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Elucidation of the mechanism of glucocorticoid-induced osteoporosis by suppression of Wnt signaling pathway and the development of prediction method at its preclinical stage

阐明糖皮质激素通过抑制Wnt信号通路诱发骨质疏松的机制并开发临床前阶段的预测方法

基本信息

批准号：
17390272
负责人：
TAKAYANAGI Ryoichi
金额：
$ 10.16万
依托单位：
Kyushu University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2007
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390272/
关键词：
Wnt LRP5 glucocorticoid glucocorticoid-induced osteoporosis dexamethasone β-catenin Dickkopf-1 sFRP-1 LLRP5 Tcf Lef

项目摘要

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 … More 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

我们研究了糖皮质激素对经典Wnt信号传导的影响，该信号传导成为促进骨形成的一种新的关键途径。Wnt 3a增加了原代培养的人成骨细胞中T细胞因子（Tcf）/淋巴增强因子（Lef）依赖的转录活性。地塞米松以剂量依赖性方式抑制这种转录活性，而1，25-二羟维生素D3增加这种转录活性。LiCl，糖原合成酶激酶-3 β的抑制剂，也增强Tcf/Lef-dependent转录活性，这是，然而，不受地塞米松抑制。抗dickkopf-1抗体的加入部分恢复了地塞米松抑制的转录活性。地塞米松可降低Wnt 3a诱导的β-catenin在胞浆中的积累，并抑制Wnt 3a诱导的β-catenin的核转位。我们进一步研究了Wnt拮抗剂分泌型卷曲相关蛋白1（SFRP 1）基因是否参与了Wnt 3a诱导的β-catenin核转位。 ...更多信息骨质疏松症的病因学研究。在931名日本女性中，对SFRP 1基因的7个单核苷酸多态性（SNPs）进行基因分型，并分析其与骨密度（BMD）的相关性。位于sFRP 1基因内含子的一个SNP（rs 16890444）和位于3'非翻译区的另一个SNP（rs3242）分别与腰椎BMD值、股骨颈和全髋BMD值显著相关。与C/C或C/T基因型的妇女相比，具有前一种SNP的T/T基因型的妇女腰椎（L2-L4）的BMD值较低（根据年龄、绝经后持续时间和体重指数调整的BMD值，后一种SNP的T/T基因型妇女股骨颈和全髋骨密度值高于C/C或C/T基因型妇女。这些数据表明，糖皮质激素抑制典型的Wnt信号在培养的人成骨细胞，部分通过增强dickkopf-1的生产和SFRP 1可能是一个候选基因的BMD决定因素。少