| Matrix metalloproteinases(MMP) are members of family of Zn-dependent endopeptidases that are responsible for degradation of various protein components of the extracellular matrix(ECM), The activity of MMP is controlled by the tissue inhibitor of metalloproteinases(TIMP),which inhibit active MMP by binding in a 1:1 molar ration to form tight non-covalent complex. The balance between MMP and TIMP play an important role in physiological and pathological processes, including tissue remodeling and repairing, migration of cell, inflammatory reaction, angiogenesis, immunological response, tummor invasion and metastasis. of the MMP family, matrix metalloproteinase-3(MMP-3) and matrix metalloproteinase-9(MMP-9) are the important members, MMP-3 is also named stromelysin-1, which can degrade type III, IV, V, VI, VII collagens, fibronectin, elastin, laminin, vitronectin aggrecan, MMP-9 is also named Gelatinase B whitch can degrade type IV, V, VII, X, XI collagens, fibronectin, laminin, vitronectin aggrecan, gelatin and elastin.Tissue inhibitor of metalloproteinase-1(TIMP-1) is the specific inhibitor of MMP-3 or MMP-9.Systemic lupus erythematosus(SLE) is a systemic autoimmune disease characterized by the increased production of a broad spectrum of autoantibodies against several self-antigens and immune complex depositions in the kidneys and other organs,The latter are associated with the infiltration of leucocyte and production of inflammatory reaction. The disease occurs predominantly in young women, the pathogenetic mechanism of SLE has not yet been defined, the infiltration of inflammatory cells, vascular lesions and abnormality of ECM metabolism have been showed in SLE. Thus MMP-3, MMP-9 and TIMP-1 may play roles in the pathogenesis of SLE. Presently, Serum levels of MMP-3 and MMP-9 were reported inconsistently. To study the role of MMP-3, MMP-9 and TIMP-1 in the pathogenesis of SLE, Serum levels of MMP-3,MMP-9 and TIMP-1 in 45 patients with SLE and 30 healthy controls were measured, and discuss their clinical significance in this paper.Materials and Methods1. clinical data45 patients with SLE and 30 healthy controls were evaluated in this study. All patients fit for the American-Rheumatism Association 1997 revised criteria for the diagnosis of SLE. The patients include 41 femals and 4 males whose age ranged from 9 to 64 with an average of 28.41±11.32(SD) years,The healthy controls include 27 femals and 3 males whose age ranged from 20 to 43 with an average of 26.95±10.63(SD) years,The age and sex of healthy controls matched that of patients.Disease activity of patients with SLE was evaluated using the SLEDAI standard. active SLE was defined according to the Zhengmin's criteria, and renal lupus was confirmed by urine analysis(proteinuria higher than 500mg/24h or ++).2. Laboratory studiesThe serum samples were stored at -80°C until use, Serum levels of MMP-3,MMP-9 and TIMP-1 were measured by enzyme-linked immunosorbent assay(ELISA). ELISA kits for MMP-3, MMP-9 and TIMP-1 were purchased from shang hai sheng xiong CO. assays were performed according to the manufactor's instruction. 3. Stastistical analysisAll date analyses were performed using SPSS 11.0 software, Because serum levels of MMP-3, MMP-9 and TIMP-1 did not follow a gaussian distribution, results are expressed as median values with the 25 to 75 centiles(interquartile range). Between group differences were analysed with the non-parametric Mann-Whitney U test. The wilcoxon rank sum test was used to compair paired groups. Correlations were determined by spearman' rank order correlation and linear regression after . P values of less than 0.05 were considered significant.Results1. Serum levels of MMP-3,MMP-9 and TIMP-1 in patients with SLE and healthy controls1)Serum levels of MMP-3 in patients with SLE were significantly increased as compared with controls(P<0.01), and that serum levels of MMP-9 in patients with GLE were significantly decreased as compared with controls(P<0.01), but serum levels of TIMP-1 had no significant difference between the patients and controls(P>0.05).2) No correlation was found between serum levels of MMP-3 and TIMP-1, MMP-9 and TIMP-1 in patients or controls(r=-0.065;-0.092;0.117;0.436 P>0.05,respetively), but a significantly negative correlation was found between serum levels of MMP-3 and MMP-9 in patients but not in controls(r=-0.687 P<0.01, r=-0.019 P>0.05,respectively).2. Influence of disease activity on serum levels of MMP- 3,MMP-9 and TIMP-1.1)Serum levels of MMP-3 in patients with active SLE were significantly higherthan those of the inactive(P<0.05),but serum levels of MMP-9 were significantly lower than those of the inactive(P<0.05),serum levels of TIMP-1 show no significant difference between active and inactive patients(P>0.05).2)A significantly positive correlation between MMP-3 and SLEDAI scores and a significantly negative correlation between MMP-9 levels and SLEDAI scores were found in patients with SLE (r=0.854 P<0.01,r=-0.676 