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C/EBPalpha regulates osteoclast lineage commitment.

Authors: Chen, W  Zhu, G  Hao, L  Wu, M  Ci, H  Li, YP 
Citation: Chen W, etal., Proc Natl Acad Sci U S A. 2013 Apr 30;110(18):7294-9. doi: 10.1073/pnas.1211383110. Epub 2013 Apr 11.
Pubmed: (View Article at PubMed) PMID:23580622
DOI: Full-text: 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-kappaB, 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/EBPalpha) is the critical cis-regulatory element binding protein. Our results indicate that C/EBPalpha is highly expressed in pre- OCs and OCs. The combined presence of macrophage colony-stimulating factor and receptor activator of NF-kappaB ligand significantly induces high C/EBPalpha expression. Furthermore, C/EBPalpha(-/-) newborn mice exhibited impaired osteoclastogenesis, and a severe osteopetrotic phenotype, but unaffected monocyte/macrophage development. Impaired osteoclastogenesis of C/EBPalpha(-/-) mouse bone marrow cells can be rescued by c-fos overexpression. Ectopic expression of C/EBPalpha in mouse bone marrow cells and monocyte/macrophage cells, in the absence of receptor activator of NF-kappaB ligand, induces expression of receptor activator of NF-kappaB, c-fos, Nfatc1, and Ctsk, and it reprograms monocyte/macrophage cells to OC-like cells. Our results demonstrate that C/EBPalpha directly up-regulates c-fos expression. C/EBPalpha(+/-) mice exhibit an increase in bone density compared with C/EBPalpha(+/+) controls. These discoveries establish C/EBPalpha 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.

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CRRD Object Information
CRRD ID: 10401187
Created: 2015-09-30
Species: All species
Last Modified: 2015-09-30
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.