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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
Author(s) -
Johanson Matthew,
Zhao Xiang R.,
HuynhBa Guy,
Villar Cristina C.
Publication year - 2013
Publication title -
journal of periodontology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.036
H-Index - 156
eISSN - 1943-3670
pISSN - 0022-3492
DOI - 10.1902/jop.2012.120224
Subject(s) - matrix metalloproteinase , fibroblast , extracellular matrix , inflammation , oral mucosa , secretion , pathogenesis , immunology , chemistry , medicine , in vitro , pathology , biochemistry
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.