title: Matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases, and inflammation in cyclosporine A-induced gingival enlargement: a pilot in vitro study using a three-dimensional model of the human oral mucosa.
abstract: BACKGROUND
  It has been suggested that cyclosporine A (CsA) induces gingival enlargement by promoting an increase in the gingival extracellular matrix (ECM). Nonetheless, the variable occurrence of CsA-induced gingival enlargement in patients receiving this medication indicates a multifactorial pathogenesis. Clinical observations suggest that local inflammation is associated with the development and severity of CsA-induced gingival enlargement. Therefore, the purpose of this study is to investigate the effects of CsA and inflammation on the production of ECM homeostatic mediators.
  
  
  METHODS
  The effects of CsA and inflammation (as assessed using interleukin [IL]-1β) on the secretion of mediators involved in ECM homeostasis were determined using fibroblast monolayers and three-dimensional (3D) models of the human oral mucosa. Fibroblast monolayers and 3D cultures were treated with CsA alone or in combination with IL-1β for up to 72 hours, and the secretion of matrix metalloproteinases (MMPs) 1, 2, 3, 8, 9, 10, and 13 and tissue inhibitors of MMPs (TIMPs) 1, 2, and 4 into the culture medium was assessed using enzyme-linked immunoassay-based antibody arrays.
  
  
  RESULTS
  Fibroblast monolayers responded to CsA with no changes in the secretion of ECM mediators. Conversely, 3D cultures responded to CsA treatment with a reduction in MMP-10 secretion. IL-1β alone triggered higher secretory levels of MMPs in both fibroblast monolayers (MMP-3 and MMP-10) and 3D cultures (MMP-9 and MMP-10). Importantly, fibroblast monolayers and 3D cultures treated with a combination of IL-1β and CsA showed a decrease in the MMP-1/TIMP-1 ratio.
  
  
  CONCLUSIONS
  These data support the hypothesis that inflammation may alter the pathogenesis of CsA-induced gingival enlargement by promoting a synergistic decrease in the MMP-1/TIMP-1 ratio.
authors.affiliation: Department of Periodontics, The University of Texas Health Science Center, San Antonio, TX, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Johanson
authors.forename: Xiang R
authors.initials: XR
authors.lastname: Zhao
authors.forename: Guy
authors.initials: G
authors.lastname: Huynh-Ba
authors.forename: Cristina C
authors.initials: CC
authors.lastname: Villar
mesh_terms: D000704:Analysis of Variance; D002478:Cells, Cultured; D016572:Cyclosporine / Q000009:adverse effects; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005881:Gingiva / Q000166:cytology / Q000378:metabolism; D019214:Gingival Overgrowth / Q000139:chemically induced* / Q000201:enzymology* / Q000209:etiology; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D020781:Matrix Metalloproteinase 1 / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D008953:Models, Anatomic; D009061:Mouth Mucosa / Q000166:cytology / Q000201:enzymology*; D010865:Pilot Projects; D018709:Statistics, Nonparametric; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*
chemical_list: D016326:Extracellular Matrix Proteins; D036341:Intercellular Signaling Peptides and Proteins; D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D016572:Cyclosporine; D020782:Matrix Metalloproteinases; D020781:Matrix Metalloproteinase 1