Significance of Tissue Inhibitors of Matrix Metalloproteinases Expression in Pathogenesis and Differential Diagnosis of Periodontal Pathology

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Abstract

Background. The balance of metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) is crucial for the manifestation and progression of periodontal diseases and is one of the promising areas of scientific research in terms of developing methods for selective inhibition of MMPs. Aims — to determine the significance of TIMP1 and TIMP2 expression parameters in gingival biopsies to identify the type of periodontitis at the stage of disease manifestation. Methods. A prospective study with parallel inclusion of patients with different forms of periodontitis in the compared groups was performed. The object of this study were patients with various forms of periodontitis. Pathological examination with morphometric analysis of TIMPs expression and subsequent statistical data analysis was performed using AperioImageScope v12.4.0.5043, Statistica 10.0, MedCalc19.6. Results. The study included 67 patients with aggressive (AgP, Grade C, n = 19), chronic simplex (CSP, Grade В, n = 10) and chronic complex (CCP, in the presence of occlusal trauma, Grade В, n = 38) periodontitis and 15 conditionally healthy patients (control group). The expression of TIMP1 and TIMP2 was detected with variable intensity both in the epithelium and in the stroma of the gingiva, and was significantly higher in periodontitis groups compared with the control group (MeTIMP1/2 = 32%/70%). Parameters of TIMP1 and TIMP2 expression had no significant differences in the groups with AgP (MeTIMP1/2 = 84%/98%) and CCP (MeTIMP1/2 = 83%/94%), except for higher parameters of the positivity of epithelial expression of TIMP2 (U = 61 372; p < 0.05) and lower levels of intensity of its expression in AgP (MeAgP/CCP=180/171; U = 56 491; p < 0.001). Correlation analysis revealed an inverse relationship of TIMPs expression parameters with those MMPs, including those most significant for the development of AgP — MMP1 (ρ = –0.40), MMP8 (ρ = –0.34), and MMP14 (ρ = –0.24). ROC analysis established acceptable informativeness of all studied parameters of total expression and positivity of epithelial expression of TIMP1, as well as positivity of total expression and intensity of epithelial expression of TIMP2 to distinguish between aggressive and chronic forms of periodontitis at the stage of disease manifestation. Conclusion. Our results show an increase in the expression of TIMP1 and TIMP2 in various forms of periodontitis and an inverse relationship with the MMPs inhibited by them. This complements both the fundamental knowledge of the development and progression of periodontal pathology and may have applied significance in terms of using the studied TIMP1 and TIMP2 expression criteria to establish the aggressive course of periodontitis already at the stage of disease manifestation, which will allow to individualize treatment, prevent or slow down tooth loss in order to preserve and/or improve the quality of life of this patient group.

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About the authors

Ludmila A. Kazeko

Belarusian State Medical University

Author for correspondence.
Email: 1kaf.terstom@gmail.com
ORCID iD: 0000-0002-0821-0366
SPIN-code: 7607-7910

MD, PhD, Associate Professor

Belarus, Minsk

Viktoryia A. Zakharava

N.N. Alexandrov National Cancer Centre of Belarus

Email: zakharava.vikt@gmail.com
ORCID iD: 0000-0003-2050-9800
SPIN-code: 6638-7980

