title: Role of unfolded protein response in affecting osteoblast differentiation induced by fluoride.
abstract: The objective of this study was to determine the expression of classic bone markers and unfolded protein response (UPR) signaling factors through MC3T3-E1 cells exposed to varying concentrations of fluoride. Excessive fluoride exposure caused the skeletal disease. During this process, osteoblasts played a critical role in the advanced skeletal fluorosis. Recent literature showed that endoplasmic reticulum (ER) stress and UPR were involved in numerous aspects of bone biology. Our results indicated that co-exposure of low-dose fluoride and mineral induction medium stimulated the expression of alkaline phosphatase, runt-related transcription factor 2 (Runx2), and osterix in MC3T3-E1 cells. Accordingly, the expression of double-stranded RNA-activated protein kinase (PKR)-like ER kinase, activating transcription factor 6, and X-box binding protein 1 also increased under the same fluoride exposure condition. The upregulation of three UPR factors was similar with osteogenic differentiation markers and transcription factors, which implied the relation between osteoblast differentiation and UPR pathways. Moreover, the role of UPR affecting osteoblast differentiation was investigated by decreasing the expression of binding immunoglobulin protein (BiP) mRNA through small interfering RNA (siRNA) technique. BiP knockdown led to suppress activation of UPR pathways. The deletion of BiP expression hardly stimulated the osteogenic cells differentiation but inhibited cell function under fluoride and mineralization induction exposure. In conclusion, fluoride had dual effect on osteogenic action. The UPR possibly involved in the mechanism of osteoblasts differentiation induced by fluoride.
authors: Department of Endemic Diseases, Jilin University, Changchun, 130021, People's Republic of China.
authors: Xi-ning
authors: XN
authors: Li
authors: Peng
authors: P
authors: Lv
authors: Zhi
authors: Z
authors: Sun
authors: Guang-sheng
authors: GS
authors: Li
authors: Hui
authors: H
authors: Xu
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects* / Q000235:genetics; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D000091342:Endoplasmic Reticulum Chaperone BiP; D005459:Fluorides / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000235:genetics; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D005459:Fluorides; D006360:Heat-Shock Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D019892:eIF-2 Kinase; C497112:Atf6 protein, mouse