Systemic Inflammation in Preclinical Ulcerative Colitis.

BACKGROUND & AIMS: Preclinical ulcerative colitis is poorly defined. We aimed to characterize the preclinical systemic inflammation in ulcerative colitis, using a comprehensive set of proteins. METHODS: We obtained plasma samples biobanked from individuals who developed ulcerative colitis later in life (n = 72) and matched healthy controls (n = 140) within a population-based screening cohort. We measured 92 proteins related to inflammation using a proximity extension assay. The biologic relevance of these findings was validated in an inception cohort of patients with ulcerative colitis (n = 101) and healthy controls (n = 50). To examine the influence of genetic and environmental factors on these markers, a cohort of healthy twin siblings of patients with ulcerative colitis (n = 41) and matched healthy controls (n = 37) were explored. RESULTS: Six proteins (MMP10, CXCL9, CCL11, SLAMF1, CXCL11 and MCP-1) were up-regulated (P < .05) in preclinical ulcerative colitis compared with controls based on both univariate and multivariable models. Ingenuity Pathway Analyses identified several potential key regulators, including interleukin-1ß, tumor necrosis factor, interferon-gamma, oncostatin M, nuclear factor-κB, interleukin-6, and interleukin-4. For validation, we built a multivariable model to predict disease in the inception cohort. The model discriminated treatment-naïve patients with ulcerative colitis from controls with leave-one-out cross-validation (area under the curve = 0.92). Consistently, MMP10, CXCL9, CXCL11, and MCP-1, but not CCL11 and SLAMF1, were significantly up-regulated among the healthy twin siblings, even though their relative abundances seemed higher in incident ulcerative colitis. CONCLUSIONS: A set of inflammatory proteins are up-regulated several years before a diagnosis of ulcerative colitis. These proteins were highly predictive of an ulcerative colitis diagnosis, and some seemed to be up-regulated already at exposure to genetic and environmental risk factors.

Plasma Glycosaminoglycan Profiles in Systemic Sclerosis: Associations with MMP-3, MMP-10, TIMP-1, TIMP-2, and TGF-Beta.

The aim of the study was to determine whether plasma levels of total glycosaminoglycans (GAGs), matrix metalloproteinases (MMPs) (MMP-3, MMP-10), and their tissue inhibitors (TIMPs) (TIMP-1, TIMP-2) as well as transforming growth factor ß (TGF-ß) differ in the patients with systemic sclerosis (SSc) in relation to the healthy subjects. Plasma samples were obtained from 106 people (64 patients with SSc and 42 healthy individuals) and measured for MMP-3, MMP-10, TIMP-1, TIMP-2, and TGF-ß levels using ELISA methods. GAGs isolated from plasma samples were quantified using a hexuronic acid assay. The plasma levels of total GAGs, TIMP-1, TIMP-2, and TGF-ß were significantly higher, while MMP-3 was significantly decreased in SSc patients compared to the controls. We have revealed a significant correlation between plasma GAGs and TGF-ß (r = -0.47) and TIMP-2 (r = 0.38), respectively. The results of this study revealed that remodeling of the extracellular matrix, reflected by quantitative changes in plasma glycosaminoglycans, occurs during systemic sclerosis. Thus, the alterations in GAG metabolism connected with SSc may lead to systemic changes in the properties of the connective tissue extracellular matrix.

Effect of High Intensity Interval Training on Matrix Metalloproteinases in Women with Breast Cancer Receiving Anthracycline-Based Chemotherapy.

