Home Evaluation of inductive effects of different concentrations of cyclosporine A on MMP-1, MMP-2, MMP-3, TIMP-1, and TIMP-2 in fetal and adult human gingival fibroblasts
Article
Licensed
Unlicensed Requires Authentication

Evaluation of inductive effects of different concentrations of cyclosporine A on MMP-1, MMP-2, MMP-3, TIMP-1, and TIMP-2 in fetal and adult human gingival fibroblasts

  • Bahareh Nazemisalman , Neda Sajedinejad , Shayan Darvish , Surena Vahabi EMAIL logo and Hoda Gudarzi
Published/Copyright: March 26, 2019

Abstract

Background

The etiology of gingival overgrowth due to cyclosporine A (CsA) is still unknown. The aim of this study was to determine the possible role of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) on extra-cellular matrix (ECM) homeostasis when treated with different levels of CsA and its difference between fetal and adult human gingival fibroblasts (HGFs).

Methods

Each group of cells (adult and fetal) was cultured in 40 wells that consisted of four different CsA treatment concentrations. Every 10 wells were treated with 0, 50, 100, and 150 ng/mL of CsA which makes a total of 80 wells. Supernatants of every well were used to determine the concentration of MMPs and TIMPs using the Elisa kits from Boster, CA, USA.

Results

MMP-1 level increased with the treatment of CsA when treated with 50 and 150 ng/mL of CsA (p = 0.02 and p = 0.04) as TIMP-1 decreased (p < 0.0001) in adult group; while in the fetal group, TIMP-1 level increased with treatment of 150 ng/mL (p < 0.0001). MMP-2 level increased in both adult and fetal groups (p < 0.0001). MMP-3 level decreased in adult group (p < 0.0001) but went up in fetal HGFs (p = 0.01) when treated with 150 ng/mL CsA. TIMP-2 level increased in all wells significantly when treated with CsA (p < 0.0001). The study showed that CsA affects secretion of MMPs and TIMPs. MMP-1 increment and TIMP-1 decrement were observed, which indicate more degradation of ECM. This may be due to single donor use in this study. TIMP-2 and MMP-2 were both more active when treated with CsA which may be due to the gelatinase activity of them and that in CsA gingival overgrowth. There was more inflammation rather than fibrosis.

  1. Author contributions: Bahareh Nazemisalman: Designed and supervised the project. Neda Sajedinejad: Cooperated in practical steps. Shayan Darvish: Gathered the data and coordinate the clinics and the laboratory process. Surena Vahabi: Designed and supervised the project. Hoda Gudarzi: Performed the lab process. All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: This study was funded and supported by Zanjan University of Medical Sciences, Zanjan, Iran.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

References

[1] Tarantino A, Aroldi A, Stucchi L, Montagnino G, Mascaretti L, Vegeto A, et al. A randomized prospective trial comparing cyclosporine monotherapy with triple-drug therapy in renal transplantation. Transplantation 1991;52:53–7.10.1097/00007890-199107000-00011Search in Google Scholar PubMed

[2] Wright G, Wilbur R, Hosey M. Cyclosporin-induced gingival overgrowth in children. Int J Paediatr Dent 2005;15:403–11.10.1111/j.1365-263X.2005.00676.xSearch in Google Scholar PubMed

[3] Bolzani G, Coletta RD, Júnior HM, De Almeida OP, Graner E. Cyclosporin A inhibits production and activity of matrix metalloproteinases by gingival fibroblasts. J Periodontal Res 2000;35:51–8.10.1034/j.1600-0765.2000.035001051.xSearch in Google Scholar PubMed

[4] Trackman P, Kantarci A. Molecular and clinical aspects of drug-induced gingival overgrowth. J Dent Res 2015;94:540–6.10.1177/0022034515571265Search in Google Scholar PubMed PubMed Central

[5] Rezzani R. Cyclosporine A and adverse effects on organs: histochemical studies. Prog Histochem Cytochem 2004;39:85–128.10.1016/j.proghi.2004.04.001Search in Google Scholar PubMed

[6] Nagata T, Ninomiya M, Mihara C, Kido J, Nishikawa S, Kataoka M. Etiology of drug-induced gingival overgrowth. Curr Issues Peridontics. 2016;7:37–44.Search in Google Scholar

