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Effects of cyclosporine and phenytoin on biomarker expressions in gingival fibroblasts of children and adults: an in vitro study

  • Surena Vahabi , Bahareh Nazemi Salman EMAIL logo , Fahimeh Rezazadeh and Mahshid Namdari
Published/Copyright: August 2, 2013

Abstract

Background: Both phenytoin (PhT) and cyclosporine (CsA) have been related to gingival overgrowth, but the presence and incidence of cytokines in gingival tissues are associated with different mechanisms. On the basis of a few epidemiologic data, children are more prone to have gingival overgrowth than adults and there is no obvious plausibility to justify this difference. The aim of this study was to investigate the effect of PhT and CsA on the some biological marker expression and compare it among adults and children.

Methods: Gingival fibroblasts that had been harvested from adults and children with normal gingiva were incubated with CsA and PhT and then cultured for 48 h. Matrix metalloproteinases (MMP-1 and MMP-2), tissue inhibitor of metalloproteinases (TIMP), collagen (CoL), elastin (Eln), lysyl oxidase (Lysyl), cathepsin (Cat) L and B, and mRNA levels in culture were determined by reverse transcription polymerase chain reaction. The amounts of transforming growth factor-β (TGF-β) and epidermal growth factor (EGF) were assessed by enzyme-linked immunosorbent assay.

Results: CsA and PhT stimulated TGF-β and Cat B production and inhibited expression of MMP-1 by fibroblasts. CsA suppressed TIMP in children, but PhT stimulated its expression. In adults, both CSA and PHT increased TGF-β, Lysyl, and EGF levels. CsA reduced Eln level, whereas PhT increased it.

Conclusions: The results suggest that CsA and PhT have different effects on biogene marker expression in adults and children, or drug-induced gingival overgrowth is affected by different cellular pathways in children in contrast to that in adults. It seems that in children the MMP-1/TIMP system, and in adults the Lysyl/Eln pathway, plays an important role in impaired CoL metabolism.


Corresponding author: Dr. Bahareh Nazemi Salman, DDS, MSc, Assistant Professor, Dental School, ZUMS, Zanjan, Iran, Phone: +98 21 88680842, +98 912 3777185, E-mail:

Acknowledgments

The authors would like to thank the research committee of Shahid Beheshti University of Medical Sciences for its kind support of this project.

Conflict of interest statement

Authors’ conflict of interest disclosure: The authors stated that there are no conflicts of interest regarding the publication of this article. Research support 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.

Research funding: This study was supported by a grant from Shahid Beheshti Medical University, Tehran, Iran.

Employment or leadership: None declared.

Honorarium: None declared.

References

1. Mavrogiannis M, Ellis JS, Thomason JM, Seymour RA. The management of drug-induced gingival overgrowth. J Clin Periodontol 2006;33:434–9.10.1111/j.1600-051X.2006.00930.xSearch in Google Scholar PubMed

2. Brunet L, Miranda J, Farré M, Berini L, Mendieta C. Gingival enlargement induced by drugs. Drug Saf 1996;15:219–31.10.2165/00002018-199615030-00007Search in Google Scholar PubMed

3. Gonzalez OA, Gonzalez JM. Morphological and phenotypic difference in fibroblasts obtained from gingival overgrowth secondary to phenytoin: pilot study. Rev Odont Mex 2009;13:17–23.Search in Google Scholar

4. Wright G, Welbury RR, Hosey MT. 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

5. Silverstein LH, Koch JP, Lefkove MD, Garnick JJ, Singh B, Steflik DE. Nifedipine-induced gingival enlargement around dental implants: a clinical report. J Oral Implantol 1995;21:116–20.Search in Google Scholar

6. Reynolds EH. Chronic antiepileptic toxicity, a review. Epilepsia 1975;16:319–52.10.1111/j.1528-1157.1975.tb06062.xSearch in Google Scholar PubMed

7. Bhatia A, Prakash S. Topical phenytoin for wound healing. Dermatol Online J 2004;10:5.10.5070/D30Z3612W1Search in Google Scholar

8. Doufexi A, Mina M, Loannidou E. Gingival overgrowth in children: epidemiology, pathogenesis and complications, a literature review. J Periodontol 2005;76:3–10.10.1902/jop.2005.76.1.3Search in Google Scholar PubMed

9. Carranza FA, Take H, Newman M. Clinical periodontology, 10th ed. Philadelphia: WB Saunders, 2007:270–2.Search in Google Scholar

