CCAAT/Enhancer-binding Protein ? (C/EBP?) Is Important for Osteoclast Differentiation and Activity.

ABSTRACT: CCAAT/enhancer-binding protein (C/EBP?) can appoint mouse bone marrow (MBM) cells to the osteoclast (OC) lineage for osteoclastogenesis. However, whether C/EBP? is also involved in OC differentiation and activity is unknown. Here we demonstrated that C/EBP? 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-?B ligand-evoked OC lineage priming. Furthermore, while investigating the specific stage of OC differentiation that is regulated by C/EBP?, our gene overexpression studies revealed that, although C/EBP? plays a stronger role in the early stage of OC differentiation, it is also involved in the later stage. Accordingly, C/EBP? knockdown drastically inhibits osteoclastogenesis and markedly abrogates the expression of NFATc1, Cstk, and TRAP during OC differentiation. Consistently, C/EBP? silencing revealed that, although lack of C/EBP? affects all stages of OC differentiation, it has more impact on the early stage. Importantly, we showed that ectopic expression of rat C/EBP? restores osteoclastogenesis in C/EBP?-depleted MBM cells. Furthermore, our subsequent functional assays showed that C/EBP? 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/EBP? is important for receptor activator of NF-?B ligand-induced Akt activation, which is crucial for OC survival. Collectively, these results indicate that C/EBP? functions throughout osteoclastogenesis as well as in OC function. This study provides additional understanding of the roles of C/EBP? in OC biology.

SUBMITTER: Jules J 

PROVIDER: S-EPMC4965585 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature