Journal of Periodontal and Implant Science

Korean Academy of Periodontology (대한치주과학회)
권호 표지

Inhibiton of MMP-13 mRNA expression by Doxycycline combination with Mefenamic Acid in the rat Periodontal ligament cells

백서 치주인대세포에서 Doxycycline의 Mefenamic Acid 병용사용 시 MMP-13mRNA 발현 억제 효과

  • Seo, Jin-Hee (Dept. of Periodonology, Chonnam National University, Graduate School, Dept. of Dental Science, Chonnam National University) ;
  • Ciu, De-Zhe (Graduate School, Dept. of Dental Science, Chonnam National University, Dental Science Research Institute, Chonnam National University) ;
  • Kim, Young-Joon (Dept. of Periodonology, Chonnam National University, Dental Science Research Institute, Chonnam National University)
  • 서진희 (전남대학교 치과대학 치주과학교실, 전남대학교 대학원 치의학과) ;
  • 최득철 (전남대학교 대학원 치의학과, 전남대학교 치의학연구소) ;
  • 김영준 (전남대학교 치과대학 치주과학교실, 전남대학교 치의학연구소)
  • Published : 2005.03.30
Download PDF
⟨ Previous Next ⟩

Abstract

It has been focused on the importance of the host inflammatory response in periodontal pathogenesis and progression, treatment has been introduced to control the host response and the method, which diminishes production and activity of MMP by doxycycline, has been used in periodontal field. MMP is a proteolytic enzyme which plays a major role in tissue destruction and MMP-1 is secreted in the periodontally healthy tissue, while MMP-8, 9, 13, etc in the inflammatory state. Among these, MMP-13 has been discovered lately and reported to degrade primarily type II collagen. Periodontal ligament (PDL) cell plays a role in destruction of periodontal tissue. This study was to evaluate the effect of doxycycline and mefenamic acid, non-steroidal antiinflammatory drug on MMP-13 mRNA expression in the rat PDL cell. Doxycycline concentration of $1{\sim}100\;{\mu}g/ml$ was added rat PDL cell and cell activity was measured by MIT assay at day 1 and 3. MMP-13 gene expression was evaluated by RT-PCR after PDL cells were pre-treated for 1hour with doxycycline (50 ${\mu}g/ml$) alone or with mefenamic acid ($10^{-6}M$), then added $IL-1{\beta}$(1.0 ng/ml) and incubated for 16-18 hours. The results are as follows: 1. Cell activity decreased Significantly at 24 and 72 hours in 100 ${\mu}g/ml$ (p<0.05). 2. Level of MMP-13 mRNA was in 20.2% increase by $IL-1{\beta}$ and in pre-treating doxycycline group, expression of $IL-1{\beta}$ induced MMP-13 mRNA was inhibited by 31% than $IL-1{\beta}$ treated only. 3. Mefenamic acid did not inhibit on the expression of $IL-1{\beta}$ induced MMP-13 mRNA, while mefenamic acid in combination with doxycycline inhibited the expression by 41% compared to only $IL-1{\beta}$ stimulation. These results suggest that doxycycline synergistically inhibit the expression of $IL-1{\beta}$ induced MMP-13 mRNA in combination with mefenamic acid.