Anthracycline chemotherapy is commonly used to treat breast cancer yet may increase the level of matrix metalloproteinases (MMP) -2 and -9, which increase the risk of atherosclerosis. While exercise has been shown to reduce the level of MMP in patients with diabetes, high intensity interval training (HIIT) has not been utilized to improve level of MMP in women with breast cancer receiving anthracycline chemotherapy. Thirty women were randomized to either 8-week HIIT or control (CON) group. The CON group was offered the HIIT intervention after 8 weeks. MMP-1, -2 -7, -9, tissue inhibitor of MMP (TIMP) -1, and-2 were measured at baseline and post-intervention. Repeated measures ANCOVA and paired t-test were performed to assess changes in MMP and TIMP. Post-intervention, no significant between-group differences were observed for MMP and TIMP. However, within-group decrease in MMP-9 was observed in the HIIT group [104.3(51.9) to 65.2(69.1); P = 0.01]. MMP-9 in the CON group was not significantly changed [115.5(47.2) to 90.4(67.9);]. MMP-2 significantly increased in both the HIIT group [76.6(11.2) to 83.2(13.1); P = 0.007) and the CON group [69.0(8.9) to 77.6(11.1) P = 0.003). It is unclear whether an 8-week HIIT intervention influences MMP-9 in breast cancer patients undergoing anthracycline chemotherapy. Additional investigations are required to understand the exercise-induced changes in MMP-2 and -9 in women undergoing anthracycline chemotherapy.

MMP-10 and TIMP-1 as indicators of severe sepsis in adult hematological patients with febrile neutropenia.

Commonly used indicators of sepsis are nonspecific and insufficient for predicting the course of febrile neutropenia (FN) in hematological patients. We analyzed data from 91 adult FN patients who received intensive chemotherapy for acute myeloid leukemia or autologous stem cell transplantation. Compared to patients with non-severe sepsis, patients with severe sepsis had significantly higher serum levels of tissue inhibitor of metalloproteinases-1 on the day of first occurrence of fever (day 0: 172 vs. 112 µg/L, p= .002) and for the two following days (day 1: 219 vs. 128 µg/L, p< .001; day 2: 443 vs. 128 µg/L, p= .001), and significantly higher serum levels of matrix metalloproteinase-10 on day 1 (1975 vs. 876 ng/L, p= .001) and day 2 (2020 vs. 841 ng/L, p< .001). We conclude that the measurement of these biomarkers may be useful in predicting the severity of sepsis in FN patients.

Associations between serum S100A8/S100A9 and knee symptoms, joint structures and cartilage enzymes in patients with knee osteoarthritis.

OBJECTIVE: Animal studies suggest that S100A8/S100A9 may be involved in the pathogenesis of osteoarthritis (OA); however, there has been no clinical study examining the associations between serum S100A8/S100A9 and knee symptoms, joint structures and cartilage degradation enzymes in knee OA patients so far. Therefore, this study was designed to investigate the cross-sectional associations between serum levels of S100A8/S100A9 and the outcomes in patients with knee OA. DESIGN: A total of 141 subjects with clinical knee OA were included. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score was used to assess joint symptoms. Magnetic resonance imaging (MRI) was used to measure knee structural abnormalities including cartilage defects. Knee radiography was used to assess joint space narrowing (JSN), osteophytes and the radiographic severity of OA. Enzyme-linked immunosorbent assay (ELISA) was used to measure the serum levels of S100A8/S100A9, matrix metalloproteinase (MMP)-3, MMP10 and MMP13. RESULTS: In multivariable analyses, serum S100A8/S100A9 were positively associated with total WOMAC score (ß: 0.111 per 10 ng/ml, P = 0.021), WOMAC weight-bearing pain (ß: 0.015 per 10 ng/ml, P = 0.043) and WOMAC physical dysfunction (ß: 0.091 per 10 ng/ml, P = 0.010), and had positive associations with total cartilage defects and cartilage defects at lateral femoral, lateral tibial and medial femoral sites (ORs: 1.006-1.008 per 10 ng/ml, all P < 0.05) and serum levels of MMP3 (ß: 0.002 per 10 ng/ml, P = 0.032) in patients with clinical knee OA. CONCLUSIONS: Serum levels of S100A8/S100A9 were positively associated with increased knee symptoms, cartilage defects and serum cartilage degradation enzymes in patients with knee OA, suggesting that S100A8/S100A9 may have a role to play in knee OA. Future longitudinal studies are required to confirm these findings.

Autoantibodies against aldehyde-modified collagen type IV are associated with risk of development of myocardial infarction.

