Binge alcohol-induced bone damage is accompanied by differential expression of bone remodeling-related genes in rat vertebral bone.
Binge alcohol-induced bone damage is accompanied by differential expression of bone remodeling-related genes in rat vertebral bone.
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DOI：
10.1007/s00223-009-9240-z
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发表时间：
2009-06
影响因子：
4.2
通讯作者：
Brownson, Kirstyn
中科院分区：
文献类型：
--
作者：
Callaci, John J.;Himes, Ryan;Lauing, Kristen;Wezeman, Frederick H.;Brownson, Kirstyn
同时服用双膦酸盐可以预防与酗酒相关的骨损伤，这表明酒精暴露会激活骨吸收。尽管已知长期酗酒会导致骨质减少，但人们对酗酒对骨代谢的影响知之甚少。我们研究了酗酒对骨损伤和骨重塑特异性基因表达谱调节之间关系的影响。我们的假设是，在年轻成年大鼠中观察到的酗酒后的骨损伤与骨重塑相关基因表达的差异表达有关。我们进一步假设这种特定于骨重塑（骨吸收或形成相关）的差异基因表达将受到酗酒持续时间的影响。每周连续 3 天向成年雄性大鼠施用狂饮酒精（3 g/kg，腹腔注射），持续 1 或 4 周。匹配的对照动物注射等体积的等渗盐水。通过定量计算机断层扫描和抗压强度分析，分析腰椎 L4-5 是否存在骨损伤。从相邻椎骨 (L3) 中分离总 RNA，并获得每个样本的全转录组基因表达数据。通过定量逆转录酶-聚合酶链反应验证了骨形成和骨吸收相关差异表达基因子集的表达水平。治疗 1 周后未观察到骨质流失，但在四个酗酒周期后观察到骨质流失，与对照值相比，松质骨矿物质密度下降 23%，椎体抗压强度下降 17%（P < 0.05）。我们观察到，酗酒治疗的持续时间影响了调节骨形成过程的基因表达谱的调节。急性酗酒后骨形成相关关键标志基因如骨钙素和碱性磷酸酶的表达显着降低（P < 0.05），成骨细胞活性调节因子如骨形态发生蛋白和甲状旁腺激素受体的表达差异表达显着降低（P < 0.05）。硬化蛋白（一种关键的经典 Wnt 抑制蛋白）的表达在急性酗酒治疗后显着增加。酗酒使椎骨中破骨细胞成熟和活性的重要调节因子如NF-κβ（核因子κβ）配体（RANKL）和白细胞介素6的表达显着增加（P < 0.05），而骨保护素水平显着降低（P < 0.05）。这些结果表明，几个关键骨重塑基因的表达模式受到酗酒治疗的显着干扰，这表明与骨重塑相关的基因表达的扰动可能是导致啮齿类动物酗酒后观察到的骨量稳态破坏和随后观察到的骨质流失的一种机制。
Binge alcohol-related bone damage is prevented by concurrent administration of bisphosphonates, suggesting an activation of bone resorption with patterned alcohol exposure. Although chronic alcohol abuse is known to cause osteopenia, little is known about the effects of binge drinking on bone metabolism. We examined the effects of binge alcohol exposure on the relationship between bone damage and modulation of bone remodeling-specific gene expression profiles. Our hypothesis was that bone damage observed in young adult rats after binge alcohol exposure is associated with differential expression of bone remodeling-related gene expression. We further hypothesized that this differential gene expression specific to bone remodeling (bone resorption or formation related) would be influenced by the duration of binge alcohol exposure. Binge alcohol (3 g/kg, i.p.) was administered on 3 consecutive days each week, for 1 or 4 weeks, to adult male rats. Matched control animals were injected with an equal volume of isotonic saline. Lumbar vertebrae, L4-5, were analyzed for the presence of bone damage by quantitative computed tomography and compressive strength analysis. Total RNA was isolated from an adjacent vertebrae (L3), and whole transcriptome gene expression data were obtained for each sample. The expression levels of a subset of bone formation and resorption-associated differentially expressed genes were validated by quantitative reverse transcriptase–polymerase chain reaction. Bone loss was not observed after 1 week of treatment but was observed after four binge alcohol cycles with a 23% decrease in cancellous bone mineral density and 17% decrease in vertebral compressive strength compared with control values (P < 0.05). We observed that the duration of binge alcohol treatment influenced the modulation of expression profiles for genes that regulate the bone formation process. The expression of key bone formation-related marker genes such as osteocalcin and alkaline phosphatase were significantly reduced (P < 0.05) after acute binge alcohol exposure, and expression of regulators of osteoblast activity such as bone morphogenetic proteins and parathyroid hormone receptor displayed significantly (P < 0.05) decreased differential expression. The expression of sclerostin, a key canonical Wnt inhibitory protein, was significantly increased after acute binge alcohol treatment. The expression of important regulators of osteoclast maturation and activity such as NF-κβ (nuclear factor κβ) ligand (RANKL) and interleukin-6 were significantly increased (P < 0.05) by binge alcohol, and osteoprotegerin levels were significantly decreased (P < 0.05) in vertebral bone. These results show that expression patterns of several key bone remodeling genes are significantly perturbed by binge alcohol treatment, suggesting that perturbation of gene expression associated with bone remodeling may be one mechanism contributing to the disruption of bone mass homeostasis and subsequent bone loss observed after binge alcohol exposure in rodents.
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DOI：
10.1084/jem.20031454
发表时间：
2004-03-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
van Bezooijen RL;Roelen BA;Visser A;van der Wee-Pals L;de Wilt E;Karperien M;Hamersma H;Papapoulos SE;ten Dijke P;Löwik CW
通讯作者：
Löwik CW
影响因子：
2.3
作者：
Wezeman, FH;Juknelis, D;Callaci, JJ
通讯作者：
Callaci, JJ
影响因子：
64.5
作者：
Gong, YQ;Slee, RB;Warman, ML
通讯作者：
Warman, ML
影响因子：
2.8
作者：
PREEDY, VR;SHERWOOD, RA;BLACK, D
通讯作者：
BLACK, D
DOI：
10.1097/00000374-200011000-00012
发表时间：
2000-11-01
影响因子：
3.2
作者：
Turner, RT
通讯作者：
Turner, RT