title: Effects of arsenic on osteoblast differentiation in vitro and on bone mineral density and microstructure in rats.
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.
  
  
  OBJECTIVE
  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.
authors: Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors: Cheng-Tien
authors: CT
authors: Wu
authors: Tung-Ying
authors: TY
authors: Lu
authors: Ding-Cheng
authors: DC
authors: Chan
authors: Keh-Sung
authors: KS
authors: Tsai
authors: Rong-Sen
authors: RS
authors: Yang
authors: Shing-Hwa
authors: SH
authors: Liu
mesh_terms: D000818:Animals; D001151:Arsenic / Q000633:toxicity*; D000077237:Arsenic Trioxide; D001152:Arsenicals; D015519:Bone Density / Q000187:drug effects*; D055396:Bone Morphogenetic Protein 2 / Q000378:metabolism; D001842:Bone and Bones / Q000648:ultrastructure*; D002454:Cell Differentiation / Q000187:drug effects; D050659:Core Binding Factor Alpha 1 Subunit; D060766:Drinking Water / Q000737:chemistry; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015386:Hazardous Substances / Q000633:toxicity*; D008297:Male; D010006:Osteoblasts / Q000187:drug effects*; D010012:Osteogenesis / Q000187:drug effects*; D010087:Oxides / Q000633:toxicity; D051381:Rats
chemical_list: D001152:Arsenicals; D055396:Bone Morphogenetic Protein 2; D050659:Core Binding Factor Alpha 1 Subunit; D060766:Drinking Water; D015386:Hazardous Substances; D010087:Oxides; D048049:Extracellular Signal-Regulated MAP Kinases; D001151:Arsenic; D000077237:Arsenic Trioxide