Development of a phenytoin-induced gingival overgrowth mouse model, and effects of lovastatin
Date
2015
DOI
Authors
Assaggaf, Mohammad Ahmad A
Version
OA Version
Citation
Abstract
Drug-induced gingival overgrowth is caused by the anti-seizure medication phenytoin, anti-hypertensive calcium channel blockers, and the immunosuppressant cicIosporin. Characteristics of these drug-induced gingival overgrowth lesions considerably differ at clinical and histopathoIogical levels. In order to establish an in vivo system for studying the progression of the pathoIogy, we developed a mouse model, which mimics human phenytoin-induced gingival overgrowth and assessed the ability of a drug to prevent its development. Lovastatin was chosen as the therapeutic. Based on previous analyses of tissue-specific regulation of CCN2 production in human gingival fibroblasts and the known roles of CCN2 in promoting fibrosis and epithelial to mesenchymal transition, we have studied its mechanism of action in preventing phenytoin- induced gingival overgrowth. Based on gross tissue observations and histomorphometry of tissue sections, data indicated that the overgrowth predominantly occurred in anterior gingival tissues of phenytoin-treated mice. Similar to humans, molecular markers of epithelial plasticity and fibrosis, such as TGF-β, E-cadherin, CCN2 and LOXL2, were regulated by phenytoin in gingival epithelial tissues and in connective tissues in mice. Lovastatin attenuated epithelial gingival tissue growth and altered the expressions of markers for epithelial to mesenchymal transition. Quantitative findings revealed that phenytoin lead to overexpression of TGF-β and CCN2, and downregulation of E-cadherin expression (P [less than] 0.05) in the phenytoin treated mice. Also, quantitative findings of the phenytoin plus lovastatin treated mice revealed that lovastatin was capable to reduce or abolish the phenytoin induction effect in upregulating TGF-P, CCN2, and downregulating E-cadherin expression (P [less than] 0.05). Phenytoin-induced gingival overgrowth in mice mimicked molecular aspects of human gingival overgrowth and lovastatin normalized the tissue morphology and the expression of the molecular markers. Molecular data were consistent characteristics of cultured human gingival epithelial and connective tissue cells.
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Dissertation (DScD) --Boston University, Henry M. Goldman School of Dental Medicine, 2015 (Department of Molecular and Cell Biology).
Includes bibliographic references: leaves 117-133.
Dissertation (DScD) --Boston University, Henry M. Goldman School of Dental Medicine, 2015 (Department of Molecular and Cell Biology).
Includes bibliographic references: leaves 117-133.
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This work is protected by copyright. Downloading is restricted to the BU community. If you are the author of this work and would like to make it publicly available, please contact open-help@bu.edu.