BACKGROUND: Oxidation of LDL particles entrapped in the extracellular matrix of the arterial wall is a key factor in the development of atherosclerosis. Lipid oxidation products, such as malondialdehyde (MDA), react with surrounding extracellular matrix proteins and cause modifications that are recognized by the immune system. MDA modification of collagen type IV is increased in carotid lesions from symptomatic patients and correlates with autoantibodies against MDA-modified collagen type IV in plasma. OBJECTIVE: The aim of this study was to determine whether autoantibodies against MDA-modified collagen type IV predict risk of development of myocardial infarction (MI). METHODS: Plasma levels of MDA-modified collagen type IV IgM and IgG antibodies were analysed by enzyme-linked immunosorbent assay in 385 subjects with incident MI during 13 years of follow-up and 410 age- and sex-matched controls in the Malmö Diet and Cancer study. RESULTS: MDA-modified collagen type IV IgG levels were higher in cases with incident MI than in controls. Subjects in the highest tertile of MDA-modified collagen type IV IgG had an increased risk of MI (hazard ratio 1.56, 95% confidence interval 1.22-2.00, P for trend 0.0004). This association remained significant after adjusting for factors included in the Framingham risk score and diabetes. High levels of MDA-collagen type IV IgG were associated with increased carotid intima-media thickness and elevated plasma levels of matrix metalloproteinase 10 and 12. CONCLUSIONS: Immune responses against MDA-modified collagen type IV are associated with more severe carotid disease and increased risk of MI. These immune responses may reflect LDL oxidation in the artery wall, but could also affect the atherosclerotic disease process.

Profile of upregulated inflammatory proteins in sera of Myasthenia Gravis patients.

This study describes specific patterns of elevated inflammatory proteins in clinical subtypes of myasthenia gravis (MG) patients. MG is a chronic, autoimmune neuromuscular disease with antibodies most commonly targeting the acetylcholine receptors (AChRab), which causes fluctuating skeletal muscle fatigue. MG pathophysiology includes a strong component of inflammation, and a large proportion of patients with early onset MG additionally present thymus hyperplasia. Due to the fluctuating nature and heterogeneity of the disease, there is a great need for objective biomarkers as well as novel potential inflammatory targets. We examined the sera of 45 MG patients (40 AChRab seropositive and 5 AChRab seronegative), investigating 92 proteins associated with inflammation. Eleven of the analysed proteins were significantly elevated compared to healthy controls, out of which the three most significant were: matrix metalloproteinase 10 (MMP-10; p = 0.0004), transforming growth factor alpha (TGF-α; p = 0.0017) and extracellular newly identified receptor for advanced glycation end-products binding protein (EN-RAGE) (also known as protein S100-A12; p = 0.0054). Further, levels of MMP-10, C-X-C motif ligand 1 (CXCL1) and brain derived neurotrophic factor (BDNF) differed between early and late onset MG. These novel targets provide valuable additional insight into the systemic inflammatory response in MG.

Exploratory study to suggest the possibility of MMP-8 and MMP-9 serum levels as early markers for remission after traumatic spinal cord injury.

STUDY DESIGN: A prospective observational study reporting the correlation between matrix metalloprotein serum levels and remission after traumatic spinal cord injury (SCI). OBJECTIVES: To investigate serum cytokine levels as predictive markers. SETTING: Germany, Rhineland-Palatinate (Rheinland-Pfalz). METHODS: Between 2010 and 2015, data sets from 115 patients (33 female, 82 male) after traumatic SCI were recorded at the BG Trauma Centre Ludwigshafen. We examined the serum levels of Matix metallopraoteinases (MMPs) MMP-2, MMP-8, MMP-9, MMP-10 and MMP-12 over a 12-week period, that is, at admission and 4, 9, 12 h, 1 and 3 days and 1, 2, 4, 8 and 12 weeks after trauma. Following the same match-pair procedure as in our previous studies, we selected 10 patients with SCI and neurological remission (Group 1) and 10 patients with an initial American Spinal Injury Association (ASIA) A grade and no neurological remission (Group 0). Ten patients with an isolated vertebral fracture without neurological deficits served as a control group (Group C). Our analysis was performed using a Luminex Performance Human High Sensitivity Cytokine Panel. Multivariate logistic regression models were used to examine the predictive value of MMPs with respect to neurological remission vs no neurological remission. RESULTS: MMP-8 and MMP-9 provided significantly different values. The favoured predictive model allows to differentiate between neurological remission and no neurological remission in 97% of cases. CONCLUSIONS: The results indicate that further studies with an enlarged collective are warranted in order to investigate current monitoring, prognostic and tracking techniques as well as scoring systems.

