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 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.
Ohnaka
Keizo
K
Department of Geriatric Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. oonaka@geriat.med.kyushu-u.ac.jp
Taniguchi
Hiroshi
H
Kawate
Hisaya
H
Nawata
Hajime
H
Takayanagi
Ryoichi
R
D002478:Cells, Cultured; D003907:Dexamethasone / Q000494:pharmacology; D005270:Femur Head / Q000166:cytology; D005938:Glucocorticoids / Q000009:adverse effects / Q000494:pharmacology*; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008565:Membrane Proteins / Q000096:biosynthesis; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010024:Osteoporosis / Q000139:chemically induced* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D011956:Receptors, Cell Surface; D011973:Receptors, LDL / Q000096:biosynthesis; D015533:Transcriptional Activation
C501126:DKK1 protein, human; D005938:Glucocorticoids; D006728:Hormones; D036341:Intercellular Signaling Peptides and Proteins; C486075:KREMEN1 protein, human; C486076:KREMEN2 protein, human; D026502:LDL-Receptor Related Proteins; C555482:LRP5 protein, human; D060492:Low Density Lipoprotein Receptor-Related Protein-5; D008565:Membrane Proteins; D011506:Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D011973:Receptors, LDL; D003907:Dexamethasone