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Glucocorticoid osteoporosis is a serious side effect of long term glucocorticoid uptake and it is caused by osteoblast apoptosis and imbalance in the major bone remodeling pathway RANK/RANKL/OPG. The impact of glucocorticoid on the maintenance of RANK/RANKL/OPG is well explored; dexamethasone was shown to disturb the ratio between  OPG  and  RANKL  level by decreasing the expression level of  OPG  and increasing level of  RANKL . Here, were aimed to decipher whether glucocorticoid receptor directly influences  RANKL  promoter activity and its transcriptional regulation. We demonstrate that overexpression of glucocorticoid receptor (GR) NR3C1 increased  RANKL  promoter activity in human osteosarcoma, cervical cancer (2-fold) and adenocarcinoma cells (4.5-fold). Mutational analysis revealed that +352 site in the  RANKL  promoter is functional glucocorticoid responsive element (GRE) since the effect of GR on  RANKL  promoter activity was diminished by mutation at this site. Overexpression of  NR3C1  upregulated  RANKL  mRNA expression 1.5-fold in human A549 and HOS cells. On the other hand silencing of  NR3C1  caused slight decrease in  RANKL  mRNA level, suggesting that NR3C1 directly accounts for  RANKL  transcriptional regulation. Using electrophoretic mobility shift assay we demonstrate that NR3C1 binds to the proximal  RANKL  promoter region. Our study provides evidences that NR3C1 directly upregulates  RANKL  transcription in human cell lines and connects the missing link in the mechanism of RANK/RANKL/OPG imbalance of glucocorticoid induced osteoporosis.

Glucocorticoid Receptor Regulates TNFSF11 Transcription by Binding to Glucocorticoid Responsive Element in TNFSF11 Proximal Promoter Region