Serum MMP7, MMP10 and MMP12 level as negative prognostic markers in colon cancer patients.

BACKGROUND: Matrixmetalloproteinases (MMPs) comprise a family of zinc-dependent endopeptidases which are involved in angiogenesis, tumor invasion and metastatic formation. Up to date, the prognostic relevance of MMPs in serum of patients with colon cancer remains unknown. Thus, we wanted to assess an expression pattern of MMPs in a homogenous cohort of colon cancer patients to assess their potential as prognostic biomarkers. METHODS: Differences in the expression pattern of MMP7, MMP10 and MMP12 in 78 serum specimens of patients with an adenocarcinoma of the colon and serum specimens of a healthy control group were assessed using Luminex-100 technologies. Subsequently, we correlated these results with histopathological and clinical data of the patients. RESULTS: Luminex based expression analysis revealed a significant overexpression of MMP7 and an overexpression of MMP10 and MMP12 in the sera of colon cancer patients compared to the healthy control group. Patients with vascular invasion showed a significantly higher MMP12 expression than V0-staged patients. Moreover overexpression of MMP7, MMP10 and MMP12 in colon cancer patients´ sera displayed a significantly impaired overall survival. Multivariate analysis revealed high MMP10 serum levels to be an independent adverse prognostic marker in colon cancer patients. CONCLUSIONS: Expression patterns of MMP7, MMP10 and MMP12 in colon cancer patients´ sera are different compared to serum specimens of healthy individuals. Furthermore, overexpression of MMP7, MMP10 and MMP12 in colon cancer patients´ sera correlates with a dismal prognosis and may help to stratify patients into different risk groups.

Association of matrix metalloproteinase-10 polymorphisms with susceptibility to pelvic organ prolapse.

AIM: The aim of this study was to explore the correlation between genetic mutations in matrix metalloproteinase-10 (MMP-10) and susceptibility to pelvic organ prolapse (POP). MATERIAL AND METHODS: From September 2011 to December 2013, 263 subjects were recruited, including 91 patients with POP (case group) and 172 non-POP patients (control group). Total MMP-10 concentrations in serum were measured by enzyme-linked immunosorbent assay. The genotyping of MMP-10 was achieved by quantitative real-time polymerase chain reaction. All data were analyzed with SPSS 18.0. RESULTS: We found that parity, menopause, history of total hysterectomy, and family history of POP were all significantly higher in the POP group than in the control group (P = 0.017, P = 0.046, P = 0.0029 and P < 0.001, respectively). Serum MMP-10 levels were obviously higher in the POP group than in the control group (P < 0.05). In addition, there was a statistically significant difference between the two groups in the distribution frequency of the MMP-10 (rs17435959G/C) genotype (P < 0.05). However, the distribution frequency of the MMP-10 (rs17293607C/T) genotype between the two groups showed no significant differences (P > 0.05). Furthermore, the patients with parity > 2 and postmenopausal women had elevated serum MMP-10 levels, and the patients with parity > 2 and postmenopausal women who carried the G/C + C/C genotype in the MMP-10 gene had an increased risk of POP. CONCLUSION: We support the view that the rs17435959 polymorphism of the MMP-10 gene may be associated with an increased risk of POP.

Matrix metalloproteinase-10: a novel biomarker for idiopathic pulmonary fibrosis.