[7] Boltchi FE, Rees TD, Iacopino AM. Cyclosporine A-induced gingival overgrowth: a comprehensive review. Quintessence Int. 1999;30:775–83.Search in Google Scholar

[8] Margiotta V, Pizzo I, Pizzo G, Barbaro A. Cyclosporin-and nifedipine-induced gingival overgrowth in renal transplant patients: correlations with periodontal and pharmacological parameters, and HLA-antigens. J Oral Pathol Med 1996;25:128–34.10.1111/j.1600-0714.1996.tb00207.xSearch in Google Scholar PubMed

[9] Friskopp J, Klintmalm G. Gingival enlargement. A comparison between cyclosporine and azathioprine treated renal allograft recipients. Swed Dent J 1985;10:85–92.Search in Google Scholar

[10] Kantarci A, Cebeci I, Tuncer Ö, Çarin M, Firatli E. Clinical effects of periodontal therapy on the severity of cyclosporin A-induced gingival hyperplasia. J Periodontol 1999;70:587–93.10.1902/jop.1999.70.6.587Search in Google Scholar PubMed

[11] Ilgenli T, Atilla G, Baylas H. Effectiveness of periodontal therapy in patients with drug-induced gingival overgrowth. Long-term results. J Periodontol 1999;70:967–72.10.1902/jop.1999.70.9.967Search in Google Scholar PubMed

[12] Dannewitz B, Edrich C, Tomakidi P, Kohl A, Gabbert O, Eickholz P, et al. Elevated gene expression of MMP-1, MMP-10, and TIMP-1 reveal changes of molecules involved in turn-over of extracellular matrix in cyclosporine-induced gingival overgrowth. Cell Tissue Res 2006;325:513–22.10.1007/s00441-006-0200-xSearch in Google Scholar PubMed

[13] Johanson M, Zhao XR, Huynh-Ba G, Villar CC. 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. J Periodontol 2013;84:634–40.10.1902/jop.2012.120224Search in Google Scholar PubMed

[14] Ma S, Liu W, Liu P, Liu J, Chen L, Qin C. Tanshinone IIA treatment alleviated the rat gingival connective tissue overgrowth induced by cyclosporine A. J Periodontal Res 2016;51:567–76.10.1111/jre.12335Search in Google Scholar

[15] Zebrowski EJ, Pylypas SP, Odlum O, Johnson RB. Comparative metabolism of 3H-glucosamine by fibroblast populations exposed to cyclosporine. J Periodontol 1994;65:565–7.10.1902/jop.1994.65.6.565Search in Google Scholar

[16] Kitamura K, Morisaki I, Adachi C, Kato K, Mihara J, Sobue S, et al. Gingival overgrowth induced by cyclosporin A in rats. Arch Oral Biol 1990;35:483–6.10.1016/0003-9969(90)90213-TSearch in Google Scholar

[17] Reynolds J. Collagenases and tissue inhibitors of metalloproteinases: a functional balance in tissue degradation. Oral Dis 1996;2:70–6.10.1111/j.1601-0825.1996.tb00206.xSearch in Google Scholar

[18] Sukkar T, Thomason J, Cawston T, Lakey R, Jones D, Catterall J, et al. Gingival fibroblasts grown from cyclosporin-treated patients show a reduced production of matrix metalloproteinase-1 (MMP-1) compared with normal gingival fibroblasts, and cyclosporin down-regulates the production of MMP-1 stimulated by pro-inflammatory cytokines. J Periodontal Res 2007;42:580–8.10.1111/j.1600-0765.2007.00986.xSearch in Google Scholar

[19] Kelly EA, Jarjour NN. Role of matrix metalloproteinases in asthma. Curr Opin Pulm Med 2003;9:28–33.10.1097/00063198-200301000-00005Search in Google Scholar

[20] Yurchenko V, Pushkarsky T, Li J-H, Dai WW, Sherry B, Bukrinsky M. Regulation of CD147 cell surface expression involvement of the proline residue in the CD147 transmembrane domain. J Biol Chem 2005;280:17013–9.10.1074/jbc.M412851200Search in Google Scholar

