title: CCAAT/Enhancer-binding Protein α (C/EBPα) Is Important for Osteoclast Differentiation and Activity.
abstract: CCAAT/enhancer-binding protein (C/EBPα) can appoint mouse bone marrow (MBM) cells to the osteoclast (OC) lineage for osteoclastogenesis. However, whether C/EBPα is also involved in OC differentiation and activity is unknown. Here we demonstrated that C/EBPα overexpression in MBM cells can promote OC differentiation and strongly induce the expression of the OC genes encoding the nuclear factor of activated T-cells, c1 (NFATc1), cathepsin K (Cstk), and tartrate-resistant acid phosphatase 5 (TRAP) with receptor activator of NF-κB ligand-evoked OC lineage priming. Furthermore, while investigating the specific stage of OC differentiation that is regulated by C/EBPα, our gene overexpression studies revealed that, although C/EBPα plays a stronger role in the early stage of OC differentiation, it is also involved in the later stage. Accordingly, C/EBPα knockdown drastically inhibits osteoclastogenesis and markedly abrogates the expression of NFATc1, Cstk, and TRAP during OC differentiation. Consistently, C/EBPα silencing revealed that, although lack of C/EBPα affects all stages of OC differentiation, it has more impact on the early stage. Importantly, we showed that ectopic expression of rat C/EBPα restores osteoclastogenesis in C/EBPα-depleted MBM cells. Furthermore, our subsequent functional assays showed that C/EBPα exhibits a dispensable role on actin ring formation by mature OCs but is critically involved in bone resorption by stimulating extracellular acidification and regulating cell survival. We revealed that C/EBPα is important for receptor activator of NF-κB ligand-induced Akt activation, which is crucial for OC survival. Collectively, these results indicate that C/EBPα functions throughout osteoclastogenesis as well as in OC function. This study provides additional understanding of the roles of C/EBPα in OC biology.
authors.affiliation: From the Department of Pathology, University of Alabama, Birmingham, Alabama 35294.
authors.forename: Joel
authors.initials: J
authors.lastname: Jules
authors.affiliation: From the Department of Pathology, University of Alabama, Birmingham, Alabama 35294 wechen@uab.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: From the Department of Pathology, University of Alabama, Birmingham, Alabama 35294.
authors.forename: Xu
authors.initials: X
authors.lastname: Feng
authors.affiliation: From the Department of Pathology, University of Alabama, Birmingham, Alabama 35294 ypli@uab.edu.
authors.forename: Yi-Ping
authors.initials: YP
authors.lastname: Li
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D001862:Bone Resorption; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D055785:Gene Knockdown Techniques; D051379:Mice; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D051381:Rats; D000071681:Tartrate-Resistant Acid Phosphatase / Q000235:genetics / Q000378:metabolism
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; C530718:CEBPA protein, mouse; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase
keywords: Akt PKB; CCAAT-enhancer-binding protein (C/EBP); bone; differentiation; osteoclast; transcription factor