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48. Variation of matrix metalloproteinase 1 and 3 haplotypes 50. Ye S. Influence of matrix metalloproteinase genotype on and their serum levels in patients with rheumatoid arthritis cardiovascular disease susceptibility and outcome // and osteoarthritis / S.H. Abd-Allah, S.M. Shalaby, H.F. Cardiovasc Res.-2006.-Vol.69, N 3.-P.636-645.
Pasha et al. // Genet Test Mol Biomarkers.-2012.-Vol.16, N 1.-P.15-20.
49. Visse R., Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry // Circ Res.-2003.-Vol. 92.-P.827-839.
English version: ROLE OF MATRIX METALLOPROTEINASES POLYMORPHISMS IN SYSTEMIC CHRONIC INFLAMMATORY
5k
DISEASES AND CHRONIC PERIODONTITIS
Shynkevich V.I.
Higher State educational if Ukraine "Ukrainian Medical Dental Academy", Poltava
The current evidence links periodontal diseases to diabetes meltus, cardiovascular disease (CVD), rheumatoid arthritis (RA). The main pathogenetic role of matrix metalloproteinases (MMPs) in inflammation is mediation of leukocyte migration, which is associated with overcoming tissue barriers and relate destruction. MMPs polymorphisms may participate in the pathogenesis of some common systemic inflammatory diseases and chronic periodontitis. The review identified common MMPs polymorphisms in diabetes, CVD, RA and chronic periodontitis and allowed to detect that the most ciinically significant polymorphisms such as MMP-3 5A(-1612)6A, MMP-8 C(-799)T and MMP-9 C(-1562)T. The prevalence and significance of MMP polymorphisms in the Ukrainian population have to be explore to determine ist of genotyping for prognosis and choice of chronic periodontitis treatment.
Key words: matrix metalloproteinases, genetic polymorphism, chronic periodontitis, diabetes, cardiovascular diseases, rheumatoid arthritis, pathogenesis
Matrix metalloproteinases (MMPs) hydrolyze components of the extracellular matrix (ECM), remodel normal tissue, guide wound healing, angiogenesis, immune cells migration and regulate the function of cytokines, chemokines, apoptotic ligands releasing etc. These proteinases play a central role in diseases such as regeneration disturbance, cancer, arthritis, periodontitis, fibrosis, tissue ulceration [10, 49].
MMPs degrade not only ECM but non-ECM substrates as well. The ability to cleave non-ECM proteins, such as cell surface membrane proteins, is an important mechanism to regulate cellular functions. Proteolysis can stimulate or deactivate intracellular signaling pathways, such as apoptosis and autophagy pathways. The main effect of MMPs depends on the substrate: MMP null models and transgenic MMP available the same phenotypes as in substrate absence [44].
The main pathogenetic MMPs participation in inflammation is mediation of leukocyte migration, which is associated with overcoming tissue barriers. The cells migration associates with micropores formation in biological membranes, extracellular matrix, and hence results in tissues microdestruction, so MMPs polymorphisms affecting the enzymes function, can enhance or disregulate such destruction.
The current evidence links periodontal diseases to diabetes mellitus, cardiovascular disease (CVD), rheumatoid arthritis (RA) [39]. The phenomenon of the combination of certain diseases in one individual and his relatives defined as syntropia - the combining in one person clinically different diseases with a common pathogenesis. Current clinical experience confirms the frequent combination in one patient diseases such as coronary heart disease, hypertension, atherosclerosis, on the background of obesity and sarkopenia [2].
Inflammatory periodontal disease (chronic gingivitis, periodontitis) rank second after caries by prevalence. Elevated levels of MMP-2, MMP-9 [41] and MMP-8 [31] detected in oral fluid of people with chronic periodontitis (CP). It was identified up-regulated gene MMP-2 in periodontitis-affected gingival tissues; that may be related to the stimulation of leukocyte transendothelial migration [5]. The ratios of MMP-1, MMP-3, MMP-9 from periodontitis lesions were significantly higher [6]. The increased expression of genes MMP-1 and MMP-3 was revealed at refractory periodontitis [43].
