| First Author | Chen W | Year | 2018 |
| Journal | J Bone Miner Res | Volume | 33 |
| Issue | 4 | Pages | 691-703 |
| PubMed ID | 29149533 | Mgi Jnum | J:315971 |
| Mgi Id | MGI:6831927 | Doi | 10.1002/jbmr.3342 |
| Citation | Chen W, et al. (2018) Monocyte-Specific Knockout of C/ebpalpha Results in Osteopetrosis Phenotype, Blocks Bone Loss in Ovariectomized Mice, and Reveals an Important Function of C/ebpalpha in Osteoclast Differentiation and Function. J Bone Miner Res 33(4):691-703 |
| abstractText | CCAAT/enhancer-binding protein alpha (C/ebpalpha) is critical for osteoclastogenesis by regulating osteoclast (OC) lineage commitment and is also important for OC differentiation and function in vitro. However, the role of C/ebpalpha in postnatal skeletal development has not been reported owing to lethality in C/ebpalpha(-/-) mice from hypoglycemia within 8 hours after birth. Herein, we generated conditional knockout mice by deleting the C/ebpalpha gene in monocyte via LysM-Cre to examine its role in OC differentiation and function. C/ebpalpha(f/f) LysM-Cre mice exhibited postnatal osteopetrosis due to impaired osteoclastogenesis, OC lineage priming defects, as well as defective OC differentiation and activity. Furthermore, our ex vivo analysis demonstrated that C/ebpalpha conditional deletion significantly reduced OC differentiation, maturation, and activity while mildly repressing macrophage development. At the molecular level, C/ebpalpha deficiency significantly suppresses the expressions of OC genes associated with early stages of osteoclastogenesis as well as genes associated with OC differentiation and activity. We also identified numerous C/ebpalpha critical cis-regulatory elements on the Cathepsin K promoter that allow C/ebpalpha to significantly upregulate Cathepsin K expression during OC differentiation and activity. In pathologically induced mouse model of osteoporosis, C/ebpalpha deficiency can protect mice against ovariectomy-induced bone loss, uncovering a central role for C/ebpalpha in osteolytic diseases. Collectively, our findings have further established C/ebpalpha as a promising therapeutic target for bone loss by concurrently targeting OC lineage priming, differentiation, and activity. (c) 2017 American Society for Bone and Mineral Research. |
