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J. Biol. Chem., Vol. 280, Issue 24, 23194-23202, June 17, 2005

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Fluoride Induces Endoplasmic Reticulum Stress in Ameloblasts Responsible for Dental Enamel Formation^*

Kaori Kubota, Daniel H. Lee, Masahiro Tsuchiya¶, Conan S. Young, Eric T. Everett||, Esperanza A. Martinez-Mier**, Malcolm L. Snead, Linh Nguyen, Fumihiko Urano, and John D. Bartlett¶¶

From the Department of Cytokine Biology, Forsyth Institute, and Department of Oral and Developmental Biology, Harvard School of Dental Medicine, Boston, Massachusetts 02115, ^¶Division of Aging and Geriatric Dentistry, Tohoku University Graduate School of Dentistry, Sendai, 980-8575, Japan, ^||Department of Pediatric Dentistry and the Carolina Center for Genome Sciences, University of North Carolina, North Chapel Hill, North Carolina 27599, ^**Department of Preventive and Community Dentistry, Oral Health Research Institute, Indiana University School of Dentistry and Medicine, Indianapolis, Indiana 46202, Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry, Los Angeles, California 90033, and Program in Gene Function and Expression, Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655

The mechanism of how fluoride causes fluorosis remains unknown. Exposure to fluoride can inhibit protein synthesis, and this may also occur by agents that cause endoplasmic reticulum (ER) stress. When translated proteins fail to fold properly or become misfolded, ER stress response genes are induced that together comprise the unfolded protein response. Because ameloblasts are responsible for dental enamel formation, we used an ameloblast-derived cell line (LS8) to characterize specific responses to fluoride treatment. LS8 cells were growth-inhibited by as little as 1.9–3.8 ppm fluoride, whereas higher doses induced ER stress and caspase-mediated DNA fragmentation. Growth arrest and DNA damage-inducible proteins (GADD153/CHOP, GADD45), binding protein (BiP/glucose-responsive protein 78 (GRP78), the non-secreted form of carbonic anhydrase VI (CA-VI), and active X-box-binding protein-1 (Xbp-1) were all induced significantly after exposure to 38 ppm fluoride. Unexpectedly, DNA fragmentation increased when GADD153 expression was inhibited by short interfering RNA treatment but remained unaffected by transient GADD153 overexpression. Analysis of control and GADD153^-/- embryonic fibroblasts demonstrated that caspase-3 mediated the increased DNA fragmentation observed in the GADD153 null cells. We also demonstrate that mouse incisor ameloblasts are sensitive to the toxic effects of high dose fluoride in drinking water. Activated Ire1 initiates an ER stress response pathway, and mouse ameloblasts were shown to express activated Ire1. Ire1 levels appeared induced by fluoride treatment, indicating that ER stress may play a role in dental fluorosis. Low dose fluoride, such as that present in fluoridated drinking water, did not induce ER stress.

Received for publication, March 25, 2005

^* This work was supported in part by NIDCR, National Institutes of Health Grants DE14084 (to J. D. B.) and DE13237 (subproject 4, to J. D. B.) and was conducted in a laboratory renovated with National Institutes of Health Grant support CO6RR11244. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶¶ To whom correspondence should be addressed: Dept. of Cytokine Biology, Forsyth Institute, Boston MA 02115. Tel.: 617-262-5200 (ext. 8388); Fax: 617-892-8432; E-mail: jbartlett{at}forsyth.org.

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