Glucocorticoid enhances the expression of dickkopf-1 in human osteoblasts: novel mechanism of glucocorticoid-induced osteoporosis

To clarify the underlying mechanism of glucocorticoid-induced osteoporosis, we investigated the effect of glucocorticoid on the expression of dickkopf-1 (Dkk-1), an antagonist of Writ signaling, in primary cultured human osteoblasts. Dexamethasone markedly induced the expression of mRNA for Dkk-1 in a dose- and time-dependent manner. The expression of Kremen], a receptor for Dkk, did not change by the treatment with dexamethasone, while that of low-density lipoprotein receptor-related protein 5 (LRP5), a Writ coreceptor, slightly decreased by the treatment with dexamethasone. Dexamethasone increased the transcriptional activity of the Dkk-1 gene promoter in human osteoblasts. Serial deletion and mutation analyses of the Dkk-1 promoter showed that one putative glucocorticoid responsive element-like sequence located from -788 to -774 bp is essential for the enhancement of the Dkk-1 promoter activity by dexamethasone in human osteoblasts. Since the Writ signal is now recognized as a crucial regulator for bone formation, the Dkk-1 enhanced by glucocorticoid may inhibit the Writ signal in osteoblasts, which may be involved in the pathogenesis of glucocorticoid-induced osteoporosis. (C) 2004 Elsevier Inc. All rights reserved.