Glucocorticoid suppresses the canonical Wnt signal in cultured human osteoblasts.
To explore the mechanism of glucocorticoid-induced osteoporosis, we investigated the effect of glucocorticoid on canonical Wnt signaling that emerged as a novel key pathway for promoting bone formation. Wnt3a increased the T-cell factor (Tcf)/lymphoid enhancer factor (Lef)-dependent transcriptional activity in primary cultured human osteoblasts. Dexamethasone suppressed this transcriptional activity in a dose-dependent manner, while 1,25-dihydroxyvitamin D3 increased this transcriptional activity. LiCl, an inhibitor of glycogen synthase kinase-3beta, also enhanced the Tcf/Lef-dependent transcriptional activity, which was, however, not inhibited by dexamethasone. The addition of anti-dickkopf-1 antibody partially restored the transcriptional activity suppressed by dexamethasone. Dexamethasone decreased the cytosolic amount of beta-catenin accumulated by Wnt3a and also inhibited the nuclear translocation of beta-catenin induced by Wnt3a. These data suggest that glucocorticoid suppresses the canonical Wnt signal in cultured human osteoblasts, partially through the enhancement of the dickkopf-1 production.
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
Tanabe
Mizuho
M
Kawate
Hisaya
H
Nawata
Hajime
H
Takayanagi
Ryoichi
R
D021581:Active Transport, Cell Nucleus; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D002117:Calcitriol / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000378:metabolism; D005938:Glucocorticoids / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D018021:Lithium Chloride / Q000494:pharmacology; D018613:Microscopy, Confocal; D010006:Osteoblasts / Q000378:metabolism*; D010024:Osteoporosis; D010957:Plasmids / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014162:Transfection; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein
D000276:Adjuvants, Immunologic; C501126:DKK1 protein, human; D005938:Glucocorticoids; D036341:Intercellular Signaling Peptides and Proteins; D011506:Proteins; C555510:WNT3A protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D049452:Green Fluorescent Proteins; D003907:Dexamethasone; D002117:Calcitriol; D018021:Lithium Chloride