TY - JOUR
T1 - Matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases, and inflammation in cyclosporine a-induced gingival enlargement
T2 - A pilot in vitro study using a three-dimensional model of the human oral mucosa
AU - Johanson, Matthew
AU - Zhao, Xiang R.
AU - Huynh-Ba, Guy
AU - Villar, Cristina C.
PY - 2013/4
Y1 - 2013/4
N2 - 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-1b 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-1b 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-1b 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.
AB - 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-1b 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-1b 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-1b 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.
KW - Collagen
KW - Cyclosporine
KW - Gingival overgrowth
KW - Inflammation
KW - Metalloproteases
KW - Tissue inhibitor of metalloproteinases
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U2 - 10.1902/jop.2012.120224
DO - 10.1902/jop.2012.120224
M3 - Article
C2 - 22934840
AN - SCOPUS:84877115439
VL - 84
SP - 634
EP - 640
JO - Journal of Periodontology
JF - Journal of Periodontology
SN - 0022-3492
IS - 5
ER -