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Advance Publication

Environ Health Perspect; DOI:10.1289/ehp.1307832

Effects of Arsenic on Osteoblast Differentiation in Vitro and on Bone Mineral Density and Microstructure in Rats

Cheng-Tien Wu,1 Tung-Ying Lu,1 Ding-Cheng Chan,2 Keh-Sung Tsai,3,* Rong-Sen Yang,4,* and Shing-Hwa Liu1,5,*
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1Institute of Toxicology, 2Department of Geriatrics and Gerontology, 3Department of Laboratory Medicine, and4Department of Orthopaedics, College of Medicine, National Taiwan University, Taipei, Taiwan; 5Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan. *These authors contributed equally to this study.
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This EHP Advance Publication article has been peer-reviewed, revised, and accepted for publication. EHP Advance Publication articles are completely citable using the DOI number assigned to the article. This document will be replaced with the copyedited and formatted version as soon as it is available. Through the DOI number used in the citation, you will be able to access this document at each stage of the publication process.

Citation: Wu CT, Lu TY, Chan DC, Tsai KS, Yang RS, Liu SH. Effects of Arsenic on Osteoblast Differentiation in Vitro and on Bone Mineral Density and Microstructure in Rats. Environ Health Perspect; http://dx.doi.org/10.1289/ehp.1307832.

Received: 1 November 2013
Accepted: 11 February 2014
Advance Publication: 14 February 2014

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Background: Arsenic is a ubiquitous toxic element and 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 effect and mechanism of arsenic on osteoblast differentiation in vitro and evaluated the bone mineral density (BMD) and bone microstructure in rats at doses relevant to human exposure from drinking water.

Methods: A cell model of rat primary bone marrow stromal cells (BMSCs) and a rat model of long-term exposure with arsenic-contaminated drinking water were used. The bone microstructure and BMD in rats were determined by micro-computed tomography (μ-CT).

Results: Exposure of BMSCs to arsenic trioxide (0.5 and 1 μM) significantly attenuated the osteoblast differentiation. The expressions of runt-related transcription factor-2 (Runx2), bone morphogenetic protein-2, and osteocalcin in BMSCs were inhibited and the phosphorylation of enhanced extracellular signal-regulated kinase (ERK) was increased by arsenic treatment during differentiation. These changed differentiation-related molecules could be reversed by ERK inhibitor PD98059. Exposure of rats to arsenic trioxide (0.05 and 0.5 ppm) in drinking water for 12 weeks obviously altered BMD and microstructure, decreased Runx2 expression, and increased ERK phosphorylation in bones. In BMSCs isolated from arsenic-treated rats, the osteoblast differentiation was inhibited.

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

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