Circulating myeloid-derived MMP8 in stress susceptibility and depression.

Psychosocial stress has profound effects on the body, including the immune system and the brain1,2. Although a large number of pre-clinical and clinical studies have linked peripheral immune system alterations to stress-related disorders such as major depressive disorder (MDD)3, the underlying mechanisms are not well understood. Here we show that expression of a circulating myeloid cell-specific proteinase, matrix metalloproteinase 8 (MMP8), is increased in the serum of humans with MDD as well as in stress-susceptible mice following chronic social defeat stress (CSDS). In mice, we show that this increase leads to alterations in extracellular space and neurophysiological changes in the nucleus accumbens (NAc), as well as altered social behaviour. Using a combination of mass cytometry and single-cell RNA sequencing, we performed high-dimensional phenotyping of immune cells in circulation and in the brain and demonstrate that peripheral monocytes are strongly affected by stress. In stress-susceptible mice, both circulating monocytes and monocytes that traffic to the brain showed increased Mmp8 expression following chronic social defeat stress. We further demonstrate that circulating MMP8 directly infiltrates the NAc parenchyma and controls the ultrastructure of the extracellular space. Depleting MMP8 prevented stress-induced social avoidance behaviour and alterations in NAc neurophysiology and extracellular space. Collectively, these data establish a mechanism by which peripheral immune factors can affect central nervous system function and behaviour in the context of stress. Targeting specific peripheral immune cell-derived matrix metalloproteinases could constitute novel therapeutic targets for stress-related neuropsychiatric disorders.

MMP-9/BDNF ratio predicts more severe COVID-19 outcomes.

COVID-19 clinically manifests from asymptomatic to the critical range. Immune response provokes the pro-inflammatory interactions, which lead to the cytokines, reactive oxygen/nitrogen species, peptidases, and arachidonic acid metabolites enlargement and activation of coagulation components. Matrix metalloproteinases (MMPs) contribute to tissue destruction in the development of COVID-19. Due to the endothelial, systemic course of the disease, VEGF A participates actively in COVID-19 development, while neurotrophic and metabolic effects of BDNF recommends for the prediction of complications in COVID-19 patients. Searching for a marker that would improve and simplify the ranking in COVID-19, the study intended to evaluate the relationship of MMP-9 with VEGF A, BDNF, and MMP-8 with the COVID-19 severity. Upon admission to the hospital and before the therapy administration, 77 patients were classified into a mild, moderate, severe, or critical group. Due to the inflammatory stage in COVID-19, a comparison between groups showed related differences in leukocytes, neutrophils, lymphocytes, and platelets counts as anticipated. Only in seriously ill patients, there is a significant increase in the serum concentration of MMP-9, MMP-8, and VEGF A, while BDNF values did not show significant variations between groups. However, all those parameters positively correlated with each other. The ratio of MMP-9/BDNF markedly decreased in the severe and critically patients compared to the mild group. Testing the capability of this ratio to predict the COVID-19 stage by ROC curves, we found the MMP-9/BDNF could be a suitable marker for differentiating stages I/II (AUC 0.7597), stage I/III (AUC 0.9011), and stage I/IV (AUC 0.7727). Presented data describe for the first time the high-level systemic MMP-9/BDNF ratio in patients with COVID-19. This parameter could contribute to a more precise determination of the phase of the disease.

Targeted Inhibition of Matrix Metalloproteinase-8 Prevents Aortic Dissection in a Murine Model.

