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砷对体外成骨细胞分化以及对大鼠骨密度和微观结构的影响。

Effects of arsenic on osteoblast differentiation in vitro and on bone mineral density and microstructure in rats.

作者信息

Wu Cheng-Tien, Lu Tung-Ying, Chan Ding-Cheng, Tsai Keh-Sung, Yang Rong-Sen, Liu Shing-Hwa

机构信息

Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.

出版信息

Environ Health Perspect. 2014 Jun;122(6):559-65. doi: 10.1289/ehp.1307832. Epub 2014 Feb 14.

DOI:10.1289/ehp.1307832
PMID:24531206
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4050517/
Abstract

BACKGROUND

Arsenic is a ubiquitous toxic element and is known to contaminate drinking water in many countries. Several epidemiological studies have shown that arsenic exposure augments the risk of bone disorders. However, the detailed effect and mechanism of inorganic arsenic on osteoblast differentiation of bone marrow stromal cells and bone loss still remain unclear.

OBJECTIVES

We investigated the effects and mechanism of arsenic on osteoblast differentiation in vitro and evaluated bone mineral density (BMD) and bone microstructure in rats at doses relevant to human exposure from drinking water.

METHODS

We used a cell model of rat primary bone marrow stromal cells (BMSCs) and a rat model of long-term exposure with arsenic-contaminated drinking water, and determined bone microstructure and BMD in rats by microcomputed tomography (μCT).

RESULTS

We observed significant attenuation of osteoblast differentiation after exposure of BMSCs to arsenic trioxide (0.5 or 1 μM). After arsenic treatment during differentiation, expression of runt-related transcription factor-2 (Runx2), bone morphogenetic protein-2 (BMP-2), and osteocalcin in BMSCs was inhibited and phosphorylation of enhanced extracellular signal-regulated kinase (ERK) was increased. These altered differentiation-related molecules could be reversed by the ERK inhibitor PD98059. Exposure of rats to arsenic trioxide (0.05 or 0.5 ppm) in drinking water for 12 weeks altered BMD and microstructure, decreased Runx2 expression, and increased ERK phosphorylation in bones. In BMSCs isolated from arsenic-treated rats, osteoblast differentiation was inhibited.

CONCLUSIONS

Our results suggest that arsenic is capable of inhibiting osteoblast differentiation of BMSCs via an ERK-dependent signaling pathway and thus increasing bone loss.

摘要

背景

砷是一种普遍存在的有毒元素，已知在许多国家会污染饮用水。多项流行病学研究表明，砷暴露会增加骨骼疾病的风险。然而，无机砷对骨髓基质细胞成骨细胞分化和骨质流失的具体作用及机制仍不清楚。

目的

我们研究了砷对体外成骨细胞分化的影响及机制，并评估了与人类饮用水暴露剂量相关的大鼠骨密度（BMD）和骨微结构。

方法

我们使用大鼠原代骨髓基质细胞（BMSCs）的细胞模型和长期饮用含砷污染水的大鼠模型，并通过微型计算机断层扫描（μCT）测定大鼠的骨微结构和BMD。

结果

我们观察到BMSCs暴露于三氧化二砷（0.5或1μM）后成骨细胞分化显著减弱。在分化过程中进行砷处理后，BMSCs中与 runt 相关的转录因子-2（Runx2）、骨形态发生蛋白-2（BMP-2）和骨钙素的表达受到抑制，而细胞外信号调节激酶（ERK）的磷酸化增加。这些与分化相关的分子变化可被 ERK 抑制剂 PD98059 逆转。大鼠饮用含三氧化二砷（0.05或0.5 ppm）的水12周后，骨密度和微结构发生改变，Runx2表达降低，骨骼中ERK磷酸化增加。在从砷处理大鼠分离的BMSCs中，成骨细胞分化受到抑制。

结论

我们的结果表明，砷能够通过ERK依赖的信号通路抑制BMSCs的成骨细胞分化，从而增加骨质流失。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2877/4050517/a7130acb806b/ehp.1307832.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2877/4050517/ca0c82231967/ehp.1307832.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2877/4050517/4e23ec181ce1/ehp.1307832.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2877/4050517/4bdd6b46f0d3/ehp.1307832.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2877/4050517/795918d2aec2/ehp.1307832.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2877/4050517/d79655f5d3e0/ehp.1307832.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2877/4050517/51177d67987c/ehp.1307832.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2877/4050517/a7130acb806b/ehp.1307832.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2877/4050517/ca0c82231967/ehp.1307832.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2877/4050517/4e23ec181ce1/ehp.1307832.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2877/4050517/4bdd6b46f0d3/ehp.1307832.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2877/4050517/795918d2aec2/ehp.1307832.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2877/4050517/d79655f5d3e0/ehp.1307832.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2877/4050517/51177d67987c/ehp.1307832.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2877/4050517/a7130acb806b/ehp.1307832.g007.jpg

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