Correlation Between Plasma Matrix Metalloproteinase-28 Levels and Severity of Calcific Aortic Valve Stenosis.

BACKGROUND Calcific aortic valve disease is a common cardiovascular disorder worldwide. This study aimed to investigate the correlation between plasma matrix metalloproteinase-28 (MMP-28) levels and the severity of calcific aortic valve stenosis. MATERIAL AND METHODS Calcific aortic valve stenosis patients who were admitted to the heart center of our hospital between January 2016 and January 2019 to undergo surgery were successively enrolled in this study (55 males and 24 females with an average age of 58.5±9.6). Information on echocardiography, plasma MMP-28 levels, and other clinical data of the patients was retrospectively collected. RESULTS The average plasma MMP-28 level was 2.43±2.22 ng/mL (range, 0.22-8.27 ng/mL). Plasma MMP-28 levels in patients with mild (n=24), moderate (n=31), or severe (n=24) aortic valve stenosis were 0.74 (0.25-2.23), 1.46 (0.50-3.22), and 4.13 (1.54-6.18) ng/mL, respectively, indicating that the patients with severe aortic valve stenosis had significantly higher MMP-28 levels than the patients with moderate or mild aortic valve stenosis (both P<0.01). Regression analysis using the general linear model further revealed that plasma MMP-28 level was correlated with the peak blood flow velocity and mean pressure gradient of the transaortic valve, and the correlations were statistically significant (both P<0.01). CONCLUSIONS MMP-28 level is significantly elevated in severe cases of calcific aortic valve stenosis. Moreover, plasma MMP-28 levels are positively correlated with the mean pressure gradients and peak blood flow velocity of the transaortic valve.

Association between MMP/TIMP Levels in the Aqueous Humor and Plasma with Axial Lengths in Myopia Patients.

PURPOSE: The present study investigated the profiles of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) of the aqueous humor (AH) and plasma (PL) in myopia patients, to determine whether there was an association between these levels with their axial length (AL) and to investigate if MMPs/TIMPs were regulated locally or systemically. METHODS: A cross-sectional study was conducted. Thirty-nine patients (78 eyes) diagnosed with high myopia were recruited. The AL was measured using IOL Master. And the patients were divided into three groups based on their AL, Group A (AL ≤ 26 mm), Group B (26 < AL ≤ 28 mm), and Group C (AL > 28 mm). The AH in both eyes and blood samples were collected before the patients underwent implantable collamer lens surgery. In all, 78 samples of the AH and 39 samples of the PL were analyzed using MILLIPLEX map assays, followed by statistical analyses of the results. RESULTS: There were 8 patients (16 eyes) in Group A, 22 patients (44 eyes) in Group B, and 9 patients (18 eyes) in Group C. MMP-1 (p = 0.014, Β = 0.118), MMP-2 (p ≤ 0.001, Β = 0.278), MMP-9 (p ≤ 0.001, Β = 0.019), and TIMP-1 (p = 0.014, Β = 0.062) in the AH were positively associated with the AL. MMP-1 (p = 0.004, Β = 0.001) and TIMP-1 (p = 0.030, Β = 1.171) concentrations in the PL increased linearly with longer ALs. No concentration-dependent relationship was found between MMP-2 in the PL and AL. CONCLUSIONS: There was a consistent relationship between MMP-2 in the AH and AL. AL was not consistently or substantially affected by MMP-2 in the PL, indicating myopia formation was possibly a localized process. Associations among MMP-1, MMP-9, and TIMP-1 in the AH and AL were also observed.

Locomotion replacement exercise cannot counteract cartilage biomarker response to 5 days of immobilization in healthy adults.

