2007 Fiscal Year Final Research Report Summary
Elucidation of the mechanism of glucocorticoid-induced osteoporosis by suppression of Wnt signaling pathway and the development of prediction method at its preclinical stage
| Project/Area Number |
17390272
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Endocrinology
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| Research Institution | Kyushu University |
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Principal Investigator |
TAKAYANAGI Ryoichi Kyushu University, Graduate School of Medical Sciences, Professor (30154917)
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| Co-Investigator(Kenkyū-buntansha) |
OHNAKA Keizo Kyushu University, Graduate School of Medical Sciences, Associate Professor (30325518)
KAWATE Hisaya Kyushu University, Hspital, Assistant Professor (20336027)
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| Project Period (FY) |
2005 – 2007
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| Keywords | Wnt / LRP5 / glucocorticoid / glucocorticoid-induced osteoporosis / dexamethasone / β-catenin / Dickkopf-1 / sFRP-1 |
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| Research Abstract |
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.
We further examine whether the gene of secreted frizzled-related protein 1 (SFRP1), a Wnt antagonist, is involved in
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the etiology of osteoporosis using association study. Seven single nucleotide polymorphisms (SNPs) in the SFRP1 gene were genotyped and analyzed for association with bone mineral density (BMD) in 931 Japanese women. One SNP (rs16890444) located in intron and another (rs3242) located in the 3' untranslated region of the sFRP1 gene were significantly associated with the lumbar spine BMD value, and BMD values for both the femoral neck and the total hip, respectively. Women with the T/T genotype of the former SNP had a lower BMD value of the lumbar spine (L2-L4) compared with those with C/C or C/T (BMD value adjusted for age, duration after menopause, and body mass index, while women with the T/T genotype of the latter SNP had higher BMD values of femoral neck and total hip compared with those with C/C or C/T.
These data suggest that glucocorticoid suppresses the canonical Wnt signal in cultured human osteoblasts, partially through the enhancement of the dickkopf-1 production and that the SFRP1 may be a candidate gene for a BMD determinant. Less
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Research Products
(34 results)
