A role for ethanol-induced oxidative stress in controlling lineage commitment of mesenchymal stromal cells through inhibition of Wnt/beta-catenin signaling.
A role for ethanol-induced oxidative stress in controlling lineage commitment of mesenchymal stromal cells through inhibition of Wnt/beta-catenin signaling.
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DOI：
10.1002/jbmr.7
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发表时间：
2010-05
影响因子：
6.2
通讯作者：
Ronis, Martin J.
中科院分区：
文献类型：
--
作者：
Chen, Jin-Ran;Lazarenko, Oxana P.;Shankar, Kartik;Blackburn, Michael L.;Badger, Thomas M.;Ronis, Martin J.
长期摄入乙醇导致骨质丢失的机制尚不清楚。在女性中，骨骼对乙醇的反应取决于生理状态(例如，骑自行车、怀孕或哺乳期)。乙醇诱导的氧化应激似乎是导致骨骼毒性的关键事件。在本研究中，以含乙醇的液体饲料喂养哺乳后雌性SD大鼠，从断奶开始，连续4周。在哺乳结束后的骨重建期间，与对照组相比，酒精摄入降低了骨密度(BMD)。联合应用抗氧化剂N-乙酰半胱氨酸(NAC)可阻止骨丢失，下调骨形成标志物碱性磷酸酶和骨钙素的表达及骨组织中的基因表达。从骨组织中提取的总RNA的实时阵列分析显示，大多数Wnt信号成分在慢性乙醇注射后下调。实时定量聚合酶链式反应证实，乙醇下调了Wnt信号元件的一个子集的基因表达。然而，Wnt拮抗剂Dkk1被乙醇上调。关键的Wnt信号分子β-连环蛋白在骨和成骨细胞中的表达受到抑制，而糖原合成酶-3-β被乙醇去磷酸化。乙醇的上述作用可被NAC阻断。乙醇处理使成骨细胞Tcf/Lef基因转录失活，消除成骨细胞β-catenin核转位，从而抑制成骨细胞的生成，促进脂肪生成。NAC可消除乙醇对骨髓间充质干细胞向祖细胞定向分化的影响。这些观察结果与乙醇通过刺激氧化应激抑制Wnt信号从而抑制骨形成的假设是一致的。©2010美国骨与矿物研究学会。
The mechanisms by which chronic ethanol intake induces bone loss remain unclear. In females, the skeletal response to ethanol varies depending on physiologic status (e.g., cycling, pregnancy, or lactation). Ethanol-induced oxidative stress appears to be a key event leading to skeletal toxicity. In this study, ethanol-containing liquid diets were fed to postlactational female Sprague-Dawley rats intragastrically for 4 weeks beginning at weaning. Ethanol consumption decreased bone mineral density (BMD) compared with control animals during this period of bone rebuilding following the end of lactation. Coadministration of the antioxidant N-acetylcysteine (NAC) was able to block bone loss and downregulation of the bone-formation markers alkaline phosphatase and osteocalcin in serum and gene expression in bone. Real-time array analysis of total RNA isolated from bone tissue revealed that the majority of Wnt signaling components were downregulated by chronic ethanol infusion. Real-time PCR confirmed downregulated gene expression in a subset of the Wnt signaling components by ethanol. However, the Wnt antagonist DKK1 was upregulated by ethanol. The key canonical Wnt signaling molecule β-catenin protein expression was inhibited, while glycogen synthase kinase-3-β was dephosphorylated by ethanol in bone and preosteoblastic cells. These actions of ethanol were blocked by NAC. Ethanol treatment inactivated TCF/LEF gene transcription, eliminated β-catenin nuclear translocation in osteoblasts, and reciprocally suppressed osteoblastogenesis and enhanced adipogenesis. These effects of ethanol on lineage commitment of mesenchymal stem cells were eliminated by NAC pretreatment. These observations are consistent with the hypothesis that ethanol inhibits bone formation through stimulation of oxidative stress to suppress Wnt signaling. © 2010 American Society for Bone and Mineral Research.
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影响因子：
6.2
作者：
Bowman, BM;Siska, CC;Miller, SC
通讯作者：
Miller, SC
影响因子：
4.8
作者：
Gustafson, B;Smith, U
通讯作者：
Smith, U
影响因子：
15.9
作者：
Lean, JM;Davies, JT;Chambers, TJ
通讯作者：
Chambers, TJ
影响因子：
4
作者：
Maddalozzo, G. F.;Turner, R. T.;Iwaniec, U. T.
通讯作者：
Iwaniec, U. T.
DOI：
10.1359/jbmr.081011
发表时间：
2009-02
期刊：
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
影响因子：
--
作者：
Chen JR;Lazarenko OP;Haley RL;Blackburn ML;Badger TM;Ronis MJ
通讯作者：
Ronis MJ