Obviously, MMPs polymorphism may participate in the pathogenesis of some common systemic inflammatory diseases and progressive dental. The purpose of the review was to identify common MMPs polymorphisms in diabetes, CVD, RA and chronic periodontitis (CP).
Currently 28 members of MMP family have been identified in humans. The most of them are multidomain proteins with a specific amino acid sequence, have been regulated by endogenous tissue inhibitors of metalloproteinases (TIMP-1-4). Not only activated MMPs, but pro-MMP and TIMP-bound once can realize biological effect [44].
MMPs have not cell specificity. MMPs were often named based on the cell type from which they were first identified. Further research has shown that not only leukocytes, but many others cells expresse different MMPs. Thus, MMP-1, -3 are expressed by gingival fibroblasts and dental pulp odontoblasts [37, 45]. The constitutional MMP-2 production was revealed in vascular smooth muscle cells [24]. MMPs -8, -9 are produced by neutrophils, macrophages, endothelial cells and other cell types [44]. The table shows the variety of cell types that express particular MMPs.
Table
MMP and TIMP cell expression
To cite this English version: Shynkevich V. Role of matrix metalloproteinases polymorphisms in systemic chronic inflammatory diseases and chronic periodontitis / / Problemy ekologii ta medytsyny. - 2013. - Vol 17, № 1-2. - P. 31 -36.
TOM 17. N 1-2 2013 P.
MMPs/TIMPs Additional Names Cell Expression
-1 Collagenase-1; fibroblast collagenase Endothelial, fibroblasts, macrophages
-2 Gelatinase A; 72-kDa type IV collagenase Endothelial, fibroblasts, platelets, T lymphocytes
-3 Stromelysin-1 Endothelial, fibroblasts, macrophages, vascular smooth muscle
-7 Matrilysin Macrophages
-8 Collagenase-2; neutrophil collagenase Neutrophils, endothelial, fibroblasts
-9 Gelatinase B; 92-kDa type IV collagenase Neutrophils, endothelial, eosinophils, macrophages, T lymphocytes
-10 Stromelysin-2 Fibroblasts, T lymphocytes
-11 Stromelysin-3 Fibroblasts
-12 Macrophage elastase Macrophages, stromal cells
-13 Collagenase-3 Fibroblasts
-14 MT1-MMP Fibroblasts, macrophages
-15 MT2-MMP Fibroblasts, macrophages
-16 MT3-MMP Fibroblasts, macrophages, vascular smooth muscle
-17 MT4-MMP Eosinophils, lymphocytes, monocytes
-19 RASI-1 Vascular smooth muscle, endothelial, monocytes
-19 RASI-1 Vascular smooth muscle, endothelial, monocytes
-20 Enamelysin Endothelial
-23 CA-MMP Unknown
-24 MT5-MMP Unknown
-25 MT6-MMP Neutrophils, monocytes
-26 Matrilysin-2 B lymphocytes
-27 CMMP/MMP-22 Fibroblasts
-28 Epilysin Cardiomyocytes, macropahges, T lymphocytes
TIMP-1 Collagenase inhibitor Leukocytes, fibroblasts, mesenchymal stem cells, vascular smooth muscle
TIMP-2 Fibroblasts, macrophages, vascular smooth muscle
TIMP-3 Fibroblasts, pericytes
TIMP-4 Cardiomyocytes, lymphocytes, macrophages, mast cells, vascular smooth muscle
Same MMPs polymorphisms in diabetes and chronic periodontitis
The study [19] suggests that genetic variations within the MMP-3/MMP-12 locus influence susceptibility of diabetic nephropathy in type 1 diabetes in the US population. Authors identified associations at several correlated SNPs across a 29.2kb interval on chromosome 11 q at the MMP-3/MMP-12 locus. The strongest associations occurred at 2 highly-correlated SNPs, rs610950 and rs1277718. Further examination of this locus identified 17 SNPs (2 genotyped SNPs and 15 imputed SNPs) in complete linkage disequilibrium associated with diabetic nephropathy, including a non-synonymous SNP (rs652438, Asn357Ser) located in exon 8 of MMP-12 that significantly reduced the risk of diabetic nephropathy among carriers of the serine substitution relative to homozygous carriers of asparagine.