Aortic dissection (AD) is a lethal aortic pathology without effective medical treatments since the underlying pathological mechanisms responsible for AD remain elusive. Matrix metalloproteinase-8 (MMP8) has been previously identified as a key player in atherosclerosis and arterial remodeling. However, the functional role of MMP8 in AD remains largely unknown. Here, we report that an increased level of MMP8 was observed in 3-aminopropionitrile fumarate (BAPN)-induced murine AD. AD incidence and aortic elastin fragmentation were markedly reduced in MMP8-knockout mice. Importantly, pharmacologic inhibition of MMP8 significantly reduced the AD incidence and aortic elastin fragmentation. We observed less inflammatory cell accumulation, a lower level of aortic inflammation, and decreased smooth muscle cell (SMC) apoptosis in MMP8-knockout mice. In line with our previous observation that MMP8 cleaves Ang I to generate Ang II, BAPN-treated MMP8-knockout mice had increased levels of Ang I, but decreased levels of Ang II and lower blood pressure. Additionally, we observed a decreased expression level of vascular cell adhesion molecule-1 (VCAM1) and a reduced level of reactive oxygen species (ROS) in MMP8-knockout aortas. Mechanistically, our data show that the Ang II/VCAM1 signal axis is responsible for MMP8-mediated inflammatory cell invasion and transendothelial migration, while MMP8-mediated SMC inflammation and apoptosis are attributed to Ang II/ROS signaling. Finally, we observed higher levels of aortic and serum MMP8 in patients with AD. We therefore provide new insights into the molecular mechanisms underlying AD and identify MMP8 as a potential therapeutic target for this life-threatening aortic disease.

Elevated Plasma Matrix Metalloproteinase 8 Associates With Sputum Culture Positivity in Pulmonary Tuberculosis.

Current methods for tuberculosis treatment monitoring are suboptimal. We evaluated plasma matrix metalloproteinase (MMP) and procollagen III N-terminal propeptide concentrations before and during tuberculosis treatment as biomarkers. Plasma MMP-1, MMP-8, and MMP-10 concentrations significantly decreased during treatment. Plasma MMP-8 was increased in sputum Mycobacterium tuberculosis culture-positive relative to culture-negative participants, before (median, 4993 pg/mL [interquartile range, 2542-9188] vs 698 [218-4060] pg/mL, respectively; P = .004) and after (3650 [1214-3888] vs 720 [551-1321] pg/mL; P = .008) 6 months of tuberculosis treatment. Consequently, plasma MMP-8 is a potential biomarker to enhance tuberculosis treatment monitoring and screen for possible culture positivity.

Serum Matrix Metalloproteinase-8 and Myeloperoxidase Predict Survival after Resection of Colorectal Liver Metastases.

INTRODUCTION: Matrix metalloproteinases (MMPs) have been extensively studied in several malignancies, and myeloperoxidase (MPO) is a promising new prognostic biomarker. We investigated the prognostic value of MMP-8, MMP-9, and MPO, as well as carcinoembryonic antigen (CEA), CA19-9, and C-reactive protein (CRP) in colorectal cancer with operable liver metastases. METHODS: This study included 419 patients who underwent liver resection for colorectal metastases at the Helsinki University Hospital between 2000 and 2013. Serum samples were drawn before and 3 months after liver resection. We evaluated associations of MMP-8, MMP-9, MPO, CRP, CEA, and CA19-9 concentrations to disease-free survival (DFS) and overall survival (OS) using the Cox proportional hazards model and Kaplan-Meier log-rank method. RESULTS: In univariate Cox regression analyses, pre- and postoperatively high MMP-8 (HR 1.53, 95% CI: 1.07-2.19, p = 0.021 and HR 1.45, 95% CI: 1.01-2.09, p = 0.044, respectively) associated with worse 10-year OS. Postoperatively high MPO indicated better 5-year DFS (HR 0.70, 95% CI: 0.54-0.90, p = 0.007). Elevated pre- and postoperative CEA and CA19-9 as well as postoperative CRP indicated impaired survival. CONCLUSIONS: Pre- and postoperatively high MMP-8 associates with worse 10-year OS, and postoperatively high MPO associates with better 5-year DFS. CEA, CA19-9, and CRP are also prognostic.

Matrix metalloproteinase MMP-8, TIMP-1 and MMP-8/TIMP-1 ratio in plasma in methicillin-sensitive Staphylococcus aureus bacteremia.

