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Objective: To study prospectively the association of salivary and serum matrix metalloproteinase (MMP)-8, tissue inhibitor of MMPs (TIMP)-1 and interleukin (IL)-6 with periodontal and systemic inflammation in rheumatoid arthritis (RA). We hypothesized that biomarker concentrations reflect inflammation. Methods: Fifty three early untreated RA (ERA) and 28 chronic RA (CRA) patients, underwent rheumatological and dental examinations at baseline and one year later after starting first conventional or biological disease modifying antirheumatic drug. We included 43 control subjects. Saliva and serum samples were analyzed for MMP-8, TIMP-1 and IL-6. Periodontal health was assessed by bleeding on probing (BOP), pocket depth (PD) and periodontal inflammatory burden index (PIBI); RA disease activity was assessed by disease activity score DAS28. Joint destruction was analyzed by the modified Sharp-van der Heijde (SHS) method. Results: Serum MMP-8 (p < .001; p < .001) and IL-6 (p < .001; p = .002) were significantly higher in CRA vs. other study groups during the study. Salivary MMP-8 (p = .010) and IL-6 (p = .010) were significantly higher in ERA vs. other study groups at baseline. Salivary MMP-8 was associated with periodontal parameters. Conclusion: Elevated serum concentrations of MMP-8 and IL-6 in CRA patients reflected chronic RA, while elevated salivary concentrations of MMP-8 levels in ERA patients reflected increased periodontal inflammation. Key messages: Concentrations of inflammatory biomarkers in serum and saliva were different between patients with RA and healthy controls. Concentrations of MMP-8 and of IL-6 in serum were elevated in patients with chronic RA reflecting joint inflammation and the burden of established RA. Concentrations of MMP-8 in saliva was elevated already at the early stage of RA and the level of salivary MMP-8 was associated with poor periodontal health both in patients with early and in those with chronic RA. [ABSTRACT FROM AUTHOR]

The development of several life-long diseases, such as coronary heart disease, is affected by low-grade systemic inflammation. Data on the potential long-term health effects of chronic tonsillitis are limited. Many inflammatory conditions present with enhanced systemic matrix metalloproteinase (MMP)-8 response. In head and neck cancer, high plasma level of tissue inhibitor of metalloproteinase (TIMP)-1 predicts poor prognosis. We analyzed S-MMP-8 with immunofluorometric assay and S-TIMP-1 with an immunosorbent assay in 175 consecutive patients undergoing tonsillectomy for benign tonsillar disease, and in 33 control patients with tonsillar squamous cell carcinoma. Tonsillar human papillomavirus (HPV) status was determined by PCR. In patients with benign tonsillar disease, chronic tonsillitis without hypertrophy was associated with enhanced systemic MMP-8 response. Compared to patients with benign tonsillar disease, patients with tonsillar squamous cell carcinoma had significantly higher concentrations of S-MMP-8 and S-TIMP-1. Neither S-MMP-8 nor S-TIMP-1 correlated with tonsillar HPV positivity. [ABSTRACT FROM PUBLISHER]

Aim. Prediction of prognosis in hepatocellular carcinoma (HCC) is difficult. The aim of this study was to evaluate the prognostic value of serum MMP-8, -9, -13, and TIMP-1 in patients with HCC. Methods. Pre-treatment serum samples from 134 patients with HCC were retrospectively analyzed. The serum concentration of MMP-8 was analyzed with immunofluorometric assay (IFMA), and those of MMP-9, MMP-13, and TIMP-1 were determined by enzyme-linked immunosorbent assays (ELISA). Clinical data were retrieved from patient records and survival data obtained from Statistics Finland. Results. The overall cumulative disease-specific survival was 69% at 1 year, 50% at 2 years, and 33% at 5 years. Kaplan-Meier overall survival analysis showed that patients with low concentrations of serum MMP-8 or TIMP-1 had a statistically significantly better overall survival than patients with high concentrations of serum MMP-8 or TIMP-1 ( P = 0.013 and P = 0.003). Interestingly, the overall survival in patients with high MMP-9/TIMP-1 ratio was statistically significantly better than in those patients with low MMP-9/TIMP-1 ratio ( P = 0.004). Conclusion. Our results suggest that serum MMP-8, TIMP-1, and the ratio of MMP-9/TIMP-1 might be useful adjuncts as predictors of prognosis in patients with HCC. [ABSTRACT FROM AUTHOR]

