title: Fibroblast VEGF-receptor 1 expression as molecular target in periodontitis.
abstract: OBJECTIVE
  Degradation of extracellular matrices is an integral part in periodontitis. For antagonizing this pathophysiological mechanism, we aimed at identifying gene expression profiles in disease progression contributing periodontitis-associated fibroblasts (PAFs) versus normal gingival fibroblasts to determine their molecular repertoire, and exploit it for therapeutic intervention.
  
  
  METHODS
  Applying an exploratory analysis using a small number of microarrays in combination with a three dimensional (3D) in vitro culture model that incorporates some aspects of periodontitis, PAFs were initially characterized by gene-expression analyses, followed by targeted gene down-regulation and pharmacological intervention in vitro. Further, immunohistochemistry was applied for phosphorylation analyses in tissue specimens.
  
  
  RESULTS
  PAFs were characterized by 42 genes being commonly up-regulated >1.5-fold, and by five genes that were concordantly down-regulated (<0.7-fold). Expression of vascular endothelial growth factor (VEGF)-receptor 1 (Flt-1) was highly enhanced, and was thus further explored in in vitro culture models of periodontal fibroblasts without accounting for the microbiome. Phosphorylation of the VEGF-receptor 1 was enhanced in PAFs. Receptor inhibition by a specific VEGF-receptor inhibitor or intrinsic down-regulation by RNAi of the VEGF-receptor kinase in 3D gel cultures resulted in significant reduction in collagen degradation associated with increased tissue inhibitor of metalloproteinase expression, suggesting that Flt-1 may contribute to periodontitis.
  
  
  CONCLUSIONS
  Based on the finding that VEGF-receptor kinase inhibition impaired collagen degradation pathways, Flt-1 may represent a candidate for therapeutic approaches in periodontitis.
authors.affiliation: Department of Biochemistry, Ohu University School of Pharmaceutical Sciences, Koriyama, Fukushima, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Ohshima
authors.affiliation: Department of Biochemistry, Nihon University School of Dentistry, Tokyo, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamaguchi
authors.affiliation: Department of Morphological Biology, Ohu University School of Dentistry, Koriyama, Fukushima, Japan.
authors.forename: Kimiharu
authors.initials: K
authors.lastname: Ambe
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Horie
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Saito
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine and Faculty of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Nagase
authors.affiliation: Division of Periodontology, Department of Oral Function, Kyushu Dental University, Fukuoka, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nakashima
authors.affiliation: First Department of Oral Surgery, Nihon University School of Dentistry, Tokyo, Japan.
authors.forename: Hidero
authors.initials: H
authors.lastname: Ohki
authors.affiliation: Department of Immunology, The Forsyth Institute, Cambridge, MA, USA.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Kawai
authors.affiliation: Department of Molecular Biology and Biochemistry, Nihon University School of Dentistry at Matsudo, Chiba, Japan.
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Abiko
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, Hospital, Uppsala, Sweden.
authors.forename: Patrick
authors.initials: P
authors.lastname: Micke
authors.affiliation: Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Center for Cardiovascular Research (CCR), Charité-University Medicine Berlin, Berlin, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Kappert
mesh_terms: D015536:Down-Regulation; D005347:Fibroblasts; D005881:Gingiva; D006801:Humans; D010518:Periodontitis; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000378:metabolism*
chemical_list: C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: Flt-1; fibroblasts; gene expression; gingiva; periodontal disease; vascular endothelial growth factor