BACKGROUND: Matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinases-1 (TIMP-1) have been shown to predict prognosis in sepsis. However, MMP-8 and TIMP-1 in Staphylococcus aureus bacteremia (SAB) lacks evaluation and their role in the pathogenesis of SAB is unclear. METHODS: MMP-8 and TIMP-1 and MMP-8/TIMP-1 molar ratio were determined at days 3, 5 and 28 from positive blood cultures in patients with methicillin-sensitive SAB and the connection to disease severity and early mortality was determined. RESULTS: Altogether 395 SAB patients were included. Patients with severe sepsis or infection focus presented higher MMP-8 levels at day 3 and 5 (p<0.01). Higher day 3 and 5 MMP-8 levels were associated to mortality at day 14 and 28 (p<0.01) and day 90 (p<0.05). Day 3 MMP-8 cut-off value of 203 ng/ml predicted death within 14 days with an area under the curve (AUC) of 0.70 (95% CI 0.57-0.82) (p<0.01). Day 5 MMP-8 cut-off value of 239 ng/ml predicted death within 14 days with an AUC of 0.76 (95% CI 0.65-0.87) (p<0.001). The results for MMP-8/TIMP-1 resembled that of MMP-8. TIMP-1 had no prognostic impact. In Cox regression analysis day 3 or 5 MMP-8 or day 3 MMP-8/TIMP-1 had no prognostic impact whereas day 5 MMP-8/TIMP-1 predicted mortality within 14 days (HR, 4.71; CI, 95% 1.67-13.3; p<0.01). CONCLUSION: MMP-8 and MMP-8/TIMP-1 ratio were high 3-5 days after MS-SAB diagnosis in patients with an infection focus, severe sepsis or mortality within 14 days suggesting that matrix metalloproteinase activation might play a role in severe SAB.

Causal associations of serum matrix metalloproteinase-8 level with ischaemic stroke and ischaemic stroke subtypes: a Mendelian randomization study.

BACKGROUND AND PURPOSE: Elevated serum matrix metalloproteinase-8 (MMP-8) concentrations are associated with high risk of vascular disease, but the causality remains unclear. A two-sample Mendelian randomization (MR) study was performed to examine the causal effect of serum MMP-8 concentrations on the risk of ischaemic stroke, ischaemic stroke subtypes and coronary artery disease. METHODS: Ten independent single-nucleotide polymorphisms related to serum MMP-8 concentrations were identified as instrumental variables from a genome-wide association study of 6049 European subjects. Genetic association estimates for ischaemic stroke were obtained from the Multiancestry Genome-wide Association Study of Stroke consortium with 446,696 European individuals. The inverse-variance weighted method was applied to assess the causal associations of serum MMP-8 with ischaemic stroke and its subtypes in the main analysis. RESULTS: No significant causal association was observed for MMP-8 levels with total ischaemic stroke, large artery stroke or cardioembolic stroke. Genetically determined 1 - unit higher log-transformed serum MMP-8 concentration was associated with an increased risk of small vessel stroke (odds ratio 1.25; 95% confidence interval 1.12-1.39; p < 0.001). In secondary analysis, a similar adverse impact was reported for MMP-8 on coronary artery disease (odds ratio 1.05; 95% confidence interval 1.01-1.10; p = 0.017). Sensitivity analyses further confirmed the relationship between serum MMP-8 level and small vessel stroke and coronary artery disease. Mendelian randomization Egger regression showed no evidence of pleiotropic bias. CONCLUSIONS: High serum MMP-8 concentrations were causally associated with increased risks of small vessel stroke and coronary artery disease. The mechanism underlying the effect of serum MMP-8 on the vascular system requires further investigation.

Causal Effect of MMP-1 (Matrix Metalloproteinase-1), MMP-8, and MMP-12 Levels on Ischemic Stroke: A Mendelian Randomization Study.