Higher frequency of the 2G2G polymorphism variant of the MMP-1 gene promoter in diabetic patients with coronary heart disease (OR 5.76, 95% CI (1.24; 26.87)) was found in the Polish population. And a higher frequency of the 2G allele of 1G2G (OR 1.74, CI 95% (1.01; 2.99)) and the G allele of AG polymorphism (OR 2.15, 95% CI (1.22; 3.80)) was also found [14]. It was demonstrated that the polymorphisms in the MMP-1 promoter (1G(-1607)2G, A(-519)G, A(-422)T) may have only a small effect on the etiopathogenesis of chronic periodontitis in the Czech population: thus a trend to increased frequency of the -1607 1G allele was observed in patients with chronic periodontitis (p=0.054). When the groups were further stratified by smoking status, the 1G allele was associated with chronic periodontitis among non-smokers but not among smokers (p=0.033). On the
contrary, the distribution of genotype frequencies of the MMP-1 A(-422A)T polymorphism was different between the patient and control smokers with respect to heterozygotes (73.91% versus 50.91%; p=0.017) [21]. Analysis of the same polymorphisms MMP-1 gene (1G(-1607)2G and A(-519)G) showed no differences in distribution between the healthy and periodontitis group in a Brazilian [17]. The 2G2G genotype of MMP-1 in the periodontitis patients presented frequency of 28% and the control only showed 3% in the Hong Kong populaton [9]. It was concluded that the MMP-1 -1607 polymorphism was not associated with chronic periodontitis in the Brazilian population [7]. Where the extensive chronic antigenic challenge exposure overcomes the genetic control and plays a major role in the determination of MMP-1 expression [40]. The data [8] showed that 2G of MMP-1 -1067 polymorphism associated with decreased susceptibility to CP in Chinese population [8].
C(-1562)T polymorphism MMP-9 gene was associated with a tendency to increased levels of MMP-9 in plasma and was considered as a prognostic marker of diabetic macroangiopathy in type 2 diabetes [16], that connects the pathogenesis diabetes and CVD among the Chinese population.
A systematic review [30] revealed that the MMP-9 gene polymorphism C(-1562)T reduces the risk of CP, like it was studied in the Chinese population. The polymorphism was associated with modified risk of periodontitis among Caucasian populations, although a replication of the results in independent large analysis populations is necessary to give evidence to the observation. Similarly, it was suggested that T allele of
npoSAeMH eKOAorii Ta MejHUHHH
MMP-9 -1562 gene polymorphisms might be associated with decreased susceptibility to severe CP in Turkish population [15].
It may be other polymorphisms, including genotype IL-6 -174 [22] and others cytokines that involved in common link in diabetes and CP pathogenesis.
The same MMPs polymorphisms in cardiovascular diseases and chronic periodontitis
CVD are associated with the development of "parodontal syndrome" as the chronic generalized periodontitis [2]. Efforts to test causality in the relationship between periodontitis and CVD are ongoing. Evidence to date is consistent with the notion that severe generalized periodontitis causes systemic inflammation and endothelial dysfunction. Periodontitis has effects that go beyond the oral cavity and its treatment and prevention may contribute to the prevention of atherosclerosis [1, 36, 46].
The -735T MMP-2 allele represent independent risk factor for thoracic aortic aneurysm in the Italian population in bicuspid aortic valve cases. The effects of these genotypes combined with hypertension and smoking in bicuspid aortic valve cases result in an increase in both the apoptosis (p = 0.0001) and levels of MMP-9 (p = 0.001) [12].
The data [15] suggested that MMP-2 C(-735)T polymorphism are not associated with susceptibility to severe CP in Turkish population.
This is currently best exemplified by the MMP3 gene 5A/6A polymorphism which has an effect on MMP3 expression and has been shown to be associated with coronary stenosis, myocardial infarction, coronary artery calcification, post-angioplasty coronary restenosis, carotid atherosclerosis, stroke, arterial stiffness, and blood pressure [50].
