression of receptor activator of NF-KB, 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. (ProQuest: ... denotes formulae/symbols omitted.)