Background and Purpose: MMP (matrix metalloproteinase) levels have been widely associated with ischemic stroke risk and poststroke outcome. However, their role as a risk factor or as a subeffect because of ischemia is uncertain. Methods: We performed a literature search of genome-wide studies that evaluate serum/plasma levels of MMPs. We used a 2-sample Mendelian randomization approach to evaluate the causality of MMP levels on ischemic stroke risk or poststroke outcome, using 2 cohorts: MEGASTROKE (n=440 328) and GODs (n=1791). Results: Genome-wide association studies of MMP-1, MMP-8, and MMP-12 plasma/serum levels were evaluated. A significant association, which was also robust in the sensitivity analysis, was found with all ischemic strokes: MMP-12 (odds ratio=0.90 [95% CI, 0.86­0.94]; q value=7.43×10−5), and with subtypes of stroke, large-artery atherosclerosis: MMP-1 (odds ratio=0.95 [95% CI, 0.92­0.98]; q value=0.01) and MMP-12 (odds ratio=0.71 [95% CI, 0.65­0.77]; q value=5.11×10−14); small-vessel occlusion: MMP-8 (odds ratio=1.24 [95% CI, 1.06­1.45]; q value=0.03). No associations were found in relation to stroke outcome. Conclusions: Our study suggests a causal link between lower serum levels of MMP-12 and the risk of ischemic stroke, lower serum levels of MMP-1 and MMP-12 and the risk of large-artery stroke and higher serum levels of MMP-8 and the risk of lacunar stroke.

High Expression of MMP-9 in Primary Tumors and High Preoperative MPO in Serum Predict Improved Prognosis in Colorectal Cancer with Operable Liver Metastases.

INTRODUCTION: The liver metastases of colorectal cancer (CRC) can be surgically treated in selected cases, with continuously improving results. Matrix metalloproteinases (MMPs) contribute to cancer invasion by degrading the extracellular matrix, and elevated levels of MMP-2, MMP-8, and MMP-9 have been detected in several malignancies. Myeloperoxidase (MPO) is a mediator of tissue damage that can oxidatively activate latent MMPs. We evaluated the prognostic value of MMP-2, MMP-8, and MMP-9 in tissue samples of primary tumors and liver metastases and the pre- and postoperative serum levels of MMP-8, MMP-9, and MPO in CRC patients undergoing liver resection. METHODS: Tissue and serum samples were obtained from 111 patients who had primary colorectal tumors and their liver metastases surgically treated at the Helsinki University Hospital between 1988 and 2007. Tissue expression of MMP-2, MMP-8, and MMP-9 in primary tumors and liver metastases was evaluated by immunohistochemistry. Pre- and postoperative serum concentrations of MMP-8, MMP-9, and MPO were determined using a time-resolved immunofluorometric assay or commercially available enzyme-linked immunosorbent assay kits. Clinical data were retrieved from patient records and the Central Statistical Office of Finland. Associations with disease-free survival (DFS) and overall survival (OS) were estimated using Cox regression analysis and the Kaplan-Meier method. RESULTS: High expression of MMP-9 in colorectal tumor tissue was associated with better DFS (p = 0.010), and high preoperative MPO in serum with improved DFS and OS (p < 0.001 and p = 0.014, respectively). The prognostic significance varied according to gender, age, and the synchronicity of liver metastases. CONCLUSION: Low preoperative MPO in serum might identify patients at high risk of recurrence and death after resection of colorectal liver metastases. Elevated preoperative MPO and high expression of MMP-9 in colorectal tumor tissue indicate an improved prognosis. The use of these biomarkers should be adjusted according to clinical characteristics.

The Impacts of Fish Oil and/or Probiotic Intervention on Low-Grade Inflammation, IGFBP-1 and MMP-8 in Pregnancy: A Randomized, Placebo-Controlled, Double-Blind Clinical Trial.

