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Article

Bisphosfonate matrix metalloproteinase inhibitors for the treatment of periodontitis: An in vitro study

  • Authors:
    • Marianna De Colli
    • Paolo Tortorella
    • Mariangela Agamennone
    • Cristina Campestre
    • Fulvio Loiodice
    • Amelia Cataldi
    • Susi Zara
  • View Affiliations / Copyright

    Affiliations: Department of Pharmacy, University ‘G. d'Annunzio’ Chieti‑Pescara, I‑66100 Chieti, Italy, Department of Pharmacy‑Pharmaceutical Science, University ‘A. Moro’ Bari, I‑70125 Bari, Italy
  • Pages: 651-657
    |
    Published online on: April 25, 2018
       https://doi.org/10.3892/ijmm.2018.3641
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Abstract

Periodontitis is an inflammatory disease caused by anaerobic bacteria, including Porphyromonas gingivalis. Lipopolysaccharide (LPS)‑stimulated persistent inflammation is responsible for an increase in matrix metalloproteinase (MMP) expression, resulting in periodontal tissue destruction. The aim of the present study was to investigate synthesized bisphosphonic MMP inhibitors, in an in vitro model consisting of human gingival fibroblasts exposed to LPS, and to compare the biological responses to those induced by zoledronate (ZA), a commercial bisphosphonate. MTT and lactate dehydrogenase (LDH) assays were used to measure cell viability and cytotoxicity, respectively. ELISA was performed to evaluate prostaglandin E2 (PGE2), interleukin (IL)6 and collagen secretion, while western blotting was used to analyze MMP expression. No effect on viability and low cytotoxicity were observed following treatment with bisphosphonate compounds. In the present study, treatment with compound 1 did not increase the release of PGE2 and IL6. Increased levels of collagen I secretion were reported when compound 3 and ZA were administered. An increase of MMP8 was observed following ZA treatment, while a decrease of MMP9 and MMP14 following treatment with compounds 1, 2 and ZA were reported. The performance of compound 1 was optimal in terms of cell viability. Compound 1 also did not induce inflammation, and had the ability to counteract LPS‑induced increases in MMP expression. These data suggested that compound 1 was the most suitable treatment to progress to an in vivo animal study, with the aim to confirm its use for the treatment of periodontitis.
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1 

Laine ML, Crielaard W and Loos BG: Genetic susceptibility to periodontitis. Periodontol 2000. 58:37–68. 2012. View Article : Google Scholar

2 

Darveau RP: Periodontitis: A polymicrobial disruption of host homeostasis. Nat Rev Microbiol. 8:481–490. 2010. View Article : Google Scholar : PubMed/NCBI

3 

Herath TD, Wang Y, Seneviratne CJ, Lu Q, Darveau RP, Wang CY and Jin L: Porphyromonas gingivalis lipopolysaccharide lipid A heterogeneity differentially modulates the expression of IL-6 and IL-8 in human gingival fibroblasts. J Clin Periodontol. 38:694–701. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Park BS and Lee JO: Recognition of lipopolysaccharide pattern by TLR4 complexes. Exp Mol Med. 45:e662013. View Article : Google Scholar : PubMed/NCBI

5 

Garcia de Aquino S, Manzolli Leite FR, Stach-Machado DR, Francisco da Silva JA, Spolidorio LC and Rossa C Jr: Signaling pathways associated with the expression of inflammatory mediators activated during the course of two models of experimental periodontitis. Life Sci. 84:745–754. 2009. View Article : Google Scholar : PubMed/NCBI

6 

Martinho FC, Leite FR, Nóbrega LM, Endo MS, Nascimento GG, Darveau RP and Gomes BP: Comparison of Fusobacterium nucleatum and Porphyromonas gingivalis lipopolysaccharides clinically isolated from root canal infection in the induction of pro-inflammatory cytokines secretion. Braz Dent J. 27:202–207. 2016. View Article : Google Scholar : PubMed/NCBI

