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Plasma levels of matrix metalloproteinase-1 (MMP-1), -2 (MMP-2), and -7 (MMP-7) have been shown to be independently correlated with ulcerative colitis (UC), but their relationship with each other and to disease severity remains unclear. This study aims to evaluate the relationship between MMP-1, -2, and -7 and the severity of UC. Venous blood samples were collected from 50 patients with UC and 30 normal subjects. MMP-1, -2, and -7 levels were determined by enzyme linked immunosorbent assay (ELISA). Expression of plasma levels in patients with UC was significantly higher than controls (p<0.001), and was positively correlated with disease severity (p<0.01). Plasma MMP-1, -2, and -7 levels reflect their expression in patients with UC. Plasma MMP-1, -2, and -7 levels demonstrate the potential to become biomarkers to clinically diagnose UC, predict its severity, and guide further therapy.
Keywords: Matrix metalloproteinases; MMP-1; MMP-2; MMP-7; Ulcerative colitis.
Ulcerative colitis (UC) is a chronic nonspecific inflammatory disease of the colon with unknown etiology. No specific effective treatment is available at present. Pathological lesions are usually limited to the mucosal and submucosal areas, while diarrhea, pusmucus bloody stool, and abdominal pain and common clinical symptoms.
More attention is being focused on this disease because its morbidity has increased in recent years in Turkey, where UC was once an uncommon gastrointestinal disorder. Previous studies on the pathogenesis of UC have shown that ulceration are closely related to the excessive degradation of extracellular matrix (ECM) by matrix metalloproteinases (MMPs), which are over-expressed and activated to cause colonic mucosal injury and inflammation (1). MMPs are group of zinc-dependent proteases that are produced and secreted by connective tissue cells, endothelial cells, mono-macrophages, and other cells.
Animal and clinical studies have revealed the over-expression of various MMPs in the inflammatory areas of colonic mucosa in UC; MMPs expression tend to be particularly high. It is believed that increased of MMP is one of the mechanisms in the pathogenesis of UC (2-4). MMP-1 levels are thought to be more closely associated with UC than other MMPs; studies (2, 5, 6) have reported that their expression in patients with UC is significantly higher than in normal control subjects. But, the correlation between plasma levels of these proteins and their expressions or with UC disease severity is not clear. In this study, we examined MMP-1, -2, and -7 plasma levels to study their relationship and associations with disease severity in patients with UC.
Materials and Methods.
Fifty patients (male, n=25; female, n=25; mean age, 45 years; age range, 28-70 years) with UC diagnosed by clinical symptoms, endoscopy, and pathology findings were enrolled in the study. Of the 50 patients, 8 patients had pan-colon lesions, 6 had semicolon lesions, 24 had recto-sigmoid lesions, and 12 rectal lesions. Patients were divided into groups based on the diagnostic criteria of UC severity: 21 patients were classified as mild (M group) and 29 patients as moderate- to-severe (MTS group). Meanwhile, 30 normal subjects were recruited as normal controls (male, n=13; female, n=17; mean age, 40 years; age range, 25-61 years).
Blood samples were collected after spinning at 1000 x g for 30 minutes, and then at 10000 x g for 10 minutes at 2 ° C to 8 ° C. Samples were stored at -80 ° C for ELISA.
Enzyme linked immunosorbent assay (ELISA) for plasma MMP-1, -2, and -7 levels were performed using an ELISA kit (R&D Systems, USA) following the manufacturer's instructions.
All values were expressed as mean ± SD. Analyses of variance (ANOVA) test were used. Spearman correlation analysis was used to determine the relationship between plasma levels. P<0.05 was considered statistically significant.
The ELISA study (Table 1) showed that the overall plasma levels of MMP-1, -2, and -7 in UC patients were significantly higher than those of the control group (p<0.001). Plasma MMP-1 and -2 levels in the MTS group were significantly higher than those of the M group and significantly higher in the M group compared to the normal controls (p<0.001). However, no difference was observed between plasma MMP-7 levels of patients and groups (MTS versus M group) (p>0.05).
Plasma MMP-1 and -2 levels were correlated in patients with UC. (MMP-1, p<0.01, r=0.85; MMP-2, p<0.01, r=0.73)
In this study, we determined MMP-1, -2, and -7 levels in UC patients compared with normal controls. The plasma levels of MMP-1, -2, and -7 were determined using ELISA. The levels of these proteins increased in the plasma of UC patients compared to normal controls, and the levels were correlated with disease severity (except MMP-7 levels).
Our results are consistent with findings from McKaig et al and Wang et al (4, 7) and supported previous studies demonstrating that MMP-1 and MMP-2 reflected acute tissue injury and was associated with the initial steps of ulceration in UC and new blood vessel formation (2, 4).
MMPs levels increased in the peripheral blood samples from patients with acute coronary syndrome, cancer, hepatitis, and rheumatoid arthritis (8-12). Wiercinska-Drapalo A et al (13) used ELISA to determine serum MMP-1 and found that serum MMP-1 was significantly increased in patients with UC compared with normal controls. Our study produced similar findings; plasma MMP-1, -2, and -7 levels were higher in UC patients, but did not correlate with disease severity. These findings indicate that plasma MMP-1 and -2 generally reflect the disease state. MMP-1 and -2 are primarily associated with the initial steps of ulceration in UC (2, 4) which may explain its lack of association with disease severity. In our study, most of the patients were suffering from chronic recurrent UC, so plasma MMP-1 and -2 could have been affected.
According to a previous study, (14) free MMP-1 and -2 decreased as the progressed. This may be another reason why plasma MMP-1 and -2 levels increased only in moderate-to-severe disease patients, but not mild patients.
Plasma MMP-1, -2, and -7 reflect their levels to some extent; especially MMP-1 and -2. After excluding other diseases such as coronary heart disease and liver disease that are also associated with increased MMP-1 and MMP-2 levels could possibly become useful biomarkers for UC diagnosis and disease severity, and may be useful to guide therapy.