BACKGROUND: We investigated the impact of fish oil and/or probiotics on serum and vaginal inflammatory and metabolic proteins and their relation to the onset of gestational diabetes mellitus (GDM). METHODS: Overweight/obese pregnant women received fish oil + placebo, probiotics + placebo, fish oil + probiotics or placebo + placebo from early pregnancy until six months postpartum (fish oil: 1.9 g docosahexaenoic acid and 0.22 g eicosapentaenoic acid; probiotics: Lactobacillus rhamnosus HN001 and Bifidobacterium animalis ssp. lactis 420, 1010 colony-forming units each). Serum high sensitivity C-reactive protein (hsCRP) and serum/vaginal (s/v) phosphorylated insulin-like growth factor binding-protein-1 (phIGFBP-1), IGFBP-1 and matrix metalloproteinase 8 (MMP-8) were analyzed. GDM was diagnosed according to 2 h 75 g OGTT. RESULTS: The intervention had no impact on the change in proteins during pregnancy. Nevertheless, s-MMP-8 decreased and s-IGFBP-1 increased more in obese than in overweight women in the fish oil + probiotics group, while a decrease in s-MMP-8 was seen in obese women and an increase was seen in overweight women in the probiotics + placebo group. The late pregnancy s-phIGFBP-1 was higher in women who developed GDM in fish oil + probiotics-group compared to fish oil + placebo-group. The concentrations of s-phIGFBP-1 (635.9 ± 315.3 ng/mL vs. 753.2 ± 335.1 ng/mL, p = 0.005) and s-IGFBP-1 (3.78 ± 0.72 ng/mL vs. 3.96 ± 0.69 ng/mL, p = 0.042) were lower in early pregnancy in women who developed GDM than in women remaining healthy. CONCLUSIONS: The intervention per se had no impact on the proteins, but obesity and GDM may modify the effect. IGFBPs may affect the development of GDM.

MMP-8, TRAP-5, and OPG Levels in GCF Diagnostic Potential to Discriminate between Healthy Patients', Mild and Severe Periodontitis Sites.

Biomarkers represent promising aids in periodontitis, host-mediate diseases of the tooth-supporting tissues. We assessed the diagnostic potential of matrix metalloproteinase-8 (MMP-8), tartrate-resistant acid phosphatase-5 (TRAP-5), and osteoprotegerin (OPG) to discriminate between healthy patients', mild and severe periodontitis sites. Thirty-one otherwise healthy volunteers with and without periodontal disease were enrolled at the Faculty of Dentistry, University of Chile. Periodontal parameters were examined and gingival crevicular fluid was sampled from mild periodontitis sites (M; n = 42), severe periodontitis sites (S; n = 59), and healthy volunteer sites (H; n = 30). TRAP-5 and OPG were determined by commercial multiplex assay and MMP-8 by the immunofluorometric (IFMA) method. STATA software was used. All biomarkers showed a good discrimination performance. MMP-8 had the overall best performance in regression models and Receiver Operating Characteristic (ROC) curves, with high discrimination of healthy from periodontitis sites (area under the curve (AUC) = 0.901). OPG showed a very high diagnostic precision (AUC ≥ 0.95) to identify severe periodontitis sites (S versus H + M), while TRAP-5 identified both healthy and severe sites. As conclusions, MMP-8, TRAP-5, and OPG present a high precision potential in the identification of periodontal disease destruction, with MMP-8 as the most accurate diagnostic biomarker.

Association between Matrix Metalloproteinases, Their Tissue Inhibitor and White Matter Lesions in Mild Cognitive Impairment.

BACKGROUND: White matter lesions are frequently found in mild cognitive impairments and Alzheimer's disease. Matrix metalloproteinases and the tissue inhibitor of metalloproteinases are implicated in amyloid-ß catabolism and blood brain barrier permeability. However, it remains unclear whether they are associated with white matter lesions in Alzheimer's disease. OBJECTIVE: The aim of this study was to examine the association of matrix metalloproteinases and tissue inhibitor of metalloproteinases with white matter degeneration in subjects with amyloid-positive mild cognitive impairment. METHODS: Thirty subjects with amnestic mild cognitive impairment (14 men and 16 women; mean age, 75.6 ± 5.8 years) underwent magnetic resonance imaging, 11C-Pittsburgh Compound B positron emission tomography, and 18F-fluorodeoxyglucose positron emission tomography. Levels of plasma matrix metalloproteinases and tissue inhibitor of metalloproteinases were measured using multiplex assays. All subjects had an abnormal brain amyloid burden. Subjects were divided into two groups according to the presence of white matter lesions using the Fazekas scale. Cognitive function testing results i.e., mean 11C-Pittsburgh Compound B and 18F-fluorodeoxyglucose uptake, concentrations of matrix metalloproteinases and tissue inhibitor of metalloproteinases, and matrix metalloproteinases/tissue inhibitor of metalloproteinases ratios were compared between the groups. Correlation analysis was conducted to investigate the association between Fazekas scale score and clinical and neuroimaging variables as well as concentrations of matrix metalloproteinases and tissue inhibitor of metalloproteinases. RESULTS: Matrix metalloproteinases-2, -8, and -9 levels, matrix metalloproteinases-2/ tissue inhibitor of metalloproteinases-2, matrix metalloproteinases-8/ tissue inhibitor of metalloproteinases-1, and matrix metalloproteinases-9/tissue inhibitor of metalloproteinases-1 significantly increased and tissue inhibitor of metalloproteinases-1 and-2 levels significantly decreased in the group with white matter lesions compared with the group without white matter lesions. Matrix metalloproteinases-2, -8, and -9 levels correlated positively and tissue inhibitor of metalloproteinases-1 and -2 levels correlated negatively with Fazekas scale score. CONCLUSION: Plasma matrix metalloproteinases-2, -8, -9 and tissue inhibitor of metalloproteinases-1 and -2 levels are associated with white matter lesions in the mild cognitive impairment stage of Alzheimer's disease.