10. Guncu GN, Caglayan F, Dincel A, Bozkurt A, Saygi S, Karabulut E. Plasma and gingival crevicular fluid phenytoin concentrations as risk factors for gingival overgrowth. J Periodontol 2006;77:2005–10.10.1902/jop.2006.060103Search in Google Scholar PubMed

11. Yamada H, Nishimura F, Naruishi K, Chou H, Takashiba S, Albright GM, et al. Phenytoin and cyclosporin A suppress the expression of MMP1, TIMP1 and cathepsin L, but not cathepsin B in cultured gingival fibroblast. J Periodontol 2000;71:955–60.10.1902/jop.2000.71.6.955Search in Google Scholar PubMed

12. Everts V, Van der zee E, Creemers L, Beertsen W. Phagocytosis and intracellular digestion of collagen its role in turn over and remodeling. Histochem J 1996;28:229–45.10.1007/BF02409011Search in Google Scholar PubMed

13. O’Valle F, Mesa FL, Gomez-Morales M, Aguilar D, Caracuel MD, Medina-Cano MT, et al. Immunhistochemical study of 30 cases of cyclosporine A-induced gingival overgrowth. J Periodontol 1994;65:724–30.10.1902/jop.1994.65.7.724Search in Google Scholar PubMed

14. Trackman PC, Kantarci A. Connective tissue metabolism and gingival overgrowth. Crit Rev Oral Biol Med 2004;15:165–75.10.1177/154411130401500305Search in Google Scholar

15. Kato T, Okahashi N, Ohno T, Inaba H, Kawai S, Amano A. Effect of phenytoin on collagen accumulation by human gingival fibroblasts exposed to TNF-α in vitro. Oral Dis 2006;12:156–62.10.1111/j.1601-0825.2005.01175.xSearch in Google Scholar

16. Yucel-Lindberg T, Leiner UH, Modeer T. Effect and interaction of TNF α and bradykinin on interlukin-1 production in gingival fibroblasts. J Periodontal Res 1995;30:186–91.10.1111/j.1600-0765.1995.tb01272.xSearch in Google Scholar

17. Carranza FA, Takei H, Newman M. Clinical periodontology, 9th ed. Philadelphia: WB Saunders, 2002:406–8.Search in Google Scholar

18. Lindhe J, Liljenberg B, Listgarten M. Some microbiological and histological features of periodontal disease in man. J Periodontol 1980;51:264–9.10.1902/jop.1980.51.5.264Search in Google Scholar

19. Myrillas TT, Linden GJ. Cyclosporin A regulates interleukin-1β and interleukin-6 expression in gingiva: implications for gingival overgrowth. J Periodontol 1999;70:294–300.10.1902/jop.1999.70.3.294Search in Google Scholar

20. Contrim P, Martelli-Junior H, Graner E, Sauk JJ, Coletta RD. Cyclosporine A induces proliferation in human gingival fibroblasts via induction of TGF-β1. J Periodontol 2003;74: 1625–33.10.1902/jop.2003.74.11.1625Search in Google Scholar

21. Overall CM, Wrana JL, Sodek J. Independent regulation of collagenase, 72-kDa progelatinase inhibitor expression in human fibroblast by TGF-β. J Biol Chem 1989;264:1860–9.10.1016/S0021-9258(18)94267-5Search in Google Scholar

22. Hong HH, Trackman PC. Cytokine regulation of gingival fibroblast lysyl oxidase, collagen, and elastin. J Periodontol 2002;73:145–52.10.1902/jop.2002.73.2.145Search in Google Scholar PubMed

23. Sasaki T, Maita E. Increased bFGF level in the serum of patients with phenytoin-induced gingival overgrowth. J Clin Periodontol 1998;25:42–7.10.1111/j.1600-051X.1998.tb02362.xSearch in Google Scholar PubMed

24. Birkedal-Hansen H. Role of matrix metalloproteinases in human periodontal diseases. J Periodontol 1993;64:474–84.Search in Google Scholar

25. Woessner JF. Matrix metalloproteinase and their inhibitors in connective tissue remodeling. FASEB J 1991;5:2145–54.10.1096/fasebj.5.8.1850705Search in Google Scholar

26. Kato T, Okahashi N, Kawai S, Kato T, Inaba H, Morisaki I, et al. Impaired degradation of matrix collagen in human gingival fibroblast by the antiepileptic drug, phenytoin. J Periodontol 2005;76:941–50.10.1902/jop.2005.76.6.941Search in Google Scholar