7 

Darveau RP, Pham TT, Lemley K, Reife RA, Bainbridge BW, Coats SR, Howald WN, Way SS and Hajjar AM: Porphyromonas gingivalis lipopolysaccharide contains multiple lipid A species that functionally interact with both toll-like receptors 2 and 4. Infect Immun. 72:5041–5051. 2004. View Article : Google Scholar : PubMed/NCBI

8 

Hannas AR, Pereira JC, Granjeiro JM and Tjäderhane L: The role of matrix metalloproteinases in the oral environment. Acta Odontol Scand. 65:1–13. 2007. View Article : Google Scholar : PubMed/NCBI

9 

Sorsa T, Tjäderhane L, Konttinen YT, Lauhio A, Salo T, Lee HM, Golub LM, Brown DL and Mäntylä P: Matrix metal-loproteinases: Contribution to pathogenesis, diagnosis and treatment of periodontal inflammation. Ann Med. 38:306–321. 2006. View Article : Google Scholar

10 

Mäntylä P, Stenman M, Kinane DF, Tikanoja S, Luoto H, Salo T and Sorsa T: Gingival crevicular fluid collagenase-2 (MMP-8) test stick for chair-side monitoring of periodontitis. J Periodontal Res. 38:436–439. 2003. View Article : Google Scholar : PubMed/NCBI

11 

Lagente V and Boichot E: Role of matrix metalloproteinases in the inflammatory process of respiratory diseases. J Mol Cell Cardiol. 48:440–444. 2010. View Article : Google Scholar

12 

Sorsa T, Tjäderhane L and Salo T: Matrix metalloproteinases (MMPs) in oral diseases. Oral Dis. 10:311–318. 2004. View Article : Google Scholar : PubMed/NCBI

13 

Agarwal S, Misra R and Aggarwal A: Induction of metalloproteinases expression by TLR ligands in human fibroblast like synoviocytes from juvenile idiopathic arthritis patients. Indian J Med Res. 131:771–779. 2010.PubMed/NCBI

14 

Vincenti MP and Brinckerhoff CE: Transcriptional regulation of collagenase (MMP-1, MMP-13) genes in arthritis: Integration of complex signaling pathways for the recruitment of gene-specific transcription factors. Arthritis Res. 4:157–164. 2002. View Article : Google Scholar : PubMed/NCBI

15 

Dufour A and Overall CM: Missing the target: Matrix metal-loproteinase antitargets in inflammation and cancer. Trends Pharmacol Sci. 34:233–242. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Aschi M, Besker N, Re N, Pochetti G, Coletti C, Gallina C and Mazza F: Stereoselectivity by enantiomeric inhibitors of matrix metalloproteinase-8: New insights from molecular dynamics simulations. J Med Chem. 50:211–218. 2007. View Article : Google Scholar : PubMed/NCBI

17 

Di Pizio A, Laghezza A, Tortorella P and Agamennone M: Probing the S1′ site for the identification of non-zinc-binding MMP-2 Inhibitors. ChemMedChem. 8:1475–1482. 2013. View Article : Google Scholar

18 

Campestre C, Tortorella P, Agamennone M, Preziuso S, Biasone A, Nuti E, Rossello A and Gallina C: Peptidyl 3-substituted 1-hydroxyureas as isosteric analogues of succinylhydroxamate MMP inhibitors. Eur J Med Chem. 43:1008–1014. 2008. View Article : Google Scholar

19 

Campestre C, Agamennone M, Tauro M and Tortorella P: Phosphonate emerging zinc binding group in matrix metalloproteinase inhibitors. Curr Drug Targets. 16:1634–1644. 2015. View Article : Google Scholar : PubMed/NCBI

20 

Giustiniano M, Tortorella P, Agamennone M, Di Pizio A, Rossello A, Nuti E, Gomez-Monterrey I, Novellino E, Campiglia P, Vernieri E, et al: Amino acid derivatives as new zinc binding groups for the design of selective matrix metallo-proteinase inhibitors. J Amino Acids. 2013:1783812013. View Article : Google Scholar