Keywords

References

  1. Offenbacher S. Periodontal diseases: pathogenesis. Ann Periodontol 1996;1:821-878 https://doi.org/10.1902/annals.1996.1.1.821
  2. Preshaw PM, Hefti AF, Jepsen S, Etienne D, Walker C, Bradshaw MH. Subantimicrobial dose doxycycline as adjunctive treatment for periodontitis. A review. J Clin Periodontol 2004;31:697-707 https://doi.org/10.1111/j.1600-051X.2004.00558.x
  3. Birkedal-Hansen H. Role of matrix metalloproteinases in human periodontal diseases. J Periodontol 1993;64:474-484
  4. Birkedal-Hansen H, Moore WG, Bodden MK, Windsor LJ, Birkedal-Hansen B, Decarlo A, Engler JA. Matrix metalloprotenases. A review. Crit Rev Oral Biol Med 1993;4:197-250
  5. Ryan ME, Ramamurthy NS, Golub LM. Matrix metalloprotinases and their inhibition in periodontal treatment. Curr Opin Periodontol 1996;3:85-96
  6. Fullmer H, Gibson W. Collagenolytic activity of gingivae of man. Nature 1966;209;728-729 https://doi.org/10.1038/209728a0
  7. Golub LM, Ciancio S, Ramamamurthy NS, Leung M, McNamara TF. Low-dose doxycycline therapy: effect on gingival and crevicular fluid collagenase activity in humans. J Periodont Res 1990;25:321-330 https://doi.org/10.1111/j.1600-0765.1990.tb00923.x
  8. Golub L, Lee H, Greenwald R, Ryan M, Sorsa T, Salo T, Giannobile W. A matrix metalloproteinase inhibitor reduces bone-type collagen degradation fragment and bone-type collagenase in gingival crevicular fluid during adult periodontitis. Inflam Res 1997;4:310-319
  9. Freije JMP, Diez-Itza I, Balbin M, Sanchez LM, Blasco R, Tolivia J, Lopez-Ortin C. Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinse produced by breast carcinomas. Biol Chem 1994;269:16766-16773
  10. Ejeil AL, Igondjo-Tchen S, Ghomrasseni S, Pellat B, Godeau G, Gogly B. Expression of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP) in healthy and diseased human gingiva. J Periodontol 2003;74:188-195 https://doi.org/10.1902/jop.2003.74.2.188
  11. 조종희, 김상목, 김병옥, 한경윤. 테트라사이클린계 약물이 치은섬유아세포내 MMP-13의 활성도에 미치는 영향. 대한치주과학회지 1999;29:677-691
  12. Golub LM, Sorsa T, Lee HM , Ciancio S, Sorbi D, Ramamurthy N S, Gruber B, Salo T, Konttinen YT. Doxycycline inhibits neutrophil (PMN)-type matrix metalloproteinases in human adult periodontitis gingiva. J Clin Periodontol 1995;22:100-109 https://doi.org/10.1111/j.1600-051X.1995.tb00120.x
  13. Smith GN Jr, Mickler EA, Hasty KA, Brandt KD. Specificity of inhibition of matrix metalloproteinase activity by doxycycline: relationship to structure of the enzyme. Arthritis Rheum 1999;42:1140-1146
  14. Greenwald RA, Moak SA, Ramamurthy NS, Golub LM. Tetracycline suppresses metalloproteinase activity in adjuvant arthritis and in combination with flurbiprofen, ameliorates bone damage. J Rheumatol 1992;19:927-938
  15. Lee HM, Cinacio S, Tuter G, Ryan ME, Komaroff E, Golub LM. Subantimicrobial dose doxycycline efficacy as a matrix metalloproteinases inhibitor in chronic periodontitis patients is enhanced when combined with a non-steroidal antiinflammatory drug. J Periodontol 2004;75:453-463 https://doi.org/10.1902/jop.2004.75.3.453
  16. Nishikawa M, Yamaguchi Y, Yoshitake K, Seaki Y. Effects of TNFalpha and prostaglandin E2 on the expression of MMPs in human periodontal ligament fibroblasts. J Periodont Res 2002;37:167-76 https://doi.org/10.1034/j.1600-0765.2002.00656.x
  17. Matsuda N, Lin WL, Kumar NM, Cho MI, Genco RJ. Mitogenic chemotactic and synthetic responses of rat periodontal fibroblastic cells to polypeptide growth factors in vitro. J Periodontol 1992;63:515-525 https://doi.org/10.1902/jop.1992.63.6.515
  18. Golub LM, Suomalainen K, Sorsa T. Host modulation with tetracyclines and their chemically-modified analogs. Curr Op Dent 1992;2:80-90
  19. Golub LM, Lee HM, Ryan ME, Giannobile WV, Payne J, Sorsa T. Tetracyclines inhibit connective tissue break down by multiple non-antimicrobial mechanisms. Adv Dent Res 1998;12:12-26 https://doi.org/10.1177/08959374980120010501
