酒精和 ICI 182,780（雌激素受体阻滞剂）对去卵巢大鼠骨的影响。
Effects of Alcohol and Estrogen Receptor Blockade Using ICI 182,780 on Bone in Ovariectomized Rats.
机构信息
Skeletal Biology Laboratory, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon.
Biostatistics Program, School of Biological and Population Health Sciences, Oregon State University, Corvallis, Oregon.
出版信息
Alcohol Clin Exp Res. 2019 Nov;43(11):2301-2311. doi: 10.1111/acer.14185. Epub 2019 Sep 17.
BACKGROUND
Estrogen signaling is essential for the sexual dimorphism of the skeleton, is required for normal bone remodeling balance in adults, and may influence the skeletal response to alcohol. High levels of alcohol consumption lower bone mass in ovary-intact but not ovariectomized (ovx) rats. However, the extremely rapid rate of bone loss immediately following ovx may obscure the effects of alcohol. We therefore determined (i) whether heavy alcohol consumption (35% caloric intake) influences bone in sexually mature ovx rats with established cancellous osteopenia and (ii) whether ICI 182,780 (ICI), a potent estrogen receptor signaling antagonist, alters the skeletal response to alcohol.
METHODS
Three weeks following ovx, rats were randomized into 5 groups, (i) baseline, (ii) control + vehicle, (iii) control + ICI, (iv) ethanol (EtOH) + vehicle, or (v) EtOH + ICI, and treated accordingly for 4 weeks. Dual-energy X-ray absorptiometry, microcomputed tomography, blood measurements of markers of bone turnover, and gene expression in femur and uterus were used to evaluate response to alcohol and ICI.
RESULTS
Rats consuming alcohol had lower bone mass and increased fat mass. Bone microarchitecture of the tibia and gene expression in femur were altered; specifically, there was reduced accrual of cortical bone, net loss of cancellous bone, and differential expression of 19/84 genes related to bone turnover. Furthermore, osteocalcin, a marker of bone turnover, was lower in alcohol-fed rats. ICI had no effect on weight gain, body composition, or cortical bone. ICI reduced cancellous bone loss and serum CTX-1, a biochemical marker of bone resorption; alcohol antagonized the latter 2 responses. Neither alcohol nor ICI affected uterine weight or gene expression.
CONCLUSIONS
Alcohol exaggerated bone loss in ovx rats in the presence or absence of estrogen receptor blockade with ICI. The negligible effect of alcohol on uterus and limited effects of ICI on bone in alcohol-fed ovx rats suggest that estrogen receptor signaling plays a limited role in the action of alcohol on bone in a rat model for chronic alcohol abuse.
背景
雌激素信号对于骨骼的性别二态性至关重要，是成人正常骨重塑平衡所必需的，并且可能影响骨骼对酒精的反应。大量饮酒会降低卵巢完整但未卵巢切除（ovx）大鼠的骨量。然而，ovx 后立即发生的骨丢失速度极快，可能会掩盖酒精的作用。因此，我们确定了（i）是否大量饮酒（35%的热量摄入）会影响已患有松质骨骨质疏松症的性成熟 ovx 大鼠的骨骼，以及（ii）ICI 182,780（ICI），一种有效的雌激素受体信号拮抗剂，是否会改变骨骼对酒精的反应。
方法
ovx 后 3 周，大鼠随机分为 5 组，（i）基线，（ii）对照+载体，（iii）对照+ICI，（iv）乙醇（EtOH）+载体，或（v）EtOH+ICI，并相应治疗 4 周。双能 X 射线吸收法、微计算机断层扫描、血液骨转换标志物测量以及股骨和子宫的基因表达用于评估对酒精和 ICI 的反应。
结果
饮酒的大鼠骨量较低，脂肪量增加。胫骨的骨微结构和股骨的基因表达发生改变；具体而言，皮质骨的积累减少，松质骨的净丢失，以及与骨转换相关的 19/84 个基因的表达差异。此外，骨钙素是骨转换的标志物，在饮酒大鼠中较低。ICI 对体重增加、身体成分或皮质骨没有影响。ICI 减少了松质骨丢失和血清 CTX-1，一种骨吸收的生化标志物；酒精拮抗了后两种反应。酒精或 ICI 均未影响子宫重量或基因表达。
结论
在存在或不存在雌激素受体阻断剂 ICI 的情况下，酒精加剧了 ovx 大鼠的骨丢失。酒精对子宫的影响微不足道，ICI 对饮酒 ovx 大鼠骨骼的影响有限，这表明雌激素受体信号在慢性酒精滥用大鼠模型中对酒精对骨骼的作用的作用有限。
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