title: Nifedipine induces periostin expression in gingival fibroblasts through TGF-beta.
abstract: Gingival enlargement is a fibrotic condition that can arise from systemic administration of the dihydropyridine calcium channel blocker nifedipine. Periostin, a transforming growth factor-beta (TGF-β)-inducible matricellular protein, has been associated with fibrosis in numerous tissues, but its expression has never been examined in nifedipine-influenced gingival enlargement (NIGE). The objective of this study was to assess if periostin up-regulation is associated with NIGE and whether nifedipine induces periostin expression in gingival fibroblasts. In NIGE tissue (n = 6), periostin is overexpressed in the gingival connective tissue compared with healthy control tissue (n = 6). The transcription factor p-SMAD2/3, which is associated with canonical TGF-β signaling, localizes to the nuclei in both HGFs and oral epithelial cells in NIGE tissues, but not in control healthy tissue. In vitro culture of HGFs with 30 and 100 ng/mL of nifedipine significantly increased periostin mRNA and protein levels, which correlated with increased levels of active TGF-β and increased phosphorylation and nuclear localization of SMAD3. Blocking of canonical TGF-β signaling through inhibition of the TGF-β receptor I with SB431542 significantly reduced nifedipine-induced SMAD3 phosphorylation and periostin expression. Our results demonstrate that nifedipine up-regulates periostin in HGFs in a TGF-β-dependent manner.
authors.affiliation: Department of Anatomy & Cell Biology, Children's Health Research Institute, London, ON, Canada.
authors.forename: S S
authors.initials: SS
authors.lastname: Kim
authors.forename: L
authors.initials: L
authors.lastname: Jackson-Boeters
authors.forename: M R
authors.initials: MR
authors.lastname: Darling
authors.forename: M J
authors.initials: MJ
authors.lastname: Rieder
authors.forename: D W
authors.initials: DW
authors.lastname: Hamilton
mesh_terms: D001549:Benzamides / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000032:analysis / Q000187:drug effects*; D018929:Cell Culture Techniques; D002467:Cell Nucleus / Q000187:drug effects / Q000648:ultrastructure; D003238:Connective Tissue / Q000378:metabolism; D004149:Dioxoles / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects*; D005881:Gingiva / Q000166:cytology*; D019214:Gingival Overgrowth / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009543:Nifedipine / Q000494:pharmacology*; D010766:Phosphorylation; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000032:analysis; D051900:Smad3 Protein / Q000032:analysis / Q000187:drug effects; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000187:drug effects*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D002121:Calcium Channel Blockers; D015815:Cell Adhesion Molecules; D004149:Dioxoles; C512835:POSTN protein, human; D018125:Receptors, Transforming Growth Factor beta; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; D009543:Nifedipine
keywords: SMAD3; adverse drug reaction; dihydropyridine; fibrosis; gingival overgrowth; matricellular protein