Biomarkers of cartilage metabolism are sensitive to changes in the biological and mechanical environment and can indicate early changes in cartilage homeostasis. The purpose of this study was to determine if a daily locomotion replacement program can serve as a countermeasure for changes in cartilage biomarker serum concentration caused by immobilization. Ten healthy male subjects (mean ± 1 standard deviation; age: 29.4 ± 5.9 years; body mass: 77.7 ± 4.1 kg) participated in the crossover 5-day bed rest study with three interventions: control (CON), standing (STA), and locomotion replacement training (LRT). Serum samples were taken before, during, and after bed rest. Biomarker concentrations were measured using commercial enzyme-linked immunosorbent assays. Cartilage oligomeric matrix protein (COMP) levels after 24 hours of bed rest decreased independently of the intervention (-16.8% to -9.8%) and continued to decrease until 72 hours of bed rest (minimum, -23.2% to -20.6%). LRT and STA did not affect COMP during bed rests (P = .056) but there was a strong tendency for a slower decrease with LRT (-9.4%) and STA (-11.7%) compared with CON (-16.8%). MMP-3 levels decreased within the first 24 hours of bed rest (CON: -22.3%; STA: -14.7%; LRT: -17%) without intervention effect. Both COMP and MMP-3 levels recovered to baseline levels during the 6-day recovery period. MMP-1, MMP-9, and TNF-α levels were not affected by immobilization or intervention. COMP and MMP-3 are mechano-sensitive cartilage biomarkers affected by immobilization, and simple interventions such as standing upright or LRT during bed rest cannot prevent these changes. Clinical significance: simple locomotion interventions cannot prevent cartilage biomarker change during bed rest.

Circulating matrix metalloproteinases and tissue metalloproteinase inhibitors in patients with idiopathic pulmonary fibrosis in the multicenter IPF-PRO Registry cohort.

BACKGROUND: Matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs) play important roles in the turnover of extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). This study aimed to determine the utility of circulating MMPs and TIMPs in distinguishing patients with IPF from controls and to explore associations between MMPs/TIMPs and measures of disease severity in patients with IPF. METHODS: The IPF cohort (n = 300) came from the IPF-PRO Registry, an observational multicenter registry of patients with IPF that was diagnosed or confirmed at the enrolling center in the past 6 months. Controls (n = 100) without known lung disease came from a population-based registry. Generalized linear models were used to compare circulating concentrations of MMPs 1, 2, 3, 7, 8, 9, 12, and 13 and TIMPs 1, 2, and 4 between patients with IPF and controls, and to investigate associations between circulating levels of these proteins and measures of IPF severity. Multivariable models were fit to identify the MMP/TIMPs that best distinguished patients with IPF from controls. RESULTS: All the MMP/TIMPs analyzed were present at significantly higher levels in patients with IPF compared with controls except for TIMP2. Multivariable analyses selected MMP8, MMP9 and TIMP1 as top candidates for distinguishing patients with IPF from controls. Higher concentrations of MMP7, MMP12, MMP13 and TIMP4 were significantly associated with lower diffusion capacity of the lung for carbon monoxide (DLCO) % predicted and higher composite physiologic index (worse disease). MMP9 was associated with the composite physiologic index. No MMP/TIMPs were associated with forced vital capacity % predicted. CONCLUSIONS: Circulating MMPs and TIMPs were broadly elevated among patients with IPF. Select MMP/TIMPs strongly associated with measures of disease severity. Our results identify potential MMP/TIMP targets for further development as disease-related biomarkers.

Identification of MMP28 as a biomarker for the differential diagnosis of idiopathic pulmonary fibrosis.