BACKGROUND: Matrix metalloproteinases (MMPs) are believed to be involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF), and MMP-7 has been described as a useful biomarker for IPF. However, little is known regarding the significance of MMP-10 as a biomarker for IPF. METHODS: This observational cohort study included 57 patients with IPF. Serum MMPs were comprehensively measured in all patients, and the relationships between these markers and both disease severity and prognosis were evaluated. Bronchoalveolar lavage fluid (BALF) MMP-7 and -10 levels were measured in 19 patients to investigate the correlation between these markers and their corresponding serum values. Immunohistochemical staining for MMP-10 was also performed in IPF lung tissue. RESULTS: Serum MMP-7 and -10 levels correlated significantly with both the percentage of predicted forced vital capacity (ρ = -0.31, p = 0.02 and ρ = -0.34, p < 0.01, respectively) and the percentage of predicted diffusing capacity of the lung for carbon monoxide (ρ = -0.32, p = 0.02 and ρ = -0.43, p < 0.01, respectively). BALF MMP-7 and -10 levels correlated with their corresponding serum concentrations. Only serum MMP-10 predicted clinical deterioration within 6 months and overall survival. In IPF lungs, the expression of MMP-10 was enhanced and localized to the alveolar epithelial cells, macrophages, and peripheral bronchiolar epithelial cells. CONCLUSIONS: MMP-10 may be a novel biomarker reflecting both disease severity and prognosis in patients with IPF.

Elevated Plasma Levels of MMP-12 Are Associated With Atherosclerotic Burden and Symptomatic Cardiovascular Disease in Subjects With Type 2 Diabetes.

OBJECTIVE: Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins and play important roles in development and tissue repair. They have also been shown to have both protective and pathogenic effects in atherosclerosis, and experimental studies have suggested that MMP-12 contributes to plaque growth and destabilization. The objective of this study was to investigate the associations between circulating MMPs, atherosclerosis burden, and incidence of cardiovascular disease with a particular focus on type 2 diabetes mellitus. APPROACH AND RESULTS: Plasma levels of MMP-1, -3, -7, -10, and -12 were analyzed by the Proximity Extension Assay technology in 1500 subjects participating in the SUMMIT (surrogate markers for micro- and macrovascular hard end points for innovative diabetes tools) study, 384 incident coronary cases, and 409 matched controls in the Malmö Diet and Cancer study and in 205 carotid endarterectomy patients. Plasma MMP-7 and -12 were higher in subjects with type 2 diabetes mellitus, increased with age and impaired renal function, and was independently associated with prevalent cardiovascular disease, atherosclerotic burden (as assessed by carotid intima-media thickness and ankle-brachial pressure index), arterial stiffness, and plaque inflammation. Baseline MMP-7 and -12 levels were increased in Malmö Diet and Cancer subjects who had a coronary event during follow-up. CONCLUSIONS: The plasma level of MMP-7 and -12 are elevated in type 2 diabetes mellitus, associated with more severe atherosclerosis and an increased incidence of coronary events. These observations provide clinical support to previous experimental studies, demonstrating a role for these MMPs in plaque development, and suggest that they are potential biomarkers of atherosclerosis burden and cardiovascular disease risk.

Plasma levels of matrix metalloproteinase-2, -3, -10, and tissue inhibitor of metalloproteinase-1 are associated with vascular complications in patients with type 1 diabetes: the EURODIAB Prospective Complications Study.

BACKGROUND: Impaired regulation of extracellular matrix remodeling by matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMP) may contribute to vascular complications in patients with type 1 diabetes. We investigated associations between plasma MMP-1, -2, -3, -9, -10 and TIMP-1, and cardiovascular disease (CVD) or microvascular complications in type 1 diabetic patients. We also evaluated to which extent these associations could be explained by low-grade inflammation (LGI) or endothelial dysfunction (ED). METHODS: 493 type 1 diabetes patients (39.5 ± 9.9 years old, 51% men) from the EURODIAB Prospective Complications Study were included. Linear regression analysis was applied to investigate differences in plasma levels of MMP-1, -2, -3, -9, -10, and TIMP-1 between patients with and without CVD, albuminuria or retinopathy. All analyses were adjusted for age, sex, duration of diabetes, Hba1c and additionally for other cardiovascular risk factors including LGI and ED. RESULTS: Patients with CVD (n = 118) showed significantly higher levels of TIMP-1 [ß = 0.32 SD (95%CI: 0.12; 0.52)], but not of MMPs, than patients without CVD (n = 375). Higher plasma levels of MMP-2, MMP-3, MMP-10 and TIMP-1 were associated with higher levels of albuminuria (p-trends were 0.028, 0.004, 0.005 and 0.001, respectively). Severity of retinopathy was significantly associated with higher levels of MMP-2 (p-trend = 0.017). These associations remained significant after further adjustment for markers of LGI and ED. CONCLUSIONS: These data support the hypothesis that impaired regulation of matrix remodeling by actions of MMP-2, -3 and-10 and TIMP-1 contributes to the pathogenesis of vascular complications in type 1 diabetes.

