Activation of PERK signaling through fluoride-mediated endoplasmic reticulum stress in OS732 cells.
Our proteomical analysis of osteoblasts exposed to fluoride revealed a distinctive upregulation of proteins in osteoblast. These upregulated proteins play key roles in the protein folding. The PRK-like ER kinase (PERK) signaling, one branch of unfolded protein response (UPR) to combat ER stress, is a transcription factor needed for osteoblast proliferation and differentiation. The mechanism of skeletal fluorosis by which fluoride regulates osteoblast is not fully defined. Here we studied the effect of fluoride on PERK signaling genes and x-box binding protein 1 (xbp-1) in OS7232 cells (human osteoblast-like cell line). Meantime, genes associated with bone turnover were examined in this study. We found that early and continuous fluoride exposure increased the binding immunoglobulin protein (BiP) expression and activated the PERK signaling pathway, resulting in activation of transcription factor 4 (ATF4) and nuclear factor erythroid 2-related factor 2 (Nrf2). The altered expression of cbfa1, osteoprotegerin (OPG)/nuclear factor kappa B ligand (RANKL) were viewed in this study. These results showed fluoride impelled a distinctive ER stress response in OS732 cells, primarily by activating PERK and PERK-dependent signaling. Little effects were viewed for activating xbp-1, a common target of the other two canonical sensors of ER stress, ATF6 and IRE1. In this study the altered expression of bone turnover genes were consistent with activation of ER stress and PERK signaling. This study proved that PERK signaling play major roles in action of fluoride on osteoblast, and suggested that bone response in skeletal fluorosis may be due in part to PERK signaling pathway.
Xu
Hui
H
Department of Endemic Diseases, Jilin University, 1163 Xinmin Street, Changchun 130021, PR China. huixujlu@yahoo.com
Zhou
Yu-Lai
YL
Zhang
Xiu-Yun
XY
Lu
Peng
P
Li
Guang-Sheng
GS
D045744:Cell Line, Tumor; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005458:Fluoride Poisoning / Q000201:enzymology / Q000209:etiology / Q000473:pathology; D005459:Fluorides / Q000633:toxicity*; D006801:Humans; D010006:Osteoblasts / Q000187:drug effects / Q000201:enzymology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D019892:eIF-2 Kinase / Q000378:metabolism* / Q000502:physiology
D005459:Fluorides; D019892:eIF-2 Kinase