In meta-regression analyses, effect of the MMP3 gene 6A(-1612)5A polymorphism on coronary artery disease was ethnicity-specific (p=0.048), and this effect was more prominent for myocardial infarction patients of East Asians [32].
MMP3 polymorphisms showed association with chronic periodontitis in the US population (for rs679620, p = 0.0003; and rs650108, p = 0.002) and in the Brazilian population (for rs639752, p = 0.005) [28]. Earlier studies demonstrated that MMP-3 gene polymorphism 5A(-1612)6A may contribute to periodontal tissue destruction during periodontitis in Brazilian subjects [17].
The studies [8] showed that MMP-3-1171 6A allele are associated with decreased susceptibility to CP in Chinese population.
MMPs are associated with levels of periapical tissue destruction because of theirs role in bone resorption. It was hypothesized that polymorphisms in MMPs genes may contribute to an individual's increased susceptibility to apical tissue destruction in response to deep carious lesions. The studies [18] revealed that variations in MMP-2 (altered transmission of MMP-2 marker haplotypes (P = 0.000004)) and MMP-3 (rs639752 (P = 0.03) and rs679620 (P = 0.004) genotypes) are associated with periapical lesion formation in individuals with untreated deep carious lesions in US population.
The results [29] suggested that non-smoking Taiwanese with the mMP-8 -799 T allele were associated with the risks of both CP and aggressive periodontitis. No significant relationships between MMP-8 C(-799)T and C(-17)G polymorphisms and CP were found in a Czech population [25].
The same -799TT genotype significantly associated with an increase in serum MMP-8 concentrations (p = 0.047, 0.025). The -799C allele appeared protective against arterial disease in a Finnish population [38].
It is known that MMP-9 is involved in the pathogenesis of atherosclerosis, cardiomyopathia, aortic aneurysm, RA. The investigated MMP-9 promoter C(-1562)T and exon 6 A(R279Q)G polymorphisms influenced gene- and protein expression differently. None of the polymorphisms associated with the presence of coronary artery disease, myocardial infarction or type 2 diabetes, whereas the variant allele of the R279Q polymorphism associated with hypertension (adjusted p=0.015) in a Norwegian population [20].
The MMP-9 rs1056628CC genotype had a significantly increased risk for atherosclerotic cerebral infarction as compared with carries of the rs1056628 A allele (total X2 = 12.041, P = 0.002) in a Chinese population [4].
It was shown that MMP-9 C(-1562)T (rs3918242), 90(CA)(( 14-24)) (rs2234681), Q(-279)R (rs17576)) genotypes and haplotypes affect MMP-9 levels in obese children and adolescents, and suggested that genetic factors may modify relevant pathogenetic mechanisms involved in the development of cardiovascular complications associated with obesity in childhood [27]. It was found lower plasma MMP-9 concentrations in obese subjects carrying the CC or the QQ genotypes for the C-1562T and the Q279R polymorphisms, respectively, in obese children compared with children with the other genotypes, or with non-obese children with the same genotypes (all p<0.05). Moreover, lower MMP-9 levels and lower MMP-9/TIMP-1 ratios (which reflect net MMP-9 activity) were in obese children carrying the H2 haplotype (which combines the C, H and Q alleles for the three polymorphisms, respectively) when compared with obese children carrying the other haplotypes, or with non-obese children carrying the same haplotype (p<0.05).
It was suggested that the functional C(-1562)T polymorphism (rs3918242) located in promoter region of the MMP-9 gene contribute to pathogenetic mechanisms involved in the development of obesity in women [13].
The same -1562C/T polymorphism showed higher T allele frequencies in the patient group with coronary artery disease in an Indian population [23].
In bicuspid aortic valve cases, the MMP-9 -1562T allele represent independent risk factors for thoracic aortic aneurysm [12].
As mentioned above MMP-9 -1562T allele contributed to decreased risk of chronic periodontitis in a Chinese [30] and Turkish populations [15]. And CC genotype of this polymorphism in patients with CP was more frequent (51%) in Chinese population [9].
