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.
Highlights
OCs are polykaryon bone-resorbing cells that are critical for skeletal development and bone homeostasis [12]
C/EBP␣ overexpression in mouse bone marrow (MBM) cells could initiate osteoclastogenesis by generating tartrate-resistant acid phosphatase 5 (TRAP)-positive mononucleated cells independently of RANKL compared with a GFP control
To confirm the ability of C/EBP␣ to mediate OC lineage priming, we examined its ability to induce the expression of the aforementioned OC genes independently of RANKL
Summary
OCs are polykaryon bone-resorbing cells that are critical for skeletal development and bone homeostasis [12]. Binding of RANKL to its receptor, RANK, on the cell surface of OC progenitors transduces intracellular signaling, leading to activation of many critical OC transcription factors, including NFATc1, the master regulator of OC differentiation [17, 18]. Role of C/EBP␣ Is Osteoclast Differentiation and Function age priming Consistent with this notion, we have reported that newborn C/EBP␣Ϫ/Ϫ mice display a severe osteopetrotic phenotype from impaired OC development. It remains unclear whether the defective OC formation observed in this previous study stems from a defect in OC lineage commitment or whether it is the result of the requirement for C/EBP␣ in other stages of osteoclastogenesis. This study has expanded our understanding of the roles of C/EBP␣ in OC biology but has further supported the potential of C/EBP␣ as a promising therapeutic target for bone loss stemming from bone disorders of excessive OC formation and/or activity
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
