Serum matrix metalloproteinase-1 level represents disease activity as opposed to fibrosis in patients with histologically proven nonalcoholic steatohepatitis

BACKGROUND/AIMS: Nonalcoholic steatohepatitis (NASH) is prevalent in both economically developed and developing countries. Twenty percent of NASH progresses to cirrhosis with/without hepatocellular carcinoma, and there is an urgent need to find biomarkers for early diagnosis and monitoring progression of the disease. Using immunohistochemical and immunoelectron microscopic examination we previously reported that expression of matrix metalloproteinase-1 (MMP-1) increased in monocytes, Kupffer cells and hepatic stellate cells in early stage NASH. The present study investigated whether serum MMP-1 levels reflect disease activity and pharmaceutical effects in NASH patients. METHODS: We measured the serum levels of MMPs, tissue inhibitors of metalloproteinases (TIMPs), and several cytokines/chemokines in patients with histologically proven early and advanced stages of NASH and compared them with those in healthy controls. RESULTS: Serum MMP-1 levels in stage 1 fibrosis, but not in the more advanced fibrosis stages, were significantly higher than in healthy controls (P=0.019). There was no correlation between serum MMP-1 level and fibrosis stage. Serum MMP- 1 levels in NASH patients represented disease activity estimated by serum aminotransferase values during the follow-up period. In contrast, MMP-2, MMP-9 and TIMPs did not change with disease activity. Consistent with the finding that MMP-1 is expressed predominantly in monocytes and Kupffer cells, serum levels of monocyte chemotactic protein-1 and granulocyte-colony stimulating factor were significantly increased in NASH with stage 1 fibrosis. CONCLUSIONS: These results suggest that serum MMP-1 levels represent disease activity and may serve as a potential biomarker for monitoring the progression of NASH.

Evaluation of efficacy of Zhitong-Jiangu recipes in treatment of cartilage injury in osteoarthritis using MR T2 mapping: An experimental study / 中国介入影像与治疗学

Objective To explore the value of MR T2 mapping imaging in evaluation of the effection of Zhitong-Jiangu recipes in treatment of cartilage injury in osteoarthritis.Methods The models of osteoarthritis in the knee of New Zealand white rabbits were made with intra-articular injection of papain.Totally 48 New Zealand white rabbits were randomly divided into normal control group,model control group,glucosamine hydrochloride treatment group and Zhitong-Jiangu recipes treatment group.MR T2 mapping was performed on the knee and the content of MMP-1 in articular cartilage was analyzed with immunohistochemistry 4 weeks after treatment.The differences of T2 value and MMP-1 content of articular cartilage among the four groups were compared.The correlation among the different intervention methods,MMP-1 content of articular cartilage and the T2 value of articular cartilage were analyzed.Results T2 value of articular cartilage in the model control group was significantly higher than that in the other three groups (all P＜0.01),and there was no significant difference of T2 value among the other three groups.The MMP-1 content of articular cartilage in glucosamine hydrochloride treatment group and Zhitong-Jiangu recipes treatment group was lower than that in model control group (both P＜0.05),and was higher than that in normal control group (both P＜0.05).There was no significant difference between the two groups.The relationship between MMP-1 content and T2 value of articular cartilage was nonlinear.With the increase of MMP-1 content,T2 value first increased slowly and then increased rapidly (P＜0.05).Conclusion MR T2 mapping imaging is helpful to evaluating the efficacy of Zhitong-Jiangu recipes in treatment of cartilage injury in osteoarthritis in rabbit models.The relationship between MMP-1 content and T2 value of articular cartilage may be nonlinear.

MMP-1/PAR-1 signal transduction axis and its prognostic impact in esophageal squamous cell carcinoma

The matrix metalloprotease-1 (MMP-1)/protease-activated receptor-1 (PAR-1) signal transduction axis plays an important role in tumorigenesis. To explore the expression and prognostic value of MMP-1 and PAR-1 in esophageal squamous cell carcinoma (ESCC), we evaluated the expression of two proteins in resected specimens from 85 patients with ESCC by immunohistochemistry. Sixty-two (72.9 percent) and 58 (68.2 percent) tumors were MMP-1- and PAR-1-positive, respectively, while no significant staining was observed in normal esophageal squamous epithelium. MMP-1 and PAR-1 overexpression was significantly associated with tumor node metastasis (TNM) stage and regional lymph node involvement. Patients with MMP-1- and PAR-1-positive tumors, respectively, had poorer disease-free survival (DFS) than those with negative ESCC (P = 0.002 and 0.003, respectively). Univariate analysis showed a significant relationship between TNM stage [hazard ratio (HR) = 2.836, 95 percent confidence interval (CI) = 1.866-4.308], regional lymph node involvement (HR = 2.955, 95 percentCI = 1.713-5.068), MMP-1 expression (HR = 2.669, 95 percentCI = 1.229-6.127), and PAR-1 expression (HR = 1.762, 95 percentCI = 1.156-2.883) and DFS. Multivariate analysis including the above four parameters identified TNM stage (HR = 2.035, 95 percentCI = 1.167-3.681), MMP-1 expression (HR = 2.109, 95 percentCI = 1.293-3.279), and PAR-1 expression (HR = 1.967, 95 percentCI = 1.256-2.881) as independent and significant prognostic factors for DFS. Our data suggest for the first time that MMP-1 and PAR-1 were both overexpressed in ESCC and are novel predictors of poor patient prognosis after curative resection. The MMP-1/PAR-1 signal transduction axis might be a new therapeutic target for future therapies tailored against ESCC.