It was observed interactions between antihypertensive drugs and MMP-12 N(-122)S (rs652438) for coronary heart disease and composite cardiovascular disease in a US population [33].
Same MMPs polymorphisms in rheumatoid arthritis and chronic periodontitis
Rheumatoid arthritis and periodontitis are known to have common immunopathogenetic managers and often combined in one patient [35]. Studies [42] suggested that CP can save as a risk factor for RA. It was shown that the antibody response in periodontitis is predominantly directed to the uncitrullinated peptides of the rA autoantigens. It was proposed that this loss of tolerance could then lead to epitope spreading to citrullinated
Том 17. N 1-2 2013 р.
epitopes as the autoimmune response in periodontitis evolves into that of presymptomatic RA.
Polymorphisms in the loci of matrix metalloproteinase MMP-1 and -3 genes are associated with age at onset of RA in patients of Caucasian origin. The T allele at gene MMP-3 rs3025039 was associated with an increased risk of early onset (HR=1.25 (95% CI 1.0-1.58) for the risk over time; (HR=1.84 (95% CI 1.20-2.83)) for the risk of onset <40 years old. The AA genotype at rs495366 was also associated with an increased risk (HR=1.92 (95% CI 1.27-2.89)) over time; (HR=2.54 (95% CI 1.30-4.95) for onset <40 years old [11].
The MMP1 1G(-1607)2G polymorphism had significant difference between patients with osteoarthritis disease and controls regarding allele distributions, but not between patients with RA and controls, in an Egyptian population [48]. This polymorphism increases sensibility either for coronary artery disease or for CP in different populations, as mentioned [14, 21].
Haplotype of GCGC MMP-2 polymorphisms G(-1575)A, C(-1306)T, T(-790)G, C(-735)T was more frequent in RA patients (Pcorr = 0.016; OR = 0.09; CI 0.00-0.65), whereas GCTC haplotype was noted more frequently in control group (Pcorr = 0.017; OR = 1.8; CI 1.17-2.70) [34].
The haplotype 2G6A of genetic polymorphisms MMP-1 1G(-1607)2G and MMP-3 5A(-1171)6A, which carries the abnormal alleles, showed higher frequencies in the patients with RA and osteoarthritis than in controls (28%, 30% and 8%, respectively) in an Egyptian population (Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt) [48].
It was observed a relationship of Steinbrocker index with the MMP-13 A(-77)G polymorphism (p = 0.082) in UK population with RA: patients of the AA genotype had higher score than patients of the AG or GG genotype (p = 0.005), and the association remained significant after adjusting for age, sex, erythrocyte sedimentation rate, presence of erosive disease, Ritchie score, prednisolone therapy and years of diagnosis (P = 0.003). It was also observed a relationship of Steinbrocker index with the MMP-3 5A(-1612)6A, MMP-7 A(-181)G and MMP-12 А(-82)G polymorphisms (p = 0.082, p = 0.037 and p = 0.045). No association was detected between the MMP-1 1G(-1607)2G and MMP-7 C(-153)T polymorphisms and either Steinbrocker index or Health Assessment Questionnaire score [47].
MMP-3 polymorphisms (rs679620, rs650108, rs639752, 5А(-1612)6А) were found in association with CP in US and Brazilian populations [17, 28].
Thus, it is possible that genes MMP-2 and MMP-3 polymorphisms (5A (-1612) 6A) may be a common risk factor for RA and CP.
Conclusions
The review of literature allowed to detect that the most clinically significant polymorphisms are MMP-3 5A(-1612)6A, MMP-8 C(-799)T and MMP-9 C(-1562)T, which were found significantly more often among patients with cardiovascular disease, rheumatoid arthritis and chronic periodontitis. Investigation of the prevalence of these genetic polymorphisms in Ukraine are important for the prediction of such disease, pharmacogenetic and disease course features.
Prevalence and significance of MMP polymorphisms have to be explored to determine the list of genotyping
for prognosis and choice of chronic periodontitis
treatment in the Ukrainian population.
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