Expression of membrane-type 1 matrix metalloproteinase in coronary vessels of allotransplanted primate hearts

BACKGROUND: The mechanisms of intimal thickening in cardiac allograft vasculopathy (CAV) remain controversial after heart transplantation. Matrix metalloproteinase-2 (MMP-2) plays a crucial role in degrading extracellular matrix (ECM) during neointimal formation. Recently, it has been revealed that MMP-2 is activated by membrane-type 1 matrix metalloproteinase (MT1-MMP). This process involves tissue inhibitor of MMP-2 (TIMP-2), forming an MT1-MMP/TIMP-2/pro-MMP-2 complex. In this study, we hypothesize that these components contribute to the pathogenesis of CAV. METHODS: Heterotopic cardiac allografting was performed in randomly paired Japanese monkeys with an immunosuppressive regimen of intravenous administration of antihuman CD18 monoclonal antibody. The donor hearts were harvested at Days 22, 28, 40, 41, and 95 posttransplantation. We examined expression of MMP-2, MT1-MMP, and TIMP-2 of graft vessels using immunohistochemistry and protein level by western blot analysis. RESULTS: Pathologically, various degrees of neointimal formation were observed. In the allografts harvested at Days 22, 28, 40, and 41, MT1-MMP was expressed in the endothelial cells and smooth muscle cells (SMCs) in media of some arteries without histological change, accompanied by expression of MMP-2 and TIMP-2. In the severely thickened neointima of the allograft harvested at Day 95, MMP-2 and faint MT1-MMP were expressed in SMCs of severely thickened neointima and media; TIMP-2 expression was seen only in noncollagenous tissue of severely thickened neointima. MMP-2 protein was more intensely expressed in the allograft harvested at Day 95 than in the allograft harvest at Day 41, while TIMP-2 protein level was almost same in the 2 samples. CONCLUSION: We observed the simultaneous expression of MMP-2, MT1-MMP, and TIMP-2. Thus, ECM degradation triggered by MT1-MMP/TIMP-2/pro-MMP-2 complex could be a novel mechanism of CAV.     

基质金属蛋白酶-13在骨性关节炎发病中的活性调控研究

目的 研究一氧化氮(NO)是否通过膜型基质金属蛋白酶-1(MT1-MMP)间接激活基质金属蛋白酶-13酶原(pro-MMP-13).方法 购买并传代人软骨肉瘤细胞(SW1353),用NO供体S-亚硝基-N-乙酰基青霉胺(SNAP),SNAP+NO清除荆氧合血红蛋白(OxyHb)和SNAP+组织金属蛋白酶抑制物-2(TI...     

Increased expression of matrix metalloproteinases in the uterine cervix of postmenopausal women

OBJECTIVE.: To determine whether atrophy of the uterine cervix in menopausal women is associated with an increased expression of matrix metalloproteinases (MMP), a decrease in their counter regulatory proteins (tissue inhibitors of matrix metalloproteinase [TIMP]), and a decrease in type I collagen. MATERIALS AND METHODS.: A pilot study was performed on cervical stroma harvested from 10 premenopausal and 9 postmenopausal women undergoing a hysterectomy. The amount of pro-MMP-2 and pro-MMP-9 in protein extracts from the two groups was compared by gelatin zymography. The membrane-type (MT)1-MMP, TIMP-1, and TIMP-2 were quantitated by Western immunoblotting. Total collagen was estimated by measuring hydroxyproline content. A primary fibroblast culture was developed to study estrogen regulation of MMP expression in vitro. RESULTS.: Pro-MMP-2 and pro-MMP-9 were increased in postmenopausal extracts. No difference in the amount of MT1-MMP, TIMP-1, TIMP-2, or total collagen was detected. In primary cervical fibroblast cultures, only active MMP-2 was suppressed by estrogen. CONCLUSIONS.: The protein expression of pro-MMP-2 and pro-MMP-9 is increased in cervical stroma of postmenopausal women relative to premenopausal women.     

Localization of matrix metalloproteinase 2 within the aneurysmal and normal aortic wall

BACKGROUND: Current research has shed new light on the role of matrix metalloproteinase (MMP) 2 in the development of abdominal aortic aneurysms (AAAs). MMP-2 is a major protease in the wall of small aneurysms and is produced at increased levels by smooth muscle cells derived from AAAs compared with normal controls. In vivo, MMP-2 is produced as an inactive proenzyme that is activated predominantly by the cell membrane-bound enzyme, membrane type 1 matrix metalloproteinase (MT1-MMP). This study investigated the production of the MMP-2-MT1-MMP-tissue inhibitor of metalloproteinases (TIMP) 2 system within the wall of aortic aneurysms and in age-matched control arterial tissue. METHODS: Arterial tissue from four patients with aortic aneurysms and four age-matched aortic samples was examined for the production and expression of MMP-2, TIMP-2 and MT1-MMP protein using immunohistochemistry, in situ hybridization and in situ zymography. RESULTS: All components of the MMP-2-TIMP-2-MT1-MMP enzyme system were detected in the arterial wall of both aneurysm and control samples, specifically in the medial tissue. The enzymes co-localized with medial smooth muscle cells. Gelatinolytic activity was localized to elastin fibres in normal and aneurysmal aorta. CONCLUSION: The presence of MT1-MMP within the media of arterial tissue suggests a powerful pathway for the activation of MMP-2. The localization of the MMP-2-TIMP-2-MT1-MMP enzyme system to the medial layer of the arterial wall gives support to the concept that this system may play an aetiological role in the pathogenesis of AAAs.     

基质金属蛋白酶和组织金属蛋白酶抑制剂在大肠癌中的表达

目的　研究基质金属蛋白酶 (MMPs)及组织金属蛋白酶抑制剂 (TIMPs)在大肠癌中的表达特点 ,与肿瘤发生发展的关系 ,以及在肿瘤治疗中的应用前景。　方法　采用RT PCR方法测定 2 8例大肠癌患者肿瘤组织和周围正常粘膜的基质金属蛋白酶 2 (MMP 2 )、膜型 1 基质金属蛋白酶 (MT1 MMP)、基质溶素 (MMP 7)、组织金属蛋白酶抑制剂 2 (TIMP 2 )、组织金属蛋白酶抑制剂 3(TIMP 3)的mRNA表达状况 ,并将其结果与临床及病理学资料进行统计学分析。　结果　 (1) 2 7例患者肿瘤组织中MMP 7mRNA表达阳性 ,MMP 2、MT1 MMP、TIMP 2和TIMP 3在