Matrix metalloproteinase 10 is associated with disease severity and mortality in patients with peripheral arterial disease.

OBJECTIVE: Peripheral arterial disease (PAD) is associated with poor prognosis in terms of cardiovascular (CV) morbidity and mortality. Matrix metalloproteinases (MMPs) contribute to vascular remodeling by degrading extracellular matrix components and play a role in atherosclerosis as demonstrated for MMP-10 (stromelysin-2). This study analyzed MMP-10 levels in PAD patients according to disease severity and CV risk factors and evaluated the prognostic value of MMP-10 for CV events and mortality in lower limb arterial disease after a follow-up period of 2 years. METHODS: MMP-10 was measured by enzyme-linked immunosorbent assay in 187 PAD patients and 200 sex-matched controls. RESULTS: PAD patients presented with increased levels of MMP-10 (702 ± 326 pg/mL control vs 946 ± 473 pg/mL PAD; P < .001) and decreased levels of tissue inhibitor of matrix metalloproteinase 1 (312 ± 117 ng/mL control vs 235 ± 110 ng/mL PAD; P < .001) compared with controls. Among PAD patients, those with critical limb ischemia (n = 88) showed higher levels of MMP-10 (1086 ± 478 pg/mL vs 822 ± 436 pg/mL; P < .001) compared with those with intermittent claudication (n = 99), whereas the MMP-10/tissue inhibitor of matrix metalloproteinase 1 ratio remained similar. The univariate analysis showed an association between MMP-10, age (P = .015), hypertension (P = .021), and ankle-brachial index (P = .006) in PAD patients that remained significantly associated with PAD severity after adjustment for other CV risk factors. Patients with the highest MMP-10 tertile had an increased incidence of all-cause mortality and CV mortality (P < .03). CONCLUSIONS: Our results suggest that MMP-10 is associated with severity and poor outcome in PAD.

Increased Levels of Metalloproteinase 10 and Hemostatic Markers in Patients With Noncomplicated Primary Varicose Veins.

The purpose of the study was to analyze a systemic activation of hemostasis and concentration of matrix metalloproteinase 10 (MMP-10) in patients with primary varicose veins (PVVs). A study group consisted of 41 patients with noncomplicated PVVs. A control group consisted of 30 age- and sex-matched healthy individuals without varicose veins. The concentration of d-dimers (DD), prothrombin fragments 1 and 2 (F1+2), antigen of von Willebrand factor (vWF), and activity of plasminogen activator inhibitor (PAI-1) in plasma and concentration of MMP-10 in serum were analyzed. In patients with PVVs, higher concentrations of DD (P < .001), F1+2 (P < .001), vWF (P = .027), MMP-10 (P = .006), and higher activity of PAI-1 (P < .001) were observed. However, no correlation between the concentrations of MMP-10 and prothrombotic markers was found. Noncomplicated PVVs are associated with systemic, prothrombotic activation of hemostasis and increased concentration of MMP-10, suggesting a prothrombotic and proinflammatory state.

Influence of proteolytic-antiproteolytic enzymes and prooxidative-antioxidative factors on proteoglycan alterations in children with juvenile idiopathic arthritis.