MD, PhD, Associate Professor

Belarus, Lesnoy

Julia D. Benesh

Belarusian State Medical University

Email: julia.benesh@gmail.com
ORCID iD: 0000-0003-3207-9203
SPIN-code: 8744-8970

assistant

Belarus, Minsk

Eugeny D. Cherstvoy

Belarusian State Medical University

Email: patanat@bsmu.by
ORCID iD: 0000-0002-2554-1431
SPIN-code: 1350-0976

MD, PhD, Professor

Belarus, Minsk

References

  1. Tatakis D, Kumar P. Etiology and Pathogenesis of Periodontal Diseases. Dent Clin North Am. 2005;49(3):491–516. doi: https://doi.org/10.1016/j.cden.2005.03.001
  2. Verma R, Hansch C. Matrix metalloproteinases (MMPs): Chemical–biological functions and (Q)SARs. Bioorg Med Chem. 2007;15(6):2223–2268. doi: https://doi.org/10.1016/j.bmc.2007.01.011
  3. Григоркевич О.С., Мокров Г.В., Косова Л.Ю. Матриксные металлопротеиназы и их ингибиторы // Фармакокинетика и фармакодинамика. — 2019. —№ 2. — С. 3–16. [Grigorkevich OS, Mokrov GV, Kosova LYu. Matrix metalloproteinases and their inhibitors. Pharmacokinetics and Pharmacodynamics. 2019;2:3–16. (In Russ.)] doi: https://doi.org/10.24411/2587-7836-2019-10040
  4. Gupta S. Quantitative structure-activity relationship studies on zinc-containing metalloproteinase inhibitors. Chem Rev. 2007;107(7):3042–3087. doi: https://doi.org/10.1021/cr030448t
  5. Maskos K. Crystal structures of MMPs in complex with physiological and pharmacological inhibitors. Biochimie. 2005;87(3–4):249–263. doi: https://doi.org/10.1016/j.biochi.2004.11.019
  6. Cathcart JM, Cao J. MMP Inhibitors Past present and future. Front Biosci (Landmark Ed). 2015;20(7):1164–1178. doi: https://doi.org/10.2741/4365
  7. Whittaker M, Ayscought A. Matrix metalloproteinases and their inhibitors – current status and future challenges. Celltransmissions. 2001;17(1):3–14.
  8. Gomez DE, Alonso DF, Yoshiji H, et al. Tissue inhibitors of metalloproteinases: structure, regulation and biological functions. Eur J Cell Biol. 1997;74(2):111–122.
  9. Herron GS, Banda MJ, Clark EJ et al. Secretion of metalloproteinases by stimulated capillary endothelial cells. II. Expression of collagenase and stromelysin activities is regulated by endogenous inhibitors. J Biol Chem. 1986;261(6):2814–2818.
  10. De Clerck Y, Yean TD, Ratzkin BJ, et al. Purification and characterization of two related but distinct metalloproteinase inhibitors secreted by bovine aortic endothelial cells. J Biol Chem. 1989;264(29):17445–17453.
  11. Kubota T, Matsuki Y, Nomura T, et al. In situ hybridization study on tissue inhibitors of metalloproteinases (TIMPs) mRNA-expressing cells in human inflamed gingival tissue. J Periodontal Res. 1997;32(5):467–472. doi: https://doi.org/10.1111/j.1600-0765.1997.tb00559.x
  12. Pavloff N, Staskus PW, Kishnani NS, etg al. A new inhibitor of metalloproteinases from chicken: ChIMP-3. A third member of the TIMP family. J Biol Chem. 1992;267(24):17321–17326.
  13. Apte S, Hayashi K, Seldin M, et al. Gene encoding a novel murine tissue inhibitor of metalloproteinases (TIMP), TIMP-3, is expressed in developing mouse epithelia, cartilage, and muscle, and is located on mouse chromosome 10. Dev Dyn. 1994;200(3):177–197. doi: https://doi.org/10.1002/aja.1002000302
  14. Greene J, Wang M, Liu YE, et al. Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. J Biol Chem. 1996;271(48):30375–30380. doi: https://doi.org/10.1074/jbc.271.48.30375
  15. Bigg H, Shi Y, Liu Y, et al. Specific, high affinity binding of tissue inhibitor of metalloproteinases-4 (TIMP-4) to the COOH-terminal hemopexin-like domain of human gelatinase A. J Biol Chem. 1997;272(24):15496–15500. doi: https://doi.org/10.1074/jbc.272.24.15496
  16. Tokuhara C, Santesso M, Oliveira G, et al. Updating the role of matrix metalloproteinases in mineralized tissue and related diseases. J Appl Oral Sci. 2019;27:e20180596. doi: https://doi.org/10.1590/1678-7757-2018-0596
  17. Chang Y-Ch, Yang S-F, Lai Ch-Ch, et al. Regulation of matrix metalloproteinase production by cytokines, pharmacological agents and periodontal pathogens in human periodontal ligament fibroblast cultures. J Periodontal Res. 2002;37(3):196–203. doi: https://doi.org/10.1034/j.1600-0765.2002.00663.x
  18. Mouzakiti E, Pepelassi E, Fanourakis G, et al. Expression of MMPs and TIMP-1 in smoker and nonsmoker chronic periodontitis patients before and after periodontal treatment. J Periodontal Res. 2012;47(4):532–542. doi: https://doi.org/10.1111/j.1600-0765.2011.01465.x
  19. Rathnayake N, Åkerman S, Klinge B, et al. Salivary biomarkers of oral health — a cross-sectional study. J Clin Periodontol. 2012;40(2):140–147. doi: https://doi.org/10.1111/jcpe.12038
  20. Mattot V, Raes MB, Henriet P, et al. Expression of interstitial collagenase is restricted to skeletal tissue during mouse embryogenesis. J Cell Sci. 1995;108(2):529–535. doi: https://doi.org/10.1242/jcs.108.2.529
  21. Chin JR, Werb Z. Matrix metalloproteinases regulate morphogenesis, migration and remodeling of epithelium, tongue skeletal muscle and cartilage in the mandibular arch. Development. 1997;124(8):1519–1530. doi: https://doi.org/10.1242/dev.124.8.1519
  22. Dew G, Murphy G, Stanton H, et al. Localisation of matrix metalloproteinases and TIMP-2 in resorbing mouse bone. Cell Tissue Res. 2000;299(3):385–394. doi: https://doi.org/10.1007/s004419900166
  23. Hatori K, Sasano Y, Takahashi I, et al. Osteoblasts and osteocytes express MMP2 and -8 and TIMP1, -2, and -3 along with extracellular matrix molecules during appositional bone formation. Anat Rec A Discov Mol Cell Evol Biol. 2004;277(2):262–271. doi: https://doi.org/10.1002/ar.a.20007
  24. Казеко Л.А., Захарова В.А., Анфиногенова Е.А., и др. Значение экспрессии матриксных металлопротеиназ в дифференциальной диагностике патологии пародонта // Архив патологии. — 2021. — Т. 83. — № 3. — С. 20–29. [Kazeko LA, Zakharava VA, Anfinogenova EA, et al. The significance of the expression of matrix metalloproteinases in the differential diagnosis of periodontal diseases. Arkhiv Patologii. 2021;83(3):20–29. (In Russ.)] doi: https://doi.org/10.17116/patol20218303120
  25. Soell M, Elkaim R, Tenenbaum H. Cathepsin C, matrix metalloproteinases, and their tissue inhibitors in gingiva and gingival crevicular fluid from periodontitis-affected patients. J Dent Res. 2002;81(3):174–178.
  26. Taba M, Kinney J, Kim A, et al. Diagnostic biomarkers for oral and periodontal diseases. Dent Clin North Am. 2005;49(3):551–571. doi: https://doi.org/10.1016/j.cden.2005.03.009
  27. Balogun AO, Taiwo JO, Opeodu OI, et al. Impact of Non-Surgical Periodontal Therapy on the Salivary Levels of Tissue Inhibitor of Metalloproteinse-1 (TIMP-1) in Patients with Chronic Periodontitis: A Third World Experience. Open Journal of Stomatology. 2021;11:197–207. doi: https://doi.org/10.4236/ojst.2021.115017
  28. de Brouwer P, Bikker FJ, Brand HS, et al. Is TIMP-1 a biomarker for periodontal disease? A systematic review and meta-analysis. J Periodont Res. 2021;57(2):235–245. doi: https://doi.org/10.1111/jre.12957
  29. Bostanci N., Mitsakakis K., Afacan B, et al. Validation and verification of predictive salivary biomarkers for oral health. Sci Rep. 2021;11(1):6406. doi: https://doi.org/10.1038/s41598-021-85120-w
  30. Pozo P, Valenzuela MA, Melej C, et al. Longitudinal analysis of metalloproteinases, tissue inhibitors of metalloproteinases and clinical parameters in gingival crevicular fluid from periodontitis-affected patients. J Periodontal Res. 2005;40(3):199–207. doi: https://doi.org/10.1111/j.1600-0765.2005.00786.x