[21] Birkedal-Hansen H. Role of matrix metalloproteinases in human periodontal diseases. J Periodontol 1993;64:474–84.10.1902/jop.1993.64.5.474Search in Google Scholar

[22] Havemose-Poulsen A, Holmstrup P. Factors affecting IL-1-mediated collagen metabolism by fibroblasts and the pathogenesis of periodontal disease: a review of the literature. Crit Rev Oral Biol Med 1997;8:217–36.10.1177/10454411970080020801Search in Google Scholar

[23] Sternlicht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001;17:463–516.10.1146/annurev.cellbio.17.1.463Search in Google Scholar

[24] Windsor LJ, Grenett H, Birkedal-Hansen B, Bodden MK, Engler JA, Birkedal-Hansen H. Cell type-specific regulation of SL-1 and SL-2 genes. Induction of the SL-2 gene but not the SL-1 gene by human keratinocytes in response to cytokines and phorbolesters. J Biol Chem 1993;268:17341–7.10.1016/S0021-9258(19)85340-1Search in Google Scholar

[25] Kuo PJ, Tu HP, Chin YT, Lu SH, Chiang CY, Chen RY, et al. Cyclosporine-A inhibits MMP-2 and-9 activities in the presence of porphyromonasgingivalis lipopolysaccharide: an experiment in human gingival fibroblast and U937 macrophage co-culture. J Periodontal Res 2012;47:431–8.10.1111/j.1600-0765.2011.01450.xSearch in Google Scholar

[26] Sobral L, Aseredo F, Agostini M, Bufalino A, Pereira M, Graner E, et al. Molecular events associated with cyclosporine A-induced gingival overgrowth are attenuated by Smad7 overexpression in fibroblasts. J Periodontal Res 2012;47:149–58.10.1111/j.1600-0765.2011.01412.xSearch in Google Scholar

[27] Ogata Y, Enghild J, Nagase H. Matrix metalloproteinase 3 (stromelysin) activates the precursor for the human matrix metalloproteinase 9. J Biol Chem 1992;267:3581–4.10.1016/S0021-9258(19)50563-4Search in Google Scholar

[28] Unemori EN, Bair M, Bauer E, Amento E. Stromelysin expression regulates collagenase activation in human fibroblasts. Dissociable control of two metalloproteinases by interferon-gamma. J Biol Chem 1991;266:23477–82.10.1016/S0021-9258(18)54522-1Search in Google Scholar

[29] Cotrim P, De Andrade C, Martelli-Junior H, Graner E, Sauk J, Coletta R. Expression of matrix metalloproteinases in cyclosporin-treated gingival fibroblasts is regulated by transforming growth factor (TGF)-β1 autocrine stimulation. J Periodontol 2002;73:1313–22.10.1902/jop.2002.73.11.1313Search in Google Scholar

[30] Gomez D, Alonso D, Yoshiji H, Thorgeirsson U. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol 1997;74:111–22.Search in Google Scholar

[31] Seymour R, Ellis J, Thomason J. Risk factors for drug-induced gingival overgrowth. J Clin Periodontol 2000;27:217–23.10.1034/j.1600-051x.2000.027004217.xSearch in Google Scholar

[32] Vahabi S, Salman BN, Rezazadeh F, Namdari M. Effects of cyclosporine and phenytoin on biomarker expressions in gingival fibroblasts of children and adults: an in vitro study. J Basic Clin Physiol Pharmacol 2014;25:167–73.10.1515/jbcpp-2013-0003Search in Google Scholar

[33] Uzel MI, Kantarci A, Hong H-H, Uygur C, Sheff MC, Firatli E, et al. Connective tissue growth factor in drug-induced gingival overgrowth. J Periodontol 2001;72:921–31.10.1902/jop.2001.72.7.921Search in Google Scholar

[34] Saus J, Quinones S, Otani Y, Nagase H, Harris E, Kurkinen M. The complete primary structure of human matrix metalloproteinase-3. Identity with stromelysin. J Biol Chem 1988;263:6742–5.10.1016/S0021-9258(18)68705-8Search in Google Scholar

