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.
Ng
Patrick Kwok-Shing
PK
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR.
Tsui
Stephen Kwok-Wing
SK
Lau
Carol Po-Ying
CP
Wong
Chi-Hang
CH
Wong
Winnie Hiu-Ting
WH
Huang
Lin
L
Kumta
Shekhar-Madhukar
SM
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