C/EBPα regulates osteoclast lineage commitment

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-kappa B, 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 alpha (C/EBP alpha) is the critical cis-regulatory element binding protein. Our results indicate that C/EBP alpha is highly expressed in pre-OCs and OCs. The combined presence of macrophage colony-stimulating factor and receptor activator of NF-kappa B ligand significantly induces high C/EBP alpha expression. Furthermore, C/EBP alpha(-/-) newborn mice exhibited impaired osteoclastogenesis, and a severe osteopetrotic phenotype, but unaffected monocyte/macrophage development. Impaired osteoclastogenesis of C/EBP alpha(-/-) mouse bone marrow cells can be rescued by c-fos overexpression. Ectopic expression of C/EBP alpha in mouse bone marrow cells and monocyte/ macrophage cells, in the absence of receptor activator of NF-kappa B ligand, induces expression of receptor activator of NF-kappa B, c-fos, Nfatc1, and Ctsk, and it reprograms monocyte/ macrophage cells to OC-like cells. Our results demonstrate that C/EBP alpha directly up-regulates c-fos expression. C/EBP alpha(+/-) mice exhibit an increase in bone density compared with C/EBP alpha(+/+) controls. These discoveries establish C/EBP alpha 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.