CCAAT/enhancer binding protein beta is up-regulated in giant cell tumor of bone and regulates RANKL expression.
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.
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR.
Patrick Kwok-Shing
PK
Ng
Stephen Kwok-Wing
SK
Tsui
Carol Po-Ying
CP
Lau
Chi-Hang
CH
Wong
Winnie Hiu-Ting
WH
Wong
Lin
L
Huang
Shekhar-Madhukar
SM
Kumta
D001483:Base Sequence; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers; D005786:Gene Expression Regulation; D018212:Giant Cell Tumor of Bone / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008969:Molecular Sequence Data; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D053245:RANK Ligand / Q000235:genetics*; D017154:Stromal Cells / Q000378:metabolism; D015854:Up-Regulation
D022782:CCAAT-Enhancer-Binding Protein-beta; C545012:CEBPB protein, human; D017931:DNA Primers; D053245:RANK Ligand; C505688:TNFSF11 protein, human