Prognostic Role of Matrix Metalloproteinases 2, 7, 8, 9 and Their Type 1 Tissue Inhibitor in Blood Serum of Patients with Kidney Cancer.

The study compared the levels of MMP-2,7,8,9, and TIMP-1 in blood serum of healthy people (N=97) and patients with primary renal cell carcinoma (N=93) to assess relevance of these markers to prognosis of overall survival of these patients, which were followed-up over 1 to 45 months (median 26 months). To evaluate the survival with the Kaplan-Meier estimator, the median values of examined markers in the total group of patients were taken as the threshold levels. This estimator showed that the high levels of serum MMP-7 and MMP-8 were indicative for unfavorable prognosis in the total group of patients with renal cell cancer. Of them, the most significant marker was the level of MMP-7: at its low level (<6.3 ng/ml), a 3-year survival was 93%, whereas survival dropped down to 51% at a higher value of this marker (p<0.001). For MMP-8, the threshold level was 51 ng/ml, and the corresponding survivals were 78 and 58% (p<0.01). The level of MMP-7 was also prognostically significant for the patients with stage I kidney cancer: during a 3-year follow-up, all the patients with low MMP-7 were alive, while the 3-year survival of the patients with a high level of MMP-7 was only 72% (p=0.02). There were the declining trends for survival at high TIMP-1 and low MMP-2. In contrast, the level of MMP-9 virtually did not correlate with survival of the patients with renal cell cancer.

The Role of MMP8 in Cancer: A Systematic Review.

Matrix metalloproteinases (MMPs) have traditionally been considered as tumor promoting enzymes as they degrade extracellular matrix components, thus increasing the invasion of cancer cells. It has become evident, however, that MMPs can also cleave and alter the function of various non-matrix bioactive molecules, leading to both tumor promoting and suppressive effects. We applied systematic review guidelines to study MMP8 in cancer including the use of MMP8 as a prognostic factor or as a target/anti-target in cancer treatment, and its molecular mechanisms. A total of 171 articles met the inclusion criteria. The collective evidence reveals that in breast, skin and oral tongue cancer, MMP8 inhibits cancer cell invasion and proliferation, and protects patients from metastasis via cleavage of non-structural substrates. Conversely, in liver and gastric cancers, high levels of MMP8 worsen the prognosis. Expression and genetic alterations of MMP8 can be used as a prognostic factor by examination of the tumor and serum/plasma. We conclude, that MMP8 has differing effects on cancers depending on their tissue of origin. The use of MMP8 as a prognostic factor alone, or with other factors, seems to have potential. The molecular mechanisms of MMP8 in cancer further emphasize its role as an important regulator of bioactive molecules.

High levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) in the serum are associated with poor prognosis in HPV-negative squamous cell oropharyngeal cancer.

