TY - JOUR
T1 - Glucocorticoid enhances the expression of dickkopf-1 in human osteoblasts
T2 - Novel mechanism of glucocorticoid-induced osteoporosis
AU - Ohnaka, Keizo
AU - Taniguchi, Hiroshi
AU - Kawate, Hisaya
AU - Nawata, Hajime
AU - Takayanagi, Ryoichi
N1 - Funding Information:
This work was supported in part by a Grant-in-Aid for Scientific Research (B) and the grant for the 21st Century COE Program from the Japanese Ministry of Education, Culture, Sports, Science and Technology.
PY - 2004/5/21
Y1 - 2004/5/21
N2 - 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 Wnt 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 Kremen1, a receptor for Dkk, did not change by the treatment with dexamethasone, while that of low-density lipoprotein receptor-related protein 5 (LRP5), a Wnt 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 -774bp is essential for the enhancement of the Dkk-1 promoter activity by dexamethasone in human osteoblasts. Since the Wnt signal is now recognized as a crucial regulator for bone formation, the Dkk-1 enhanced by glucocorticoid may inhibit the Wnt signal in osteoblasts, which may be involved in the pathogenesis of glucocorticoid-induced osteoporosis.
AB - 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 Wnt 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 Kremen1, a receptor for Dkk, did not change by the treatment with dexamethasone, while that of low-density lipoprotein receptor-related protein 5 (LRP5), a Wnt 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 -774bp is essential for the enhancement of the Dkk-1 promoter activity by dexamethasone in human osteoblasts. Since the Wnt signal is now recognized as a crucial regulator for bone formation, the Dkk-1 enhanced by glucocorticoid may inhibit the Wnt signal in osteoblasts, which may be involved in the pathogenesis of glucocorticoid-induced osteoporosis.
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U2 - 10.1016/j.bbrc.2004.04.025
DO - 10.1016/j.bbrc.2004.04.025
M3 - Article
C2 - 15110782
AN - SCOPUS:1942424854
SN - 0006-291X
VL - 318
SP - 259
EP - 264
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 1
ER -