title: Excess fluoride interferes with chloride-channel-dependent endocytosis in ameloblasts.
abstract: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF). Both CF and dental fluorosis result in protein retention in mature enamel. We hypothesized that excess fluoride might cause protein retention by interfering with CFTR function, resulting in abnormal expression of proteases and pathological endocytosis. Millimolar concentrations of fluoride reduced uptake of Emdogain, an enamel matrix derivative, in ameloblast-like PABSo-E cells, while stimulating an acidic intracellular environment at the same time. When CFTR function was inhibited by either an siRNA or a chloride channel inhibitor, CFTRinh-172, fluoride's effect on Emdogain uptake was partially blocked. Treatment of cells with CFTR siRNA down-regulated expression of proteases MMP20 and KLK4 and increased intracellular pH. We conclude that excess fluoride inhibits endocytic activity of ameloblasts through the CFTR chloride channel or other chloride channels. The intracellular pH might be the key mechanism by which abnormal proteolytic activity and defective endocytosis cause the residual protein observed in enamel of patients with CF and dental fluorosis.
authors.affiliation: Department of Oral Biology, The Fourth Military Medical University, 145 West Changle Road, Xi’an, Shaanxi 710032, PR China. xhduan@fmmu.edu.cn
authors.forename: X
authors.initials: X
authors.lastname: Duan
authors.forename: Y
authors.initials: Y
authors.lastname: Mao
authors.forename: X
authors.initials: X
authors.lastname: Wen
authors.forename: T
authors.initials: T
authors.lastname: Yang
authors.forename: Y
authors.initials: Y
authors.lastname: Xue
mesh_terms: D000565:Ameloblasts / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002461:Cell Line, Transformed; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000235:genetics; D003746:Dental Enamel Proteins / Q000378:metabolism*; D015536:Down-Regulation; D004705:Endocytosis / Q000187:drug effects*; D005459:Fluorides / Q000009:adverse effects*; D006863:Hydrogen-Ion Concentration; D007610:Kallikreins / Q000096:biosynthesis; D053519:Matrix Metalloproteinase 20 / Q000096:biosynthesis; D034622:RNA Interference; D013552:Swine
chemical_list: D003746:Dental Enamel Proteins; C109069:enamel matrix proteins; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D007610:Kallikreins; C120801:kallikrein 4; D053519:Matrix Metalloproteinase 20; D005459:Fluorides