Objectives.In inflammatory bowel diseases (IBD), matrix metalloproteinases (MMPs) participate in intestinal tissue damage and regenerative processes. MMP activity is inhibited by tissue inhibitors of MMPs (TIMPs) and plasma inhibitor, α2-macroglobulin (α2M). We evaluated serum MMPs, their inhibitors and markers of neutrophil activity, myeloperoxidase (MPO) and human neutrophil elastase (HNE), during glucocorticoid (GC) and anti-TNF-α therapies in pediatric IBD, in aim to find new tools for assessment of therapeutic response. Methods.Serum samples were collected before and within a month after the start of therapy with oral GC ( n = 19) or anti-TNF-α agent ( n = 16), and from 32 pediatric control patients. Serum levels of MMP-7, MMP-9, TIMP-1, TIMP-2, α2M, MPO, and HNE were analyzed with enzyme-linked immunoabsorbent assays (ELISA) and MMP-8 by immunofluorometric assay (IFMA). Disease activity was monitored with erythrocyte sedimentation rate (ESR), CRP, fecal calprotectin (FC), and physician's global assessment of clinical disease activity (PGA). Results. In IBD, pretreatment serum MMP-7, MMP-8, MMP-9, α2M, MPO, and HNE were elevated compared with controls. During GC therapy, MMP-7, TIMP-1, and MMP-7/TIMP-2 decreased (all p < 0.05). During anti-TNF-α therapy, MMP-7 decreased ( p = 0.063), but remained higher than that after GC therapy ( p < 0.05). α2M ( p < 0.05) and HNE ( p < 0.05) increased, the former higher than that in GC-treated patients. The levels of MMPs and their inhibitors did not markedly associate with inflammatory markers in blood or feces. Conclusions.In pediatric IBD, serum MMP-7 mirrors disease activity, and together with TIMP-1, reflects GC therapy response. α2-Macroglobulin expression parallels the anti-TNF-α response. [ABSTRACT FROM AUTHOR]

Background. Matrix metalloproteinases (MMPs), gelatinases, have been associated with otitis media with effusion (OME), but the role of collagenase-2/matrix metalloproteinase-8 (MMP-8) in OME has not been studied previously. We studied the levels, isoenzyme distribution, and activation of MMP-8 in childhood OME, and also the levels of pro- and active forms of MMP-2 and -9 as well as 120 kDa gelatinase complexes were assessed. Methods. Seventy middle ear fluid (MEF) samples were collected from 54 children with OME and classified to mucoid ( n == 39) or serous ( n == 31). MMPs were studied from MEF samples by time-resolved immunofluorometric assay, Western immunoblotting, and gelatin-zymography. Results. MMP-8 was found in its active form in MEF of children with OME. MMP-8 levels were significantly higher in mucous relative to serous OME. The pro- or active MMP-2 and -9 were found in MEF, but no MEF type-specific differences were found. Conclusion. Our results suggest that MMP-8 may play a role in the pathogenesis of childhood OME. New therapeutic strategies with MMP inhibitors targeting MMP-8, but allowing MMP-8 to carry out the protective action, may play a role in the future treatment of otitis media and OME. However, further studies of this topic are needed. [ABSTRACT FROM AUTHOR]

Background. Helicobacter pylori causes gastritis and is the most important risk factor of peptic ulcer disease and gastric cancer. In chronic adulthood H. pylori infection some matrix metalloproteinases (MMPs), which are proteolytic metalloendopeptidases regulated by tissue inhibitors of metalloproteinases (TIMPs), are upregulated. Our aim was to determine circulating levels of MMPs and their regulators TIMP-1, human neutrophil elastase (HNE) and myeloperoxidase (MPO) in childhood H. pylori infection. Design and methods. Twenty-six H. pylori positive and 34 H. pylori negative children whose H. pylori status was verified by histological examination of gastric biopsies were included. Serum samples were analysed by enzyme-linked immunosorbent assay. Results. Significantly decreased serum levels of TIMP-1 were detected in H. pylori-infected children (median, 97.50 ng/mL) as compared to H. pylori-negative children (median, 118.5 ng/mL, p = 0.003). However, there were no significant differences in serum levels of MMP−2, −7, −8, −9, and their regulators HNE and MPO between H. pylori-positive and -negative children. Conclusions. Differing from the recent findings in adulthood H. pylori infection, only circulating TIMP-1 levels were significantly different between H. pylori-positive and -negative children. Whether this reflects the first sign of a proteolytic cascade later leading to increased levels of MMPs remains to be shown. [ABSTRACT FROM AUTHOR]