OBJECTIVES: The influence of proteolytic-antiproteolytic enzymes and prooxidative-anti-oxidative factors on proteoglycan alterations in children with juvenile idiopathic arthritis (JIA) was evaluated in this study. DESIGN, METHODS, RESULTS: Plasma and urinary glycosaminoglycans (GAGs), as well as plasma levels of matrix metalloproteinases (MMPs) (MMP-3, MMP-10), tissue inhibitors of metalloproteinases (TIMPs) (TIMP-1, TIMP-2), total oxidative status (TOS) and total antioxidative status (TAS), were quantified in samples obtained from 30 healthy subjects and 30 JIA patients before and after treatment. Significantly decreased plasma and urinary concentration of GAGs in JIA patients before treatment was observed. Therapy resulted in an increase in the concentration of the above listed parameters. However, the plasma GAG level still remained significantly lower compared to that in controls. Increased levels of MMP-3 and TIMP-1 in both JIA patient groups were recorded. The plasma MMP-10 and TIMP-2 concentrations in untreated patients were significantly decreased. Anti-inflammatory treatment led to normalization of these parameter concentrations. Significant increase of TOS but decrease of TAS was found in the blood of untreated patients. The treatment resulted only in the normalization of TOS concentration. We have revealed a significant correlation between plasma GAGs and: MMP-3 (r=0.54), TOS (r=0.64) and urinary GAGs (r=0.55), respectively. CONCLUSIONS: Proteoglycan/glycosaminoglycan alterations in JIA patients, which are stimulated by MMP-3 and reactive oxygen species (ROS), indicate rather systemic disturbance of extracellular matrix metabolism, and not merely local changes which occur in articular structures. Given the destructive potential of ROS and MMPs and their hyperexpression in JIA, inhibition of these compounds should bring a substantial clinical benefit.

Matrix metalloproteinase levels in early HIV infection and relation to in vivo brain status.

Matrix metalloproteinases (MMPs) have been implicated in human immunodeficiency virus (HIV)-associated neurological injury; however, this relationship has not been studied early in infection. Plasma levels of MMP-1, MMP-2, MMP-7, MMP-9, and MMP-10 measured using Luminex technology (Austin, TX, USA) were compared in 52 HIV and 21 seronegative participants of the Chicago Early HIV Infection study. MMP levels were also examined in HIV subgroups defined by antibody reactivity, viremia, and antiretroviral status, as well as in available cerebrospinal fluid (CSF) samples (n = 9). MMPs were evaluated for patterns of relationship to cognitive function and to quantitative magnetic resonance measurements of the brain derived in vivo. Plasma MMP-2 levels were significantly reduced in early HIV infection and correlated with altered white matter integrity and atrophic brain changes. MMP-9 levels were higher in the treated subgroup than in the naïve HIV subgroup. Only MMP-2 and MMP-9 were detected in the CSF; CSF MMP-2 correlated with white matter integrity and with volumetric changes in basal ganglia. Relationships with cognitive function were also identified. MMP-2 levels in plasma and in CSF correspond to early changes in brain structure and function. These findings establish a link between MMPs and neurological status previously unidentified in early HIV infection.

proMetalloproteinase-10 is associated with brain damage and clinical outcome in acute ischemic stroke.

BACKGROUND: Matrix metalloproteinases (MMPs) mediate tissue injury during stroke but also neurovascular remodeling and we have shown that MMP-10 is involved in atherothrombosis. OBJECTIVE: The purpose of this study was to examine the relationship between proMMP-10 and clinical outcome, assessing inflammatory and proteolytic markers, in patients with acute ischemic stroke. METHODS: We prospectively studied 76 patients with ischemic stroke treated with tPA within the first 3 h from symptom onset, compared with 202 non-tPA-treated ischemic stroke patients and 83 asymptomatic subjects. Stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS). Hemorrhagic transformation (HT) and severe brain edema were diagnosed by cranial CT. Good functional outcome was defined as a modified Rankin scale score ≤ 2 at 90 days. Serum levels of MMP-9, proMMP-10, TIMP-1, tumor necrosis factor-α (TNFα), interleukin-6 and cellular fibronectin were measured at admission. The effect of TNFα on endothelial proMMP-10 was assessed in vitro. RESULTS: Serum proMMP-10 concentration in ischemic stroke patients, non-treated or treated with t-PA, which was higher than age-matched healthy subjects (P < 0.0001), was independently associated with higher infarct volume, severe brain edema, neurological deterioration and poor functional outcome at 3 months (all P < 0.05), but not with HT. proMMP-10 levels were also independently and positively associated with circulating levels of TNFα (P < 0.0001), which induced its endothelial expression in vitro, both mRNA and protein. MMP-9, however, was only associated with HT and severe edema (all P < 0.05). CONCLUSIONS: Increased serum proMMP-10 after acute ischemic stroke, associated with TNFα, is a new marker of brain damage and poor outcome.

