Publication: Phenytoin activates SMAD3 phosphorylation and periostin expression in drug-induced gingival enlargement
Authors
Kim, Shawna S. ; Nikoloudaki, Georgia ; Darling, Mark ; Rieder, Michael J. ; Hamilton, Douglas W.
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Publisher
Universidad de Murcia. Departamento de Biología Celular e Histología
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DOI
DOI: 10.14670/HH-18-015
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info:eu-repo/semantics/article
Description
Abstract
Drug-induced gingival enlargement (DIGE)
is a fibrotic condition associated with systemic
administration of the anti-epileptic drug, phenytoin. We
have previously demonstrated that periostin, which is
transforming growth factor-beta (TGF-β) inducible gene,
is upregulated in various fibrotic conditions including
gingival enlargement associated with nifedipine. The
objective of this study was to assess periostin expression
in phenytoin-induced gingival enlargement (PIGE)
tissues and to investigate the mechanisms underlying
periostin expression. Human PIGE tissues were assessed
using Masson’s trichrome, with cell infiltration and
changes in extracellular matrix composition
characterized through labeling with antibodies to
periostin, phospho-SMAD 3, TGF-β, as well as the
macrophage markers CD68 and RM3/1. Using human
gingival fibroblasts (HGFs) in vitro, we examined the
pathways through which phenytoin acts on fibroblasts.
In PIGE tissues, which demonstrate altered collagen
organization and increased inflammatory cell infiltration,
periostin protein was increased compared with healthy
tissues. p-SMAD2/3, the transcription factor associated
with canonical TGF-β signaling, is localized to the
nuclei in both gingival fibroblasts and oral epithelial
cells in PIGE tissues, but not in healthy tissue. In vitro
culture of HGFs with 15 and 30 μg/ml of phenytoin
increased periostin protein levels, which correlated with
p-SMAD3 phosphorylation. Inhibition of canonical
TGF-β signaling with SB431542 significantly reduced
phenytoin induction of SMAD3 phosphorylation and
periostin expression in HGFs. Analysis of PIGE tissues
showed a subset of CD68 stained macrophages were
TGF-β positive and that RM1/3 regenerative
macrophages were present in the tissues. Our results
demonstrate that phenytoin up-regulates periostin in
HGFs in a TGF-β-dependent manner.
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Citation
Histology and Histopathology, Vol.33, nº12, (2018)
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