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My commentary:

Cystic fibrosis (CF) is the most common, lethal, genetic disease in Caucasians, affecting approximately 1 in every 2,500 newborns.1 In 1989, the gene mutated in cystic fibrosis (CF) was identified and named cystic fibrosis transmembrane conductance regulator (CFTR).2 CFTR chloride channel belongs to the superfamily of the ATP-binding cassette (ABC) transporters, which bind ATP and use the energy to drive the transport of a wide variety of substrates across extra- and intracellular membranes.3 CFTR also regulates the activity of other channels and transporters. The tissues affected by CF include sweat glands, intestine, bile ducts, respiratory epithelia, submandibular glands, uterus and vas deferens.4

It is now known that dental enamel, a product of epithelial cells, and bone is also affected in CF patients. Some CF patients develop reduced bone density (osteopenia) and dental defects. Bronckers et al 2010 provide evidence that CFTR is also expressed in maturation stage ameloblasts (enamel-secreting cells of teeth), odontoblasts (layer of cells lining the pulp cavity of a tooth, from which dentin is formed), and bone cells.5 The evidence demonstrates that CFTR are probably active in the pH regulation of maturation ameloblasts, and are essential for the completion of enamel mineralization. CFTR regulate pH because they are permeable to bicarbonate and are involved in the exchange of extracellular Cl- with intracellular bicarbonate.

Fluoride has been shown to reduce endocytosis in kidney and colon.6,7 The paper by Duan et al 2011 concludes that excess fluoride, in millimolar concentrations of an ameloblast system, inhibits the endocytic activity (transport of proteins) of ameloblasts through perturbations in the CFTR chloride channel.8 Although CFTR has a high affinity for bromide and chloride, it has been found that fluoride ions also compete for transport in these channels if fluoride concentrations are high enough.9 Defective CFTR function seems to result in pathological endocytosis in ameloblasts, leading to increased protein content in mature enamel.

These papers suggest that fluoride may exacerbate symptoms for CF patients and may induce CF-like symptoms in those without the CFTR genetic anomaly, by causing perturbations in CFTR function. Research is now required to demonstrate whether fluoride interferes with CFTR in other locations.

Research by Hardin et al.10 demonstrated that transport of bovine serum albumin was significantrly inhibited with sodium fluoride. Transport of molecules is an energy dependent process, therefore work by Schmid et al.11 which demonstrates that ATP is required for receptor-mediated endocytosis, is also relevant. It is well established that fluoride, in combination with aluminum (AlFx),12 disturbs G protein function by acting as a phosphate mimic. This may result in reduced availability of cellular energy required for these cellular functions.

These papers suggest that fluoride may exacerbate symptoms for CF patients and may induce CF-like symptoms in those without the CFTR genetic anomaly, by causing perturbations in CFTR function. Research is now required to demonstrate whether fluoride interferes with CFTR in other locations.

Citations

1 Li C, Naren AP. CFTR chloride channel in the apical compartments: spatiotemporal coupling to its interacting partners. Integr Biol 2010;2(4):161-77.

2 Riordan JR, Rommens JM, Kerem B, Alon N, Rozmahel R, Grzelczak Z, et al. Identification of the cystic fibrosis gene: cloning and characterization of complementary DNA. Science. 1989;245(4922):1066-73.



3 Li C, Naren AP. Macromolecular complexes of cystic fibrosis transmembrane conductance regulator and its interacting partners. Pharmacol Ther. 2005;108(2):208-23.

4 Bronckers A, Kalogeraki L, Jorna HJ, Wilke M, Bervoets TJ, Lyaruu DM, Zandieh-Doulabi B, Denbesten P, de Jonge H. The cystic fibrosis transmembrane conductance regulator (CFTR) is expressed in maturation stage ameloblasts, odontoblasts and bone cells. Bone. 2010;46(4):1188-96.

5 Bronckers et al. 2010

6 Hardin JA, Situ Z, Duan X. CIC chloride channels in tooth germ and odontoblast-like MDPC-23 cells. Arch Oral Biol 1999;53:874-8.

7 Schmid SL, Carter LL. ATP is required for receptor-mediated endocytosis in intact cells. J Cell Biol 1990;111(6 Pt 1):2307-18.

8 Duan X, Mao Y, Wen X, Yang T, Xue Y. Excess Fluoride Interferes with Chloride-channel-dependent Endocytosis in Ameloblasts. J Dent Res. 2011 Feb;90(2):175-180.

9Duan et al 2011

10 Hardin et al 1999

11 Schmid et al 1990

12 Strunecka A, Patocka J, Blaylock RL, Chinoy N. Fluoride Interactions: From Molecules to Disease. Current Signal Transduction Therapy 2007;2:190-213.


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