Synergistic effect of thrombin and CD40 ligand on endothelial matrix metalloproteinase-10 expression and microparticle generation in vitro and in vivo.

OBJECTIVE: Thrombin induces CD40 ligand (CD40L) and matrix metalloproteinases (MMPs) under inflammatory/prothrombotic conditions. Thrombin and CD40L could modulate endothelial MMP-10 expression in vitro and in vivo. METHODS AND RESULTS: Human endothelial cells were stimulated with thrombin (0.1-10 U/mL), CD40L (0.25-1 µg/mL), or their combination (thrombin/CD40L) to assess MMP-10 expression and microparticle generation. Thrombin/CD40L elicited higher MMP-10 mRNA (5-fold; P<0.001) and protein levels (4.5-fold; P<0.001) than either stimulus alone. This effect was mimicked by a protease-activated receptor-1 agonist and antagonized by hirudin, a-protease-activated receptor-1, α-CD40L, and α-CD40 antibodies. The synergistic effect was dependent on p38 mitogen-activated protein kinase and c-Jun N-terminal kinase-1 pathways. Thrombin also upregulated the expression of CD40 in endothelial cell surface increasing its availability, thereby favoring its synergistic effects with CD40L. In mice, thrombin/CD40L further increased the aortic MMP-10 expression. Septic patients with systemic inflammation and enhanced thrombin generation (n=60) exhibited increased MMP-10 and soluble CD40L levels associated with adverse clinical outcome. Endothelial and systemic activation by thrombin/CD40L and lipopolysaccharide also increased microparticles harboring MMP-10 and CD40L. CONCLUSIONS: Thrombin/CD40L elicited a strong synergistic effect on endothelial MMP-10 expression and microparticles containing MMP-10 in vitro and in vivo, which may represent a new link between inflammation/thrombosis with prognostic implications.

Age- and gender-dependent changes in connective tissue remodeling: physiological differences in circulating MMP-3, MMP-10, TIMP-1 and TIMP-2 level.

BACKGROUND: the mechanisms which cause age-dependent remodeling of connective tissue are still not fully understood. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) constitute an important proteolytic pathway affecting physiological matrix remodeling. OBJECTIVE: the way in which changes in the extracellular matrix metabolism during the ageing process influence the level of circulating MMP-3 and MMP-10, as well as their tissue inhibitors TIMP-1 and TIMP-2, in a healthy population was investigated in this study. METHODS: blood samples were taken from 81 healthy individuals aged 6-62 years and measured for MMP-3, MMP-10, TIMP-1 and TIMP-2 levels using enzyme-linked immunosorbent assays. Polyacrylamide gel electrophoresis followed by Western immunoblotting allowed for the detection of pro- and active forms of both MMPs. RESULTS: Serum MMP-3 and TIMP-1 values were positively correlated with age (r = 0.44, p = 0.00001 and r = 0.28, p = 0.012, respectively). A contrary tendency was found for MMP-10 and TIMP-2 serum levels. A strong age-related decrease in MMP-10 (-0.53; p = 0.000) and TIMP-2 (-0.52; p = 0.000) was noticed in our study. Gender was a significant factor modifying MMP/TIMP potential, except for the MMP-10 level. CONCLUSIONS: the data presented indicate that changes in MMP/TIMP balance occur in physiological ageing. Moreover, these findings highlight the necessity of utilizing age- and sex-matched values for analysis of MMPs and TIMPs in the pathological conditions.