21 

Rubino MT, Agamennone M, Campestre C, Campiglia P, Cremasco V, Faccio R, Laghezza A, Loiodice F, Maggi D, Panza E, et al: Biphenyl sulfonylamino methyl bisphosphonic acids as inhibitors of matrix metalloproteinases and bone resorption. ChemMedChem. 6:1258–1268. 2011. View Article : Google Scholar : PubMed/NCBI

22 

Tauro M, Loiodice F, Ceruso M, Supuran CT and Tortorella P: Dual carbonic anhydrase/matrix metalloproteinase inhibitors incur porating bisphosphonic acid moieties targeting bone tumors. Biooorg Med Chem Lett. 24:2617–2620. 2014. View Article : Google Scholar

23 

De Colli M, Tortorella P, Marconi GD, Agamennone M, Campestre C, Tauro M, Cataldi A and Zara S: In vitro comparison of new bisphosphonic acids and zoledronate effects on human gingival fibroblasts viability, inflammation and matrix turnover. Clin Oral Invest. 20:2013–2021. 2016. View Article : Google Scholar

24 

Zhao L, Marquis A, La VD, Agamennone M, Loiodice F, Tortorella P and Grenier D: Effects of biphenyl sulfonylamino methyl bisphosphonic acids on Porphyromonas gingivalis and cytokine secretion by oral epithelial cells. Med Chem. 9:855–860. 2013. View Article : Google Scholar

25 

Ettorre V, De Marco P, Zara S, Perrotti V, Scarano A, Di Crescenzo A, Petrini M, Hadad C, Bosco D, Zavan B, et al: In vitro and in vivo characterization of graphene oxide coated porcine bone granules. Carbon. 103:291–298. 2016. View Article : Google Scholar

26 

Stamatova I and Meurman JH: Probiotics and periodontal disease. Periodontol 2000. 51:141–151. 2009. View Article : Google Scholar : PubMed/NCBI

27 

Picolos DK, Lerche-Sehm J, Abron A, Fine JB and Papapanou PN: Infection patterns in chronic and aggressive periodontitis. J Clin Periodontol. 32:1055–1061. 2005. View Article : Google Scholar : PubMed/NCBI

28 

Nip LH, Uitto VJ and Golub LM: Inhibition of epithelial cell matrix metalloproteinases by tetracyclines. J Periodont Res. 28:379–385. 1993. View Article : Google Scholar : PubMed/NCBI

29 

Biasone A, Tortorella P, Campestre C, Agamennone M, Preziuso S, Chiappini M, Nuti E, Carelli P, Rossello A, Mazza F and Gallina C: Alpha-biphenylsulfonylamino 2-methylpropyl phosphonates: Enantioselective synthesis and selective inhibition of MMPs. Bioorg Med Chem. 15:791–799. 2007. View Article : Google Scholar

30 

Wiktorowska-Owczarek A, Namiecińska M and Owczarek J: The effect of ibuprofen on BFGF, VEGF secretion and cell proliferation in the presence of lps in hmec-1 cells. Acta Pol Pharm. 72:889–894. 2015.PubMed/NCBI

31 

Xi ZD, Xie CY and Xi YB: Macrophage migration inhibitory factor enhances lipopolysaccharide-induced fibroblast proliferation by inducing toll-like receptor 4. BMC Musculoskelet Disord. 17:432016. View Article : Google Scholar : PubMed/NCBI

32 

De Colli M, Zara S, di Giacomo V, Patruno A, Marconi GD, Gallorini M, Zizzari VL, Tetè G and Cataldi A: Nitric oxide-mediated cytotoxic effect induced by zoledronic acid treatment on human gingival fibroblasts. Clin Oral Investig. 19:1269–1277. 2015. View Article : Google Scholar

33 

Açil Y, Möller B, Niehoff P, Rachko K, Gassling V, Wiltfang J and Simon MJ: The cytotoxic effects of three different bisphos-phonates in-vitro on human gingival fibroblasts, osteoblasts and osteogenic sarcoma cells. J Craniomaxillofac Surg. 40:e229–e235. 2012. View Article : Google Scholar