BACKGROUND AND OBJECTIVE: Idiopathic Pulmonary Fibrosis (IPF) is a progressive disease of unknown etiology. The diagnosis is based on the identification of a pattern of usual interstitial pneumonia either by high resolution computed tomography and/or histology. However, a similar pattern can be observed in other fibrotic lung disorders, and precise diagnosis remains challenging. Studies on biomarkers contributing to the differential diagnosis are scanty, and still in an exploratory phase. Our aim was to evaluate matrix metalloproteinase (MMP)-28, which has been implicated in abnormal wound healing, as a biomarker for distinguishing IPF from fibrotic non-IPF patients. METHODS: The cell localization of MMP28 in lungs was examined by immunohistochemistry and its serum concentration was measured by ELISA in two different populations. The derivation cohort included 82 IPF and 69 fibrotic non-IPF patients. The validation cohort involved 42 IPF and 41 fibrotic non-IPF patients. RESULTS: MMP28 was detected mainly in IPF lungs and localized in epithelial cells. In both cohorts, serum concentrations of MMP28 were significantly higher in IPF versus non-IPF (mostly with lung fibrosis associated to autoimmune diseases and chronic hypersensitivity pneumonitis) and healthy controls (ANOVA, p<0.0001). The AUC of the derivation cohort was 0.718 (95%CI, 0.635-0.800). With a cutoff point of 4.5 ng/mL, OR was 5.32 (95%CI, 2.55-11.46), and sensitivity and specificity of 70.9% and 69% respectively. The AUC of the validation cohort was 0.690 (95%CI, 0.581-0.798), OR 4.57 (95%CI, 1.76-12.04), and sensitivity and specificity of 69.6% and 66.7%. Interestingly, we found that IPF patients with definite UIP pattern on HRCT showed higher serum concentrations of MMP28 than non-IPF patients with the same pattern (7.8±4.4 versus 4.9±4.4; p = 0.04). By contrast, no differences were observed when IPF with possible UIP-pattern were compared (4.7±3.2 versus 3.9±3.0; p = 0.43). CONCLUSION: These findings indicate that MMP28 might be a useful biomarker to improve the diagnostic certainty of IPF.

Relevance of matrix metalloproteases in non-small cell lung cancer diagnosis.

BACKGROUND: The need for novel biomarkers that could aid in non-small cell lung cancer (NSCLC) detection, together with the relevance of Matrix Metalloproteases (MMPs) -1, -2, -7, -9 and -10 in lung tumorigenesis, prompted us to assess the diagnostic usefulness of these MMPs and the Tissue Inhibitor of Metalloproteinase (TIMP) -1 in NSCLC patients. METHODS: Markers were evaluated in an initial study cohort (19 NSCLC cases and 19 healthy controls). Those that better performed were analyzed in a larger sample including patients with benign lung diseases. Serum MMPs and TIMP-1 were determined by multiplexed immunoassays. Logistic regression was employed for multivariate analysis of biomarker combinations. RESULTS: MMPs and TIMP-1 were elevated in the serum of NSCLC patients compared to healthy controls. MMP-1, -7 and -9 performed at best and were further evaluated in the sample including benign pathologies, corroborating the superiority of MMP-9 in NSCLC discrimination, also at early-stage NSCLC. The optimal diagnostic value was obtained with the model including MMP-9, gender, age and smoking history, that demonstrated an AUC of 0.787, 85.54% sensitivity and 64.89% specificity. CONCLUSION: Our results suggest that MMP-9 is a potential biomarker for NSCLC diagnosis and its combined measurement with other biomarkers could improve NSCLC detection.

MMP26: A potential biomarker for prostate cancer.

The application of prostate-specific antigen (PSA) in the screening and diagnosis of prostate cancer (PCa) has improved the clinical management of PCa patients. However, the PSA assay has been faced with criticism due to its potential association with over-diagnosis and subsequent overtreatment of indolent patients. Matrix metalloproteinase-26 (MMP26) is a member of matrix metalloproteinases (MMPs) and has been reported to be highly expressed in many cancers. This investigation evaluated the potential of serum MMP26 as a biomarker for PCa. The level of serum MMP26 was measured by enzyme-linked immunosorbent assay (ELISA) in 160 subjects including PCa group (n=80), benign prostatic hyperplasia (BPH) group (n=40) and control group (n=40). Furthermore, we evaluated the expression of MMP26 in tissues by immunohistochemistry. The results showed the serum MMP26 levels were significantly higher in PCa group than in BPH group and control group. Similarly, the MMP26 protein was positive in PCa tissues and negative in BPH tissues and control tissues. In conclusion, these results suggested MMP26 could be used as a potential serum biomarker in the diagnosis of PCa.

A panel of novel biomarkers representing different disease pathways improves prediction of renal function decline in type 2 diabetes.