27. Botha PJ. Drug-induced gingival hyperplasia and its management – literature review. J Dent Assoc S Afr 1997;52:659–64.Search in Google Scholar

28. Mjola MP, McFrdyen ML, Connolly C, Nair YP, Govender M, Laher MH. Factors influencing phenytoin-induced gingival enlargement. J Clin Periodontol 2000;27:506–12.10.1034/j.1600-051x.2000.027007506.xSearch in Google Scholar

29. Sternilcht MD, Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 2001;17:436–516.Search in Google Scholar

30. Gillett R, Longhurst P, Johnson NW. Electron microscope quantification of inflammatory infiltrates in childhood gingivitis. J Periodontal Res 1980;15:255–8.10.1111/j.1600-0765.1980.tb00282.xSearch in Google Scholar

31. Solis-Herruzo JA, Brenner DA, Chojkier M. Tumor necrosis factor α inhibits collagen gene transcription and collagen synthesis in cultured human fibroblasts. J Biol Chem 1988;263:5841–5.10.1016/S0021-9258(18)60642-8Search in Google Scholar

32. Bolzani G, Della Coletta R, Martelli Junior H, 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

33. Suzuki AM, Yoshimura A, Ozaki Y, Kaneko T, Hara Y. Cyclosporin A and phenytoin modulate inflammatory responses. J Dent Res 2009;88:1131–6.10.1177/0022034509350566Search in Google Scholar PubMed

34. Modeer T, Dahllof G, Otteskog P. The effect of the phenytoin metabolite P-HPPH on proliferation of gingival fibroblast in vitro. Acta Odontol Scand 1982;40:353–7.10.3109/00016358209024080Search in Google Scholar PubMed

35. Carranza FA, Takei H, Newman M. Clinical periodontology, 10th ed. Philadelphia: WB Saunders, 2007:920–2.Search in Google Scholar

36. Arora PD, Silvestre L, Ganss B, Sodek J. Mechanism of cyclosporin-induced inhibition of intracellular collagen degradation. J Biol Chem 2001;276:14100–9.10.1074/jbc.M010298200Search in Google Scholar PubMed

37. Contrim P, de Andrade CR, Martelli-Junior H, Graner E, Sauk JJ, Coletta RD. Expression of matrix metalloproteinase in cyclosporin-treated in gingival fibroblasts is regulated by TGF-β1 autocrine stimulation. J Periodontol 2002;73: 1313–22.10.1902/jop.2002.73.11.1313Search in Google Scholar PubMed

38. Yoshida T, Nagata J, Yamane A. Growth factors and proliferation of cultured rat gingival cells in response to cyclosporin A. J Periodont Res 2005;40:11–9.10.1111/j.1600-0765.2004.00762.xSearch in Google Scholar PubMed

39. Gagliano N, Moscheni C, Dellavia C, Torri C, Stabellini G, Ferrario VF, et al. Effect of cyclosporin A on human gingival fibroblast collagen turnover in relation to the development of gingival overgrowth: an in vitro study. Biomed Pharmacother 2004;58:231–8.10.1016/j.biopha.2003.12.011Search in Google Scholar PubMed

40. James JA, Irwin CR, Linden GJ. Gingival fibroblast response to cyclosporin A and transforming growth factor β1. J Periodontal Res 1998;33:40–8.10.1111/j.1600-0765.1998.tb02290.xSearch in Google Scholar PubMed

41. 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

42. Doufexi A, Mina M, Loannidou E. Gingival overgrowth in children: epidemiology, pathogenesis and complications, a literature review. J Periodontol 2005;76:3–10.10.1902/jop.2005.76.1.3Search in Google Scholar PubMed

43. Majola M, Mcfadyen M, Connolly C, Nair Y, Govender M, Laher M. Factors influencing phenytoin-induced gingival enlargement. J Clin Periodontol 2000;27:506–12.10.1034/j.1600-051x.2000.027007506.xSearch in Google Scholar PubMed

44. Greenwood R, Tennison MB, Maguire JH. Phenytoin-induced gingival overgrowth and anti-epileptic co-administration. Epilepsia 1986;27:540.Search in Google Scholar

45. Seymour RA, Heasann PA. Drugs and the periodontium. J Clin Periodontol 1992;19:1–11.Search in Google Scholar

Received: 2013-1-18
Accepted: 2013-6-12
Published Online: 2013-8-2
Published in Print: 2014-5-1

©2014 by Walter de Gruyter Berlin/Boston

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