title: A role for PERK in the mechanism underlying fluoride-induced bone turnover.
abstract: While it has been well-documented that excessive fluoride exposure caused the skeletal disease and osteoblasts played a critical role in the advanced skeletal fluorosis, the underlying mechanism that mediated these effects remain poorly understood. The present study was undertaken to examine the effect of fluoride on bone of rats and MC3T3-E1 cells in vitro. Herein we found pathological features of high bone turnover in fluoride-treated rats, which was supported by an increase of osteogenic and osteoclastogenic genes expression in different stages of fluoride exposure. The skeletal toxicity of fluoride was accompanied by activation of endoplasmic reticulum (ER) stress and subsequent unfolded protein response (UPR). A novel finding of this study was that expression of PKR-like endoplasmic reticulum kinase (PERK) was the same trend with receptor activator for nuclear factor-κ B ligand (RANKL), and NF-E2 p45-related factor 2 (Nrf2) was the same trend with Runt-related transcription factor 2 (Runx2) in bones of rats exposed to varied fluoride condition. Based on these data, we hypothesized that up-regulation of PERK probably played a role in mediating bone turnover induced by fluoride. Action of fluoride on MC3T3-E1 cells differentiation was demonstrated through analysis of alkaline phosphatase (ALP) activity and mineralized nodules formation. Meantime, an increase of binding immunoglobulin protein (BiP) expression indicated the active ER stress in cells exposed to various dose of fluoride. Blocking PERK expression using siRNA showed the obvious decrease of osteogenic and osteoclastogenic factors expression in MC3T3-E1 cells exposed to certain dose of fluoride that could positively stimulate osteoblastic viability. In conclusion these findings underscore the importance of PERK in modulating fluoride induced bone formation and bone resorption. Understanding the link between PERK and bone turnover could probe into the mechanism underlying different bone lesion of skeletal fluorosis.
authors.affiliation: School of Pharmaceutical Sciences, Jilin University, Changchun 130021, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Sun
authors.affiliation: Department of Endemic Diseases, Jilin University, Changchun 130021, China.
authors.forename: Xining
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Endemic Diseases, Jilin University, Changchun 130021, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yang
authors.affiliation: Department of Endemic Diseases, Jilin University, Changchun 130021, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Lv
authors.affiliation: Department of Endemic Diseases, Jilin University, Changchun 130021, China.
authors.forename: Guangsheng
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Endemic Diseases, Jilin University, Changchun 130021, China. Electronic address: huixujlu@yahoo.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D015519:Bone Density / Q000187:drug effects; D016723:Bone Remodeling / Q000187:drug effects* / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D005269:Femur / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D005819:Genetic Markers; D008297:Male; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D034622:RNA Interference; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D012886:Skull / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D012969:Sodium Fluoride / Q000633:toxicity*; D013997:Time Factors; D014162:Transfection; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D005819:Genetic Markers; D012969:Sodium Fluoride; D019892:eIF-2 Kinase
keywords: Bone turnover; Endoplasmic reticulum stress; Osteoblast; PKR-like endoplasmic reticulum kinase; Skeletal fluorosis