OBJECTIVE: We aimed to identify a novel panel of biomarkers predicting renal function decline in type 2 diabetes, using biomarkers representing different disease pathways speculated to contribute to the progression of diabetic nephropathy. RESEARCH DESIGN AND METHODS: A systematic data integration approach was used to select biomarkers representing different disease pathways. Twenty-eight biomarkers were measured in 82 patients seen at an outpatient diabetes center in The Netherlands. Median follow-up was 4.0 years. We compared the cross-validated explained variation (R2) of two models to predict eGFR decline, one including only established risk markers, the other adding a novel panel of biomarkers. Least absolute shrinkage and selection operator (LASSO) was used for model estimation. The C-index was calculated to assess improvement in prediction of accelerated eGFR decline defined as <-3.0 mL/min/1.73m2/year. RESULTS: Patients' average age was 63.5 years and baseline eGFR was 77.9 mL/min/1.73m2. The average rate of eGFR decline was -2.0 ± 4.7 mL/min/1.73m2/year. When modeled on top of established risk markers, the biomarker panel including matrix metallopeptidases, tyrosine kinase, podocin, CTGF, TNF-receptor-1, sclerostin, CCL2, YKL-40, and NT-proCNP improved the explained variability of eGFR decline (R2 increase from 37.7% to 54.6%; p=0.018) and improved prediction of accelerated eGFR decline (C-index increase from 0.835 to 0.896; p=0.008). CONCLUSIONS: A novel panel of biomarkers representing different pathways of renal disease progression including inflammation, fibrosis, angiogenesis, and endothelial function improved prediction of eGFR decline on top of established risk markers in type 2 diabetes. These results need to be confirmed in a large prospective cohort.

Comparative analysis of the influence of Fructus Ligustri Lucidi on a rat lumbar disc herniation model.

Lumbar disc herniation (LDH) is a term used for a group of conditions, including back pain, femoral nerve pain and sciatica. Currently available treatments and surgical options are insufficient for patients with LDH. Fructus Ligustri Lucidi (FLL) is a herb that is used for treating age-associated diseases. The results of the present study suggested that FLL may be used for treatment of patients with LDH. In the present study, matrix metalloproteinase-1, -3, -8 and -9 (MMP-1, -3, -8 and -9) protein and mRNA expression downregulation was observed in patients with LDH according to western blotting and reverse transcription-quantitative polymerase chain reaction. By contrast, upregulation of interleukin-2 (IL-2), IL-6, IL-8 and tumor necrosis factor-α (TNF-α) expression was observed in patients with LDH, according to an enzyme-linked immunosorbent assay. Mechanical allodynia was observed in rats with LDH not treated with FLL; however, not in FLL­treated rats. IL-2, IL-6, IL-8 and TNF-α expression levels in the serum from untreated rats were significantly higher than that of the FLL­treated rat models. Protein expression levels of MMPs in FLL-treated rats were lower than those in untreated rats. However, the mechanisms underlying the association between FLL and protein expression levels require further investigation.

Circulating levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in patients with incisional hernia.

Incisional hernia formation is a common complication to laparotomy and possibly associated with alterations in connective tissue metabolism. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are closely involved in the metabolism of the extracellular matrix. Our aim was to study serum levels of multiple MMPs and TIMPs in patients with and without incisional hernia. Out of 305 patients who underwent laparotomy, 79 (25.9%) developed incisional hernia over a median follow-up period of 3.7 years. Pooled sera from a subset (n = 72) of these patients were screened for MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12, MMP-13, TIMP-1, TIMP-2, and TIMP-4 using a multiplex sandwich fluorescent immunoassay supplemented with gelatin zymography. The screening indicated differences in serum MMP-9 and TIMP-1 levels. Consequently, MMP-9 and TIMP-1 levels were measured in serum in the whole patient cohort with enzyme-linked immunosorbent assay. There were no significant differences in either MMP-9 (p = 0.411) or TIMP-1 (p = 0.679) levels between hernia and hernia-free patients. MMP-9 was significantly increased in smokers compared with nonsmokers (p = 0.016). In conclusion, a possible involvement of MMPs and TIMPs in the pathogenesis of incisional hernia formation was not reflected systemically.

Biomarkers for abdominal aortic aneurysms from a sex perspective.