BACKGROUND: An emerging subset of oropharyngeal squamous cell carcinomas (OPSCC) is caused by HPV. HPV-positive OPSCC has a better prognosis than HPV-negative OPSCC, but other prognostic markers for these two different diseases are scarce. Our aim was to evaluate serum levels and tumor expression of matrix metalloproteinase-8 (MMP-8) and tissue inhibitor of metalloproteinase-1 (TIMP-1) and to assess their prognostic role in HPV-positive and HPV-negative OPSCC. MATERIALS AND METHODS: A total of 90 consecutive OPSCC patients diagnosed and treated with curative intent at the Helsinki University Hospital between 2012 and 2016 were included. Serum samples were prospectively collected. An immunofluorometric assay and an enzyme-linked immunosorbent assay were used to determine MMP-8 and TIMP-1 serum concentrations, respectively. HPV status of the tumors was determined using a combination of HPV-DNA genotyping and p16-INK4a immunohistochemistry. The endpoints were overall survival (OS) and disease-free survival (DFS). RESULTS: High TIMP-1 serum levels were strongly and independently associated with poorer OS (adjusted HR 14.7, 95% CI 1.8-117.4, p = 0.011) and DFS (adjusted HR 8.7, 95% CI 1.3-57.1, p = 0.024) among HPV-negative patients; this association was not observed in HPV-positive OPSCC. Although TIMP-1 was immunoexpressed in the majority of the tumor tissue samples, the level of immunoexpression was not associated with prognosis, nor did MMP-8 serum levels. CONCLUSION: Our results indicate that serum TIMP-1 levels may serve as an independent prognostic marker for HPV-negative OPSCC patients.

MMP-8 and TIMP-1 are associated to periodontal inflammation in patients with rheumatoid arthritis under methotrexate immunosuppression - First results of a cross-sectional study.

BACKGROUND: Aim of this cross-sectional study was the investigation of associations between different rheumatoid arthritis (RA)-related blood parameters and periodontal condition as well as selected periodontal pathogenic bacteria in RA patients under methotrexate (MTX) immunosuppression. METHODS: Periodontal probing depth (PPD), bleeding on probing (BOP) and clinical attachment loss (CAL) were assessed. Periodontal condition was classified into: no/mild and moderate or severe periodontitis (P). Prevalence of selected periodontal pathogenic bacteria and concentration of matrix metalloproteinase 8 (MMP-8) was assessed from the gingival crevicular fluid (GCF) using PCR and ELISA, respectively. Blood samples were analyzed for the concentration of selected rheumatoid parameters. STATISTICAL ANALYSIS: t-test, Mann-Whitney-U-Test, exact Fisher tests or chi square test (p < 0.05). RESULTS: Fifty-six patients (mean age 55.07 years, 34 P, 22 no P) were included. While prevalence of periodontal pathogenic bacteria was higher in P patients, no substantial association of bacteria with blood parameters was found. In periodontal diseased participants, MMP-8 concentration in GCF (6.22 ± 7.01 vs. 15.99 ± 13.49; p < 0.01) and blood (2.60 ± 3.57 vs. 5.52 ± 5.92; p < 0.01) was increased, while no correlation between GCF and blood was found (Spearman's rho: 0.175; p = 0.23). Furthermore, higher blood concentrations of MMP-8 and tissue inhibitor of MMP (TIMP-1) were detected in patients with increased periodontal inflammation (BOP positive, p < 0.01). CONCLUSION: Periodontal inflammation appears associated to MMP-8 and TIMP-1 in blood. Thereby, clinical interaction between periodontal conditions, periodontal pathogenic bacteria and RA-related cytokines remain unclear.

Stress-related hormones in association with periodontal condition in adolescents-results of the epidemiologic LIFE Child study.