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2. Fig. 1. Immunohistochemical staining with antibodies to TIMP1 in the biopsy material of the gums of patients with various forms of periodontitis (×200) (chromogen - DAB, backstaining with Mayer's hematoxylin) and the result of the positive pixel count algorithm of the AperioImageScope program: RPP - rapidly progressive periodontitis; CSP - chronic complex periodontitis; CPP - chronic simple periodontitis

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3. Fig. 2. Immunohistochemical staining with antibodies to TIMP2 in the biopsy material of the gums of patients with various forms of periodontitis (×200) (chromogen — DAB, counterstaining with Mayer's hematoxylin) and the result of the positive pixel count algorithm of the AperioImageScope program: RPP — rapidly progressive periodontitis; CSP - chronic complex periodontitis; CPP - chronic simple periodontitis

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4. Fig. 3. The nature of TIMP1 expression in the biopsy material of the gums of patients with various forms of periodontitis Note. Median is a circle; 25-75% - Min-Max; * — p < 0.05; ** — p < 0.001.

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5. Fig. 4. The nature of TIMP2 expression in the biopsy material of the gums of patients with various forms of periodontitis Note. Median is a circle; 25-75% - Min-Max; * — p < 0.05; ** — p < 0.001.

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6. Fig. 5. Informativeness of TIMP1 indicators for the differential diagnosis of rapidly progressive (grade C) with chronic forms (grade B) periodontitis

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7. Fig. 6. Informativeness of TIMP2 indicators for the differential diagnosis of rapidly progressive (grade C) with chronic forms (grade B) periodontitis

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