[35] Nazemisalman B, Vahabi S, Bandehpour M, Aryankia A. Phenytoin effects on inflammatory mediator’s production by gingival fibroblasts: a comparative study in children and adults. Oral Health Dent Manag 2014;13:847–53.Search in Google Scholar

[36] Vahabi S, Moslemi M, Nazemisalman B, Yadegari Z. Phenytoin effects on proliferation and induction of IL1β and PGE2 in pediatric and adults’ gingival fibroblasts. Open J Stomatolo 2014;4:452.10.4236/ojst.2014.49061Search in Google Scholar

[37] Vahabi S, Nazemisalman B, Golpaigani MV, Ahmadi A. Effect of phenytoin and age on gingival fibroblast enzymes. J Dent (Tehran) 2014;11:270.Search in Google Scholar

[38] Vahabi S, Salman BN, Pourgolshani P. Effect of phenytoin and cyclosporine on IL-17 production by gingival fibroblasts of adults and children. J Periodontol Implant Dent 2015;7:1–6.10.15171/jpid.2015.001Search in Google Scholar

[39] Hyland PL, Traynor PS, Myrillas TT, Marley JJ, Linden GJ, Winter P, et al. The effects of cyclosporin on the collagenolytic activity of gingival fibroblasts. J Periodontol 2003;74:437–45.10.1902/jop.2003.74.4.437Search in Google Scholar PubMed

[40] Kusztal M, Radwan-Oczko M, Kościelska-Kasprzak K, Boratyńska M, Patrzałek D, Klinger M. Possible association of CTLA-4 gene polymorphism with cyclosporine-induced gingival overgrowth in kidney transplant recipients. Transplant Proc 2007;39:2763–5.10.1016/j.transproceed.2007.09.002Search in Google Scholar PubMed

[41] Luo Y, Gong Y, Yu Y. Interleukin-10 gene promoter polymorphisms are associated with cyclosporin A-induced gingival overgrowth in renal transplant patients. Arch Oral Biol 2013;58:1199–207.10.1016/j.archoralbio.2013.03.015Search in Google Scholar PubMed

[42] Ogino M, Kido J-i, Bando M, Hayashi N, Wada C, Nagata T, et al. α2 Integrin+ 807 polymorphism in drug-induced gingival overgrowth. J Dent Res 2005;84:1183–6.10.1177/154405910508401217Search in Google Scholar PubMed

Received: 2018-10-05
Accepted: 2019-01-10
Published Online: 2019-03-26

©2019 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Minireview
  2. Clinical assessment of arthritic knee pain by infrared thermography
  3. Original Articles
  4. Methanol stem bark extract of Adansonia digitata ameliorates chronic unpredictable mild stress-induced depression-like behavior: Involvement of the HPA axis, BDNF, and stress biomarkers pathways
  5. The protective effect of aqueous extract of Typha capensis rhizomes on cadmium-induced infertility in rats
  6. The aqueous and methanol extracts of Bambusa vulgaris (Poaceae) improve calcium and phosphorus levels, and bone microstructure in ovariectomized model of osteoporosis
  7. Assessment of epigenetic changes and oxidative DNA damage in rat pups exposed to polychlorinated biphenyls and the protective effect of curcumin in the prenatal period
  8. Assessment of heart rate variability for different somatotype category among adolescents
  9. Neuroprotective role of 6-Gingerol-rich fraction of Zingiber officinale (Ginger) against acrylonitrile-induced neurotoxicity in male Wistar rats
  10. Antioxidant activity of crude ethanolic extract and fractions of Ziziphus mauritiana Lam. (Rhamnaceae) leaves from Burkina Faso
  11. In vitro modulation of cytochrome P450 isozymes and pharmacokinetics of caffeine by extracts of Hibiscus sabdariffa Linn calyx
  12. Experimental hypogonadism: insulin resistance, biochemical changes and effect of testosterone substitution
  13. Accelerated wound healing process in rat by probiotic Lactobacillus reuteri derived ointment
  14. Evaluation of inductive effects of different concentrations of cyclosporine A on MMP-1, MMP-2, MMP-3, TIMP-1, and TIMP-2 in fetal and adult human gingival fibroblasts
Downloaded on 28.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/jbcpp-2018-0176/html
Scroll to top button