34 

Anitua E, Zalduendo M, Troya M and Orive G: PRGF exerts a cytoprotective role in zoledronic acid-treated oral cells. Clin Oral Investig. 20:513–521. 2016. View Article : Google Scholar

35 

Subramani T, Rathnavelu V, Alitheen NB and Padmanabhan P: Cellular crosstalk mechanism of Toll-like receptors in gingival overgrowth (Review). Int J Mol Med. 35:1151–1158. 2015. View Article : Google Scholar : PubMed/NCBI

36 

Dejonckheere E, Vandenbroucke RE and Libert C: Matrix metalloproteinase8 has a central role in inflammatory disorders and cancer progression. Cytokine Growth Factor Rev. 22:73–81. 2011. View Article : Google Scholar : PubMed/NCBI

37 

Kiili M, Cox SW, Chen HY, Wahlgren J, Maisi P, Eley BM, Salo T and Sorsa T: Collagenase-2 (MMP-8) and collagenase-3 (MMP-13) in adult periodontitis: Molecular forms and levels in gingival crevicular fluid and immunolocalisation in gingival tissue. J Clin Periodontol. 29:224–232. 2002. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
De Colli M, Tortorella P, Agamennone M, Campestre C, Loiodice F, Cataldi A and Zara S: Bisphosfonate matrix metalloproteinase inhibitors for the treatment of periodontitis: An in vitro study. Int J Mol Med 42: 651-657, 2018.
APA
De Colli, M., Tortorella, P., Agamennone, M., Campestre, C., Loiodice, F., Cataldi, A., & Zara, S. (2018). Bisphosfonate matrix metalloproteinase inhibitors for the treatment of periodontitis: An in vitro study. International Journal of Molecular Medicine, 42, 651-657. https://doi.org/10.3892/ijmm.2018.3641
MLA
De Colli, M., Tortorella, P., Agamennone, M., Campestre, C., Loiodice, F., Cataldi, A., Zara, S."Bisphosfonate matrix metalloproteinase inhibitors for the treatment of periodontitis: An in vitro study". International Journal of Molecular Medicine 42.1 (2018): 651-657.
Chicago
De Colli, M., Tortorella, P., Agamennone, M., Campestre, C., Loiodice, F., Cataldi, A., Zara, S."Bisphosfonate matrix metalloproteinase inhibitors for the treatment of periodontitis: An in vitro study". International Journal of Molecular Medicine 42, no. 1 (2018): 651-657. https://doi.org/10.3892/ijmm.2018.3641
Copy and paste a formatted citation
x
Spandidos Publications style
De Colli M, Tortorella P, Agamennone M, Campestre C, Loiodice F, Cataldi A and Zara S: Bisphosfonate matrix metalloproteinase inhibitors for the treatment of periodontitis: An in vitro study. Int J Mol Med 42: 651-657, 2018.
APA
De Colli, M., Tortorella, P., Agamennone, M., Campestre, C., Loiodice, F., Cataldi, A., & Zara, S. (2018). Bisphosfonate matrix metalloproteinase inhibitors for the treatment of periodontitis: An in vitro study. International Journal of Molecular Medicine, 42, 651-657. https://doi.org/10.3892/ijmm.2018.3641
MLA
De Colli, M., Tortorella, P., Agamennone, M., Campestre, C., Loiodice, F., Cataldi, A., Zara, S."Bisphosfonate matrix metalloproteinase inhibitors for the treatment of periodontitis: An in vitro study". International Journal of Molecular Medicine 42.1 (2018): 651-657.
Chicago
De Colli, M., Tortorella, P., Agamennone, M., Campestre, C., Loiodice, F., Cataldi, A., Zara, S."Bisphosfonate matrix metalloproteinase inhibitors for the treatment of periodontitis: An in vitro study". International Journal of Molecular Medicine 42, no. 1 (2018): 651-657. https://doi.org/10.3892/ijmm.2018.3641
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