Background. Helicobacter pylori causes chronic gastritis, peptic ulcer disease, and is the most important risk factor for non-cardia gastric cancer, and has been shown to upregulate matrix metalloproteinases (MMPs) in infected gastric mucosa. MMPs are proteolytic enzymes regulated by tissue inhibitors of metalloproteinases (TIMPs). Aims. We set up this study to find out whether H. pylori gastritis induces systemic MMP response. Methods. Serum samples were collected from patients undergoing gastroscopy; 26 patients had H. pylori gastritis and 18 were H. pylori-negative controls with normal gastric mucosa. Serum MMP levels were analysed by enzyme-linked immunosorbent assay. Results. Significantly elevated serum levels of collagenase-2 (MMP-8), gelatinase B (MMP-9), neutrophil elastase (NE), and myeloperoxidase (MPO), and reduced serum levels of gelatinase A (MMP-2) and TIMP-1 were demonstrated in patients with H. pylori gastritis as compared to H. pylori-negative controls. No significant differences were shown in serum matrilysin-1 (MMP-7) levels. Conclusions. For the first time, we show enhanced MMP-8 response in H. pylori infection together with other neutrophil degranulation products (MMP-9, MPO, NE). Elevated circulating neutrophil degranulation product levels in serum of H. pylori-positive patients reflect accelerated proteolysis and oxidative stress, and may contribute to extraintestinal sequelae, such as cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Objective . Patients with chronic obstructive pulmonary disease (COPD) are prone to acute exacerbations associated with increased morbidity and mortality. One potential group of enzymes causing tissue destruction in this disease includes neutrophil proteinase elastase (NE), collagenase-2 (matrix metalloproteinase-8 (MMP-8)) and gelatinase B (MMP-9). We investigated the activity of NE and the levels of MMP-8 and MMP-9 in a longitudinal setting at and after COPD exacerbation using a non-invasive technique, i.e. induced sputum, to ascertain whether these proteinases play a role in COPD exacerbation. Material and methods . The study included healthy non-smokers (n = 32), healthy smokers (n = 28), patients with stable COPD (n = 15), COPD patients with acute exacerbations (exa) (n = 10) and their recovery (n = 8) after 4 weeks. NE activity by synthetic peptide substrate and spectrophotometry, MMP-8 levels by immunofluorometry and MMP-9 levels by ELISA were analysed from induced sputum supernatants. Results . NE activity and the level of MMP-8 increased highly significantly in patients with COPD exacerbation compared to stable COPD and controls (NE: p = 0.001 and p<0.0001; MMP-8: p<0.001 and p<0.0001). Paired samples showed a decrease of these proteinases during the recovery period after exacerbation (p = 0.03, p = 0.04). The proteinase levels correlated not only with the percentage and number of neutrophils but also with the lung function parameters (FEV1/FVC and diffusion capacity). Conclusions . COPD exacerbations are associated with neutrophil recruitment into the airways but also transient activation and/or elevation of tissue destruction proteinases, such as NE and MMP-8, which can be detected from the induced sputum supernatants of these COPD patients. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinase-9 (MMP-9) has been shown to be involved in the development of diabetic nephropathy (DNP). We studied the levels, molecular forms, and degree of activation of urinary MMP-8, -9, -14, trypsin-1 and -2, as well as tumor-associated trypsin inhibitor (TATI) of DNP patients and healthy controls. Urinary samples were analyzed for MMPs by Western blotting and gelatin zymography and for trypsin-1, -2, and TATI by time-resolved immunofluorometric assays. Total MMP-8 immunoreactivity, the proportion of active MMP-9, and gelatinolytic activity in urine were significantly higher in DNP patients than in controls. In urine of DNP patients the proportion of active polymorphonuclear neutrophil (PMN)-type (but not fibroblast-type) MMP-8 was increased. MMP-8 and MMP-9 were found to form high molecular weight complexes in DNP urine. Total immunoreactivity of soluble urinary MMP-14 and the levels of trypsin (TRY)-1 and TRY-2, but not of TATI, were also significantly increased in DNP. Zymography, Western blotting, and immunofluorometric analysis of DNP urine showed a significant association especially between activation of MMP-9 as well as PMN-type MMP-8 and TRY-2. Our findings suggest that a trypsin-MMP cascade is involved in the pathogenesis of DNP, which may offer new possibilities for diagnosis and treatment of DNP with MMP inhibitors. [ABSTRACT FROM AUTHOR]