P<0.01,respectively),but TIMP-1 levels showed no significant correlation with SLEDAI scores (r=0.098 P>0.05).3. Relationships between clinical manifestations and serum levels of MMP-3, MMP-9 and TIMP-1When compared with the patients without renal involvement and pulmonary involvement, serum levels of MMP-3 were significantly increased(P<0.01),but MMP-9 levels were significantly decreased (P<0.01) in the patients with renal involvement and pulmonary involvement, serum levels of MMP-3, MMP-9 and TIMP-1 did not differ significantly between the following clinical findings: arthritis, malar erythema(P>0.05).4. Relationships between serum levels of MMP-3, MMP-9 and TIMP-1 and immunological parameters in patients with SLE1)Serum levels of MMP-3 in SLE patients with anti-dsDNA positive and decreased C3 levels were significantly higher than those with anti-dsDNA negative and those of decreased C3 levels(P<0.05).However, it did not show significant difference between groups of patients with or without the following immunological parameters: ANA antibody, anti-Sm antibody, anti-SSA antibody, anti-SSB antibody, anti-RNP antibody and increased IgG levels(P>0.05).2)Serum levels of MMP-9 in patients with decreased C3 levels were significantly lower than those without decreased C3 levels (P<0.05),however, it did not show significant difference between groups of patients with or without the following immunological parameters: anti-dsDNA antibody, ANA antibody, anti-Sm antibody, anti-SSA antibody, anti-SSB antibody, anti-RNP antibody and increased IgG levels(P>0.05).3)Serum levels of TIMP-1 in SLE patients with anti-Sm and anti-SSA antibody positive were significantly higher than those with anti-Sm and anti-SSA antibody negative(P<0.05),Serum levels of TIMP-1 in SLE patients with anti-RNP antibody positive were significantly lower than those with anti-RNP antibody negative(P<0.05), however it did not show significant difference between groups of patients with or without the following immunological parameters: anti-dsDNA antibody, ANA antibody, anti-SSB antibody, deceased C3 levels and increased IgG levels(P>0.05).5. Relationships between serum levels of MMP-3, MMP-9 and TIMP-1 and some blood routine parameters in SLE patients1)Serum levels of MMP-3 in SLE patients with leucocytopenia and hypoalbuminemia were significantly higher than those with normal white blood cell count and serum albumin levels(P<0.05),however, no significant difference was found in MMP-3 levels between patients with increased erythrocyte sedimentation rate(ESR) and those with normal ESR(P>0.05).2)Serum levels of MMP-9 in SLE patients with leucocytopenia and hypoalbuminemia were significantly lower than those with normal white blood cell count and serum albumin levels(P<0.05),however, no significant difference was found in MMP-9 levels between patients with increased ESR and those with normal ESR(P>0.05).3)No significant difference was found in serum levels of TIMP-1 between groups of patients with or without the following abnormalities: leucocytopenia, hypoalbuminemia or increased ESR(P>0.05).4)Serum MMP-3 levels showed negative correlation with white blood cell count and positive correlation with ESR (r=-0.725 P<0.01,r=0.894 P<0.01, respectively), however,serum MMP-9 levels showed positive correlation with white blood cell count and negative correlation with ESR (r=0.636 P<0.01,r=-0.619 P<0.01, respectively), MMP-3 and MMP-9 levels had no significant correlation with serum albumin levels(r=0.126 P>0.05,r=-0.270 P>0.05, respectively), No significant correlation was found between TIMP-1 levels and whit blood cell count, ESR and serum albumin levels (r=0.062;0.042;0.030, respectively P>0.05).6. Influence of therapy(steroid) on MMP-3, MMP-9 and TIMP-1After treatment with steroid, serum MMP-3 levels were markedly decreased in 10 patients with SLE(P<0.01),MMP-9 levels were markedly increased(P<0.01),but TIMP-1 levels showed no significant difference(P>0.05). Conclusions1. Serum levels of MMP-3 in patients with SLE are significantly increased as compared with controls, In patients with active SLE, renal lupus and lupus pheumonitis, serum MMP-3 levels are markedly increased than those of inactive SLE and without renal lupus and lupus pheumonitis,these results suggest MMP-3 may play roles in the pathogenesis of SLE.2. serum MMP-9 levels are significantly decreased compared with controls, In patients with active SLE, renal lupus and lupus pheumonitis, serum MMP-9 lcvels are markedly decreased than those of inactive SLE and without renal lupus and lupus pheumonitis,these results suggest MMP-9 may also play roles in the pathogen- esis of SLE.3. Serum MMP-3 and MMP-9 levels can be used a sensitive indictor for the disease activity of SLE.4. Serum MMP-3 and MMP-9 levels may be used an indirect indicator for lupus nephritis and lupus pheumonitis.5. Serum MMP-3 and MMP-9 levels may be a marker of disease amelioration in SLE patients taking steroid.
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