title: Arsenic trioxide affects bone remodeling by effects on osteoblast differentiation and function.
abstract: Arsenic trioxide (ATO) is widely used in tumor treatment, but excessive arsenic exposure can have adverse health effects. This study was to examine the association between ATO treatment and bone remodeling. The effects of ATO on osteoblast function were investigated in primary cell cultures and in an in vivo study in rats. Sprague-Dawley rats (n=30) were randomly assigned to 3 groups which were injected intraperitoneally with saline or 5 or 10 mg/kg of ATO for 4 weeks. In cell culture, ATO decreased osteoblast mineralization by decreasing alkaline phosphatase (ALP) expression and this effect was prevented by co-addition of inorganic phosphate (Pi). Moreover, levels of mRNAs for the transcription factors runt-related transcription factor 2 (Runx2) and osterix, the osteoblast osteogenic gene osteocalcin, and the adherence molecule vascular cell adhesion molecule-1 (VCAM-1) were decreased by ATO. Levels of mRNAs for the cytokine IL-6 were also decreased, whereas GM-CSF mRNA levels were increased. Similar effects of ATO on osteoblasts were seen in in vivo experiments in the rat. Moreover, decreases of bone turnover markers of osteocalcin, Procollagen type I N-terminal propeptide (PINP), and C-terminal cross-linked telopeptide (CTX) as well as bone mineral density (BMD) and trabecular bone volume of femur were observed in ATO-treated rats. These results suggest that ATO interferes with bone remodeling mostly through changes in osteoblast differentiation and function.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan. chingshouhu@gmail.com
authors.forename: Yu-Chen
authors.initials: YC
authors.lastname: Hu
authors.forename: Hsiao-Ling
authors.initials: HL
authors.lastname: Cheng
authors.forename: Bau-Shan
authors.initials: BS
authors.lastname: Hsieh
authors.forename: Li-Wen
authors.initials: LW
authors.lastname: Huang
authors.forename: Tzu-Ching
authors.initials: TC
authors.lastname: Huang
authors.forename: Kee-Lung
authors.initials: KL
authors.lastname: Chang
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals; D001483:Base Sequence; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D024042:Collagen Type I / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D010006:Osteoblasts / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D015675:Osteocalcin / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D010087:Oxides / Q000633:toxicity*; D010446:Peptide Fragments / Q000378:metabolism; D010455:Peptides / Q000378:metabolism; D011347:Procollagen / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: D001152:Arsenicals; D024042:Collagen Type I; D050659:Core Binding Factor Alpha 1 Subunit; D015850:Interleukin-6; D010087:Oxides; D010446:Peptide Fragments; D010455:Peptides; D011347:Procollagen; D012333:RNA, Messenger; C493717:Runx2 protein, rat; C495181:Sp7 protein, rat; D014157:Transcription Factors; D019010:Vascular Cell Adhesion Molecule-1; C052929:collagen type I trimeric cross-linked peptide; C047202:procollagen Type I N-terminal peptide; D015675:Osteocalcin; D000469:Alkaline Phosphatase; D000077237:Arsenic Trioxide