Fluoride decreased osteoclastic bone resorption through the inhibition of NFATc1 gene expression
ABSTRACT Over the past two decades, fluoride effects on osteoclasts have been evaluated; however, its molecular mechanisms remain unclear. In this study, we investigated the effect of fluoride on osteoclast formation, function, and regulation using osteoclasts formed from mice bone marrow macrophages treated with the receptor activator of NF-κB ligand and macrophage colony-stimulating factor. Our data showed that fluoride levels ≤ 8 mg/L had no effect on osteoclast formation; however, it significantly reduced osteoclast resorption at 0.5 mg/L. Fluoride activity on bone resorption occurred through the inhibition of nuclear factor of active T cells (NFAT) c1 expression. Furthermore, the expression of its downstream genes, including the dendritic cell-specific transmembrane protein, c-Src, the d2 isoform of vacuolar (H+) ATPase v0 domain, matrix metalloproteinase 9, and cathepsin K were decreased, leading to impaired osteoclast acidification, reduced secretion of proteolytic enzymes, and decreased bone resorption. In summary, our results suggested that fluoride has different roles in osteoclast formation and function. Fluoride ≤ 8 mg/L did not impact osteoclast formation; however, it significantly decreased the resorption activity of newly formed osteoclasts. The molecular mechanism of fluoride action may involve inhibition of NFATc1 and its downstream genes. © 2012 Wiley Periodicals, Inc. Environ Toxicol, 2012.
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ABSTRACT: Microarray analysis of odontoblastic cells treated with sodium fluoride has identified the asporin gene as a fluoride target. Asporin is a member of the small leucine-rich repeat proteoglycan/protein (SLRP) family which is believed to be important in the mineralization process. In this study, asporin expression and distribution were investigated by systematic analysis of dentin and enamel, with and without fluoride treatment. Specific attention was focused on a major difference between the two mineralized tissues: the presence of a collagenous scaffold in dentin, and its absence in enamel. Normal and fluorotic, continually growing incisors from Wistar rats treated with 2.5 to 7.5 mM sodium fluoride (NaF) were studied by immunochemistry, in situ hybridization, western blotting and RT-qPCR. Asporin was continuously expressed in odontoblasts throughout dentin formation as expected. Asporin was also found, for the first time, in dental epithelial cells, particularly in maturation-stage ameloblasts. NaF decreased asporin expression in odontoblasts whereas it enhanced it in ameloblasts both in vivo and in vitro. The inverse response in the two cell types suggests that the effector, fluoride, is a trigger that elicits a cell-type specific reaction. Confocal and ultrastructural immunohistochemistry evidenced an association between asporin and the type 1 collagen in the pericellular non-mineralized compartments of both bone and dentin. In addition, transmission electron microscopy revealed asporin in the microenvironment of all cells observed. Thus, asporin is produced by collagen- and non collagen-matrix-forming cells but may have different effects on the mineralization process. A model is proposed that predicts impaired mineral formation associated with the deficiency and excess of asporin. © 2013 American Society for Bone and Mineral ResearchJournal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 06/2014; 29(6). DOI:10.1002/jbmr.2153 · 6.59 Impact Factor
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ABSTRACT: Long-term excessive fluoride (F) intake disrupts the balance of bone deposition and remodeling activities and is linked to skeletal fluorosis. Type I collagen, which is responsible for bone stability and cell biological functions, can be damaged by excessive F ingestion. In this study, Sodium fluoride (NaF) was orally administrated to rat at 150mgL(-)(1) for 60 and 120d. We examined the effects of excessive F ingestion on the ultrastructure and collagen morphology of bone in rats by using transmission electron microscopy (TEM). Furthermore, we investigated the effect of F consumption on the expression levels of COL1A1 and COL1A2 in the bone tissues of rats by using quantitative real time (qRT)-PCR, to elucidate the molecular mechanisms of F-induced collagen protein damage. Our results showed that F affected collagen I arrangement and produced ultrastructural changes in bone tissue. Meanwhile, the mRNA expression of COL1A1 and COL1A2 were reduced and the COL I protein levels decreased in the fluorosis group. We concluded that excessive F ingestion adversely affected collagen I arrangement and caused ultrastructural changes in bone tissue. Reduced COL1A1 mRNA expression and altered COL I protein levels may contribute to the skeletal damage resulting from F exposure. Copyright © 2015. Published by Elsevier Ltd.Chemosphere 02/2015; 128C:36-41. DOI:10.1016/j.chemosphere.2014.12.090 · 3.50 Impact Factor
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ABSTRACT: Fluoride (F) is a naturally-occurring contaminant in the water. F is essential for normal maintenance of teeth and bones. However, prolonged exposure to high concentration of F is found to be deleterious to teeth, bones and other organs. Besides drinking water, F can enter the body through food, dental products, drugs and industrial emission. People living in areas where F contamination is much higher than the expected level, are found to suffer from not only teeth and bone problem but also other systems, including brain and its functions. Since animals respond to the toxic effects of F like human beings, the deleterious effects of F have been produced experimentally in animals in order to determine the mechanism involved in the action of F. The reports indicating the chronic harmful effects of F in teeth, bones, heart, liver, kidneys, gastrointestinal tract, lungs, brain, blood, hormones and biochemical parameters of experimental animals and in invitro studies have been reviewed in this article. The neurotoxic action of F that produces chiefly learning and memory impairment has also been included. The review also points out the harmful effects of F on reproduction, its teratogenic action and in inducing premature ageing. Finally, the reports indicating a reversal of certain toxicities of F in experimental animals after withdrawal of its exposure has been included.Toxicology Letters 09/2013; DOI:10.1016/j.toxlet.2013.09.005 · 3.36 Impact Factor