Arsenic trioxide affects bone remodeling by effects on osteoblast differentiation and function

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.

223Highlights► Arsenic trioxide decreases expressions of transcription factors, Runx2 and osterix, and of the osteogenic gene, osteocalcin and ALP cultured osteoblast. ► Osteoblast's mineralization is decreased. ► Bone mineral density and trabecular bone volume are decreased in arsenic trioxide-treated rats. ► Expressions of osteogenic genes Runx2, ALP, osteocalcin, RANKL and TRAP in femur are decreased in the arsenic trioxide-treated rat. ► Arsenic trioxide interferes with bone remodeling through changes in osteoblast differentiation and function.