Endocrine Abstracts

Glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis. Glucocorticoid is known to cause hyperparathyroidism due to parathyroid hormone (PTH) secretion. In addition, glucocorticoid and PTH have also been reported to induce RANKL mRNA expression in osteoblasts and promote osteoclastogenesis. However, little is known about cooperative effects of these hormones. The purpose of this study was to clarify the regulation of RANKL mRNA expression by glucocorticoid and PTH in osteoblasts. We used normal osteoblasts and osteoblast-like cell line MG-63. Quantitative real-time RT-PCR revealed that dexamethasone (DEX) and PTH significantly increased RANKL mRNA expression (15-fold, P<0.05) for a time-dependent manner. In addition, PTH additively up-regulated DEX-induced RANKL mRNA expression. Moreover, we found that DEX did not influence RANKL transcriptional activity by reporter gene assay using human RANKL promoter. Furthermore, treatment with actinomycin D and DEX markedly prolonged the half-life of RANKL mRNA, as compared to treatment with actinomycin D alone (T1/2=over 24 h vs 10 h), presumably indicating that DEX-induced RANKL mRNA expression is due to the stabilization of RANKL mRNA. In contrast, PTH clearly induced RANKL transactivation and did not influence the stabilization of RANKL mRNA, suggesting that PTH regulates RANKL mRNA expression mainly via RANKL gene transcriptional activation. In conclusion, we showed that RANKL mRNA expression was cooperatively up-regulated by PTH via RANKL transcriptional activation and by glucocorticoid via the stabilization of RANKL mRNA. Thus, glucocorticoid clinically regulates RANKL mRNA expression, at least in part, through two different mechanisms, because glucocorticoid prolongs the half-life of RANKL mRNA directly and activates RANKL gene transcription via glucocorticoid-induced PTH secretion indirectly.