CCAAT/enhancer binding protein beta is up‐regulated in giant cell tumor of bone and regulates RANKL expression

Abstract

Giant cell tumor (GCT) of bone is an aggressive non-cancerous tumor, which consists of multi-nucleated osteoclast-like giant cells, stromal cells, and monocytes. It is believed that stromal cells are the neoplastic component of this tumor. Expression of the receptor activator of nuclear factor kappa B ligand (RANKL) in the stromal cells stimulates the monocytes to form giant multi-nucleated osteoclast-like cells, causing bone over-resorption at the tumor site. Previously, our group has reported the up-regulation of RANKL in GCT of bone stromal cells, but the mechanism is unknown. Using stromal cell culture of GCT obtained from patients, we demonstrated the up-regulation of the transcriptional activator CCAAT/enhancer binding protein beta (C/EBPbeta). RANKL promoter studies revealed that C/EBPbeta over-expression induced RANKL promoter activity in a dose-dependent manner and a CCAAT-box within the region nt -357/-1 contributed to the basal transcription activity, with a possible C/EBPbeta binding element in the region nt -460/-358 leading to further induction. Furthermore, we also showed that C/EBPbeta bound to the RANKL promoter in GCT stromal cells in vivo by chromatin immunoprecipitation. To conclude, our study has shown that C/EBPbeta is a RANKL promoter activator in stromal cells of GCT of bone and we have proposed a model in which C/EBPbeta plays an important role in the osteolytic characteristics and pathological causes of GCT of bone.