  20. Thomas J, Metheny R, Karakioris JM, Wetzel M, Crout R. Long-term subantimicrobial doxycycline (Periostat) as adjunctive management in adult periodontitis. 1. Effects on subgingival bacterial population dynamics. Adv Dent Res 1998;12:32-39 https://doi.org/10.1177/08959374980120011601
  21. Walker C, Thomas J, Nango S, Lennon J, Wetzel J, Powala C. Long-term treatment with subantimicrobial dose doxycycline exerts no antibacterial effect on the subgingival microflora associated with adult periodontitis. J Periodontol 2000;71:1465-1471 https://doi.org/10.1902/jop.2000.71.9.1465
  22. Skidmore R, Walker C, Kouach R, Thomas J, Bradshaw M, Leyden J, Powala C, Ashley R. Effects of sub-antimicrobial dose doxycycline in the treatment of moderate acne. Arch Dermatol 2003;139:459-464 https://doi.org/10.1001/archderm.139.4.459
  23. MacNaul KL., Chartrain N, Lark M, Tocci MJ, Hutchinson NI. Discoordinate expression of stromelysin, collagenase, and tissue inhibitor of metalloproteinases-1 in rheumatoid human synovial fibroblasts. Synergistic effects of interleukin-I and tumor necrosis factor-alpha on stromelysin expression. J Bio Chem 1990;265:17238-17245
  24. Kirkwood K, Martin T, Agnello K, Kim YJ. Differential regulation of MMP-13 by chemical modified tetracycline in osteoblasts. J Int Acad Peiodontol 2004;6:39-46
  25. Chang YC, Yang SF, Lai CC, Liu JY, Hsieh YS. Regulation of matrix metalloproteinase production by cytokines, pharmacological agents and periodontal pathogens in human periodontal ligament fibroblast cultures. J Periodontal Res 2002;37:196-203 https://doi.org/10.1034/j.1600-0765.2002.00663.x
  26. Ramamurthy NS, Greenwald RA, Moak S. CMT/tenidap treatment inhibits TMJ destruction in adjuvant arthritis (AA) rats. Ann NY Acad Sci 1994;732:140-151 https://doi.org/10.1111/j.1749-6632.1994.tb24731.x
  27. Cohen DM, Lee HM, Bhattacharyya I, Sensat ML, Payne JB, Golub LM. Effective treatment for cicatricial pemphigoid using a novel combination therapy. J Clin Oncol 2001;19:584-592
  28. Golub LM, Lee HM, Ryan ME, Giannobile WV, Payne J, Sorsa T. Tetracyclines inhibit connective tissue breakdown by multiple non-antimicrobial actions. Adv Dent Res 1998;12:12-26 https://doi.org/10.1177/08959374980120010501
  29. Wasil M, Halliwell B, Moorhouse CP. Scavenging of hypochlorose acid by tetracycline, rifampicin and some other antibiotics: a possible antioxidant action of rifampicin and tetracycline? Biochem Pharmacol 1988;37;775-778 https://doi.org/10.1016/0006-2952(88)90159-1
  30. Ramamurthy NS, Vernillo AT, Greenwald RA, Lee HM, Sorsa T, Golub LM, Rifkin BR. Reactive oxygen species activate and tetracyclines inhibit rat osteoblast collagenase. J Bone and Miner Res 1993;8:1247-1253
  31. Ryan ME, Ashley RA. How do tetracycline work? Adv Dent Res 1998;12:149-151 https://doi.org/10.1177/08959374980120011101
  32. Nip LH, Uitto VJ, Golub LM. Inhibition of epithelial cell matrix metalloproteinases by tetracyclines. J Periodont Res 1993;28:379-385 https://doi.org/10.1111/j.1600-0765.1993.tb01082.x
  33. Uitto VJ, Airola K, Vaalamo M, Johansson N, Putnins EE, Firth JD, Salonen J, Lopez-Otin C, Saarialho-Kere U, Kahari VM. Collagenase-3 (matrix metalloproteinase-13) expression is induced in oral mucosal epithelium during chronic inflammation. Am J Pathol 1998;152:1489-1499
  34. Caton JG. Evaluation of Periostat for patient management. Compend Con tin Educ Dent 1999;20:451-456
  35. Kapusnik-Uner JE, Sande MA, Chambers HF, Tetracycline, chlormphenicol, erythromycin and miscellaneous antibacterial agents, In: J. G, Hardman, I. E. Limbird, P, B. Molinoff, R. W. Ruddon, A, G, Gilman (eds.), The pharmacological basis of therapeutics, New York: McGraw-Hill, Health Professions Division 1996:1123-1153
  36. Sakellari D, Goodson JM, Socransky SS, Kolokotronis A. Concentration of 3 tetracyclines in plasma, gingival crevice fluid and saliva. J Clin Periodontol 2000;27:53-60 https://doi.org/10.1034/j.1600-051x.2000.027001053.x