BACKGROUND: Abdominal aortic aneurysms (AAAs) differ in men and women. Women are older at diagnosis, have a higher risk of rupture, and worse outcome after surgery compared with men. The higher occurrence of AAAs in men accounts for the dominance of men in biomarker analyses. OBJECTIVE: The primary aim of this study was to investigate levels of established biomarkers for AAA in men and women, and the secondary aim was to compare biomarker levels in women with and without AAAs. METHODS: In this prospective case-control study, blood samples were collected from 16 women and 18 men with AAAs ≥5.5 cm, from 20 women with AAAs <5.5 cm, and from 18 women with peripheral artery disease (PAD). Plasma concentrations of matrix metalloproteinase (MMP) -2, -9, and -13; tissue inhibitor of MMP-1 (TIMP-1); plasminogen activator inhibitor 1 (PAI-1); high-sensitivity C-reactive protein (hsCRP); and estradiol levels were analyzed by ELISA. An ultrasound examination was performed in women with PAD to exclude an AAA. RESULTS: Age and other comorbid conditions were similar between men and women with AAAs. Women with AAAs had higher levels of MMP-9 compared with men with equally large AAAs (42.8 ng/mL vs 36.2 ng/mL, P = 0.036) and lower levels of estradiol (30.0 pmoL vs 86.5 pmol/L, P < 0.001). Women with AAAs had lower levels of MMP-9 compared with women without (59.5 ng/mL vs 132.6 ng/mL, P = 0.010). There was no significant difference in the plasma levels of MMP-2, MMP-13, hsCRP, PAI-1, TIMP-1, and estradiol between women with and without AAAs. CONCLUSION: The higher levels of MMP-9 in women compared with men with equally large AAAs could suggest that MMP-9 is a biomarker related to the sex differences in aneurysm development. The lower levels of estradiol in women with AAAs compared with men suggest that the possible protective effect of endogenous estrogen cannot be explained by a difference in circulating levels of estradiol.

Enhanced systemic matrix metalloproteinase response in Helicobacter pylori gastritis.

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.

Serum tissue inhibitor of metalloproteinases-1 and higher risk features of coronary plaque: a volumetric multivessel intravascular ultrasound study.

AIMS: The purpose of this study was to determine the relationship between higher-risk features of coronary plaque and serum levels of matrix metalloproteinase (MMP) family enzymes in the stable angina patients. METHODS AND RESULTS: In 36 patients, 75 coronary lesions were assessed by intravascular ultrasound. For each of the plaques remodelling index, mean calcium arc and plaque burden were measured. Positive remodelling and the values of the calcium arc and plaque burden above the respective medians were regarded as the higher-risk features and summarised for each lesion. Serum levels of MMP-2, -3, -7, -9, and tissue inhibitor of MMP (TIMP)-1 and -2 were measured in all patients. TIMP-1 level was the independent predictor of presence of a lesion with positive remodelling (OR 1.032; 95% CI: 1.004-1.061) and of a lesion with higher plaque burden (OR 1.026; 95% CI: 1.003-1.049) in a given patient. Whereas, MMP-2 level was an independent predictor of presence of a lesion with higher calcium arc (OR 1.035; 95% CI: 1.001-1.071). TIMP-1 level (p=0.003) was also an independent predictor of a number of higher-risk features in the highest-risk plaque in a given patient. CONCLUSIONS: TIMP-1 level correlates with clustering of plaque features associated with higher risk of complications in stable angina patients.

Comparison of modern marker proteins in serum and synovial fluid in patients with advanced osteoarthrosis and rheumatoid arthritis.

Numerous studies have focused on the significance of modern marker proteins in the synovial fluid of the knee joint and in the serum both, for osteoarthritis (OA) and rheumatoid arthritis (RA). The relationship between the serum concentrations and the concentrations in the synovial fluid is still unclear. Synovial fluid and serum samples were obtained from 13 patients with advanced OA and from 8 patients with severe RA and concentrations of MMP-1, MMP-3, MMP-13, TIMP-1, COMP and MIA/CD-RAP were determined. All values were normalized against the total protein concentrations. Serum concentrations of MMP-13 in the RA-group were statistically higher than the synovial values (P<0.05). MMP-13 was the only marker protein that revealed distinct higher levels in the serum than in the synovial fluid. The study design allows only conclusions about advanced stages of RA and OA. Longitudinal investigations may provide further information about the value of MMP-13 as a potential marker to monitor the course of RA and OA.