OBJECTIVES: The aim of this study was to investigate the associations between blood levels of stress-related hormones and early signs of periodontal disease in children and adolescents. MATERIALS AND METHODS: Within the LIFE (Leipzig research center for civilization diseases) Child study, 498 adolescents (10 to 18 years) were included. Early signs of periodontal inflammation were measured by probing depth (PD) at six index teeth (16, 11, 26, 36, 31, 46). Blood levels of stress-related hormones (cortisol, dehydroepiandosterone-sulfate [DHEA-S]) and, additionally interleukine-6 (IL-6) were measured. Socioeconomic status, oral hygiene, orthodontic appliances, and nutritional status, recorded by body-mass-index-standard-deviation-score (BMI-SDS), were considered as confounding factors. Additionally, in 98 participants, an oral chairside active matrix metalloproteinase-8 (aMMP-8) test was performed. Statistical tests are the Mann-Whitney U tests, chi-squared tests and multivariate logistic regression model. RESULTS: IL-6, BMI-SDS as well as positive aMMP-8 test result were significantly associated with maximum PD > 3 mm (p < 0.05). However, no statistically significant associations between stress-related hormones (cortisol and DHEA-S) and presence of maximum PD > 3 mm were found (p > 0.05). Higher DHEA-S and BMI were associated with positive aMMP-8 result, even after adjusting for age and gender (p = 0.027, padj = 0.026). CONCLUSION: The results reveal no associations between PD and stress-related hormones cortisol and DHEA-S. aMMP-8 test result might be associated with DHEA-S level. Nutritional status seems to influence periodontal disease in adolescents. CLINICAL RELEVANCE: DHEA-S and BMI-SDS show associations with early signs of periodontal disease in adolescents aged 10 to 18 years. This association should be confirmed by the investigation of high-risk groups.

The association between serum metalloproteinase concentration, obesity, and hormone levels in reproductive-aged women.

INTRODUCTION: Increased levels and activity of some matrix metalloproteinases (MMPs) are described in obesity-related vascular diseases. Factors that influence MMP blood concentration are still being investigated. This research aims to evaluate the concentration of most types of MMPs: collagenases (MMP-1, -3, -8, -13), matrilysin (MMP-7), gelatinase (MMP-9), and metalloelastase (MMP-12) in serum of women in reproductive age in relation with their body mass index (BMI), age, oestradiol, and progesterone concentrations. MATERIAL AND METHODS: Blood samples were taken from 54 healthy reproductive-aged women with normal menstrual cycles. The weight and height of all women were measured, and body mass index (BMI) was calculated. Concentration of MMP-1, -3, -7, -8, -9, -12, and MMP-13 was evaluated using a Procarta Immunoassay Kit. Serum concentrations of oestradiol and progesterone were evaluated by immunochemiluminescence (32 in the proliferative and 20 in the secretory phase of menstrual cycle). The results of the study were statistically calculated using Pearson, Spearman, and Kruskal-Wallis tests. RESULTS: Positive correlation between MMP-7, -8, -9, -12, and -13 levels and BMI was demonstrated. Significantly higher concentrations of MMPs were found especially in obese women compared to women with normal BMI. In healthy, regularly menstruating premenopausal women, MMP levels did not correlate with oestradiol and progesterone concentrations. CONCLUSIONS: The results suggest that body mass can influence MMP serum concentration in women with regular menstrual cycles.

Serum matrix metalloproteinase 8 and tissue inhibitor of metalloproteinase 1: Potential markers for malignant transformation of recurrent respiratory papillomatosis and for prognosis of laryngeal cancer.

BACKGROUND: Biomarkers that could predict malignant transformation of recurrent respiratory papillomatosis (RRP) would be useful in patient follow-up. We investigated whether serum matrix metalloproteinase 8 (MMP-8) and tissue inhibitor of metalloproteinase 1 (TIMP-1) could predict malignant transformation of RRP and whether they associate with survival in laryngeal squamous cell carcinoma (LSCC) without preexisting RRP. METHODS: We analyzed serum MMP-8 (S-MMP-8) and serum TIMP-1 (s-TIMP-1) in 114 patients: 55 were treated for RRP and 59 for LSCC without preexisting RRP. Five patients with RRP developed LSCC during follow-up. RESULTS: Elevated S-MMP-8 level in RRP was associated with malignant transformation (P = .01). Compared to patients with RRP, S-MMP-8 in patients with LSCC was significantly higher (P < .001). Increased S-TIMP-1 level in LSCC was associated with poor overall survival (P = .02) and recurrence-free survival (P = .05). CONCLUSION: In RRP, high S-MMP-8 may predict malignant transformation. In LSCC, elevated S-TIMP-1 is connected to poor survival.