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.

Chronic Inflammation in Cancer Development

“…In head and neck squamous cell carcinoma RANKL expression promotes EMT and tumor progression by inducing VEGF-independent angiogenesis (Yamada et al, 2011). Moreover, the activity of RANKL was found to be involved in the pathophysiology of osteosarcoma (Mori et al, 2007a,b), giant cell tumors of the bone (Ng et al, 2010), Paget’s sarcomas (Sun et al, 2006), and vascular diseases (Hofbauer and Schoppet, 2004). The expression of RANKL increases in response to pro-inflammatory mediators, such as IL-1 (Fernandez et al, 2010; Jurado et al, 2010).…”

CCAAT/enhancer-binding protein β promotes receptor activator of nuclear factor-kappa-B ligand (RANKL) expression and osteoclast formation in the synovium in rheumatoid arthritis

“…C/EBPβ and RANKL are upregulated in GCT. C/EBPβ induces RANKL promoter activity in GCT stromal cells, which causes osteolysis [12]. In inflammatory chronic diseases such as RA, C/EBPβ is strongly induced in response to inflammatory stimulation.…”

Gene transfection in primary stem-like cells of giant cell tumor of bone

“…Although Ng et al studied the receptor activator of the nuclear factor kappa B ligand (RANKL) promoter region in GCT stromal cells, all transfection assays in that study were performed on an osteosarcoma cell line 20. Here we report transfer of the gene for TWIST, a basic helix-loop-helix (bHLH) transcription factor implicated in the cell lineage of the GCT stem-like stromal cells, which is the first report to date of successful gene transfer of these cells.…”