Purpose: To study the cellular distribution of extracellular matrix metalloproteinase inducer (EMMPRIN; CD147) in the human eye and the corneal and retinal pigment epithelium cell lines and its possible existence as a soluble protein in ocular fluids. Methods: Immunohistochemistry was performed on human eyes and for cell cultures. Different EMMPRIN isoforms were analyzed by Western blotting in ocular fluids. Results: EMMPRIN immunostaining could be detected in the corneal and conjunctival epithelium, the endothelium, and in the stromal keratocytes, the retinal pigment epithelium, several retinal layers and nerve fibers in the optic nerve head. Both cell lines deposit EMMPRIN on the cell membranes. Soluble EMMPRIN could also be detected in the tear fluid, aqueous humor, and vitreous samples in the form of multiple immunoreactive species. Conclusions: EMMPRIN is specifically expressed in the human eye only by certain tissue structures, thus suggesting specialized functions. The protein also exists naturally in soluble forms in ocular fluids representing presumably monomeric and multimeric forms, a notion that confirm and further extends its previously known role mainly as a transmembrane protein. These findings suggest that EMMPRIN can regulate not only cell surface functions in the human eye but also certain peri- and extracellular functions. [ABSTRACT FROM AUTHOR]

Background. We recently found that direct homotypic cell‐cell contacts between human dermal fibroblasts induce a novel form of cell activation leading to non‐apoptotic programmed cell death. As the major features of this process we identified massive induction of cyclo‐oxygenase‐2 and production of inflammatory prostaglandins. On the surface of the decomposing spheroids, activation of the major extracellular proteolytic cascade, plasminogen activation, associated with surface exposure of α‐enolase, took place. Aim. To further characterize pericellular proteolysis by cell‐cell contact‐activated fibroblasts we studied the role of the other major extracellular proteolytic system, matrix metalloproteinases (MMPs). Methods. MMP expression in fibroblast clusters and monolayers was compared using mRNA microarrays and immunoblot analyses. The activities of MMPs were confirmed using MMP inhibitors and caseinolysis. Results. In microarrays MMP‐1, ‐10, and ‐14 (MT1‐MMP) were induced 5.8‐, 106‐, and 5.6‐fold, respectively. These findings were confirmed by immunoblotting. Radial caseinolysis showed low level of proteolytic activity in spheroid‐conditioned media; ilomastat, a general inhibitor of MMPs, suppressed 50% of the proteolytic activity thus confirming it to be at least in part due to MMPs. A cocktail of tetracycline‐derived MMP inhibitors suppressed lactate dehydrogenase (LDH) release only 11%, and if combined with aprotinin 28%. Conclusions. Cell‐cell contact activation of fibroblasts induced MMP‐1, ‐10, and MT1‐MMP expression, suggesting similar signaling to that in inflammation and cancer. [ABSTRACT FROM AUTHOR]

Matrix metalloproteinases (MMPs) play a major role in inflammatory processes as they degrade extracellular proteins and modify immune responses. Inflammation is the driving factor in atherogenesis and MMPs, particularly MMP-8, has been linked to atherosclerotic plaque progression. MMP-8 is shown to be strongly associated with cardiovascular diseases (CVDs) and its complications thus providing a potential marker to identify patients at risk. Previously, laborious and expensive immunofluorometric assay (IFMA) was needed to reliably detect MMP-8 levels in serum. In this study, we compared a novel in-house ELISA-assay, dentoELISA, to the standard IFMA in determination of serum MMP-8 concentrations. As a cheaper and non-laborious assay, ELISA proved to be diagnostically as sensitive and specific as the IFMA. ROC statistics showed highly similar areas under the curve for both assays (0.779 versus 0.781). Furthermore, the concentrations measured by ELISA correlated significantly with concentrations determined with IFMA (r= 0.881,P< 0.001). In our study population, MMP-8 levels were significantly higher in the acute coronary syndrome patients (n= 2071) in comparison to reference population without significant coronary artery disease (n= 653). With this background, MMP-8-ELISA could provide interesting new approaches to novel CVD diagnostics. [ABSTRACT FROM PUBLISHER]