Effects of ethanol on gene expression in rat bone: transient dose-dependent changes in mRNA levels for matrix proteins, skeletal growth factors, and cytokines are followed by reductions in bone formation.

Effects of ethanol on gene expression in rat bone: transient dose-dependent changes in mRNA levels for matrix proteins, skeletal growth factors, and cytokines are followed by reductions in bone formation.
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乙醇对大鼠骨骼中基因表达的影响:基质蛋白、骨骼生长因子和细胞因子的 mRNA 水平发生短暂的剂量依赖性变化,随后骨形成减少。

DOI:
10.1111/j.1530-0277.1998.tb03953.x
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发表时间:
1998
期刊:
Alcoholism, clinical and experimental research
影响因子:
--
通讯作者:
Sibonga,JD
Sibonga,JD
中科院分区:
--
文献类型:
--
作者:
Turner,RT;Wronski,TJ;Zhang,M;Kidder,LS;Bloomfield,SA;Sibonga,JD

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在雌性大鼠中进行了几项研究,以确定单次给予乙醇后骨中基质蛋白mRNA水平的剂量和时间过程变化。正如预期,测量到血液乙醇的剂量依赖性一过性增加。此外,存在轻度低钙血症,免疫反应性甲状旁腺激素无变化。给予乙醇后6小时,在胫骨近端干骺端观察到1型胶原、骨粘连蛋白和骨钙素的mRNA呈剂量依赖性协同增加,峰值出现在1.2 g/kg(0.4 ml)剂量下。乙醇处理后,腰椎中基质蛋白的mRNA水平也有类似的增加。这些变化是骨特异性的;乙醇对子宫或肝脏中基质蛋白的mRNA水平没有影响,尽管子宫中的mRNA浓度倾向于降低。还测定了参与骨转换调节的几种细胞因子的信使水平;在0.14 - 1.7 g/kg剂量范围内,转化生长因子-β1、转化生长因子-β2、干扰素-γ和白细胞介素-6的mRNA水平未发生变化。在最高剂量的乙醇中,肿瘤坏死因子-α的mRNA水平升高,而胰岛素样生长因子-1的水平降低。在单独的实验中测定乙醇(0.4 ml剂量)的时程效应。乙醇导致所测定的三种骨基质蛋白的mRNA水平瞬时增加。然而,通过将3 H-脯氨酸掺入胫骨近端干骺端测定的基质蛋白合成在6小时后没有变化。基质蛋白mRNA水平的变化之前是白细胞介素-1 β、干扰素-γ和迁移抑制因子mRNA水平的短暂短暂下降,随后是胰岛素样生长因子-1 mRNA水平的更长时间下降。随后进行了一项研究,以确定每日重复乙醇处理对大鼠骨的影响。7天后,1型胶原蛋白的mRNA水平高度显著降低,骨形成减少。这些结果表明,乙醇可能通过干扰调节骨基质蛋白、骨骼生长因子和细胞因子基因表达的信号转导途径来改变骨代谢。
Several studies were performed in female rats to determine dose and time course changes in mRNA levels for matrix proteins in bone after a single administration of ethanol. As expected, dose‐dependent transient increases in blood ethanol were measured. Additionally, there was mild hypocalcemia with no change in immunoreactive parathyroid hormone. Coordinated dose‐dependent increases in mRNA for type 1 collagen, osteonectin, and osteocalcin were noted in the proximal tibial metaphysis 6 hr after ethanol was given, with the peak values occurring at a dose of 1.2 g/kg (0.4 ml). Similar increases in mRNA levels for matrix proteins were noted in lumbar vertebrae after ethanol treatment. The changes were specific for bone; ethanol had no effect on mRNA levels for matrix proteins in the uterus or liver, although the mRNA concentrations tended to be reduced in uterus. Message levels for several cytokines implicated in the regulation of bone turnover were also assayed; mRNA levels for transforming growth factor‐β1, transforming growth factor‐β2, interferon‐γ, and interleukin‐6 were unchanged at doses ranging from 0.14 to 1.7 g/kg. At the highest dose of ethanol, the mRNA level for tumor necrosis factor‐α was elevated while the level for insulin‐like growth factor‐1 was reduced. The time course effects of ethanol (0.4 ml dose) were determined in a separate experiment. Ethanol resulted in a transient increase in mRNA levels for the three bone matrix proteins assayed. However, matrix protein synthesis, as determined by incorporation of3H‐proline into the proximal tibial metaphysis, was not changed after 6 hr. The changes in mRNA levels for the matrix proteins were preceded by brief, transient decreases in mRNA levels for interleukin‐1 β, interferon‐γ, and migration inhibitory factor, and followed by a more prolonged decrease in the mRNA level for insulin‐like growth factor‐1. A subsequent study was performed to determine the effects of repetitive daily treatment with ethanol on rat bone. After 7 days, there were highly significant decreases in the mRNA level for type 1 collagen, as well as decreased bone formation. These results suggest that ethanol may alter bone metabolism by disturbing signal transduction pathways that regulate the expression of genes for bone matrix proteins, skeletal growth factors, and cytokines.
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