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

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Supplementary files

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1. 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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2. 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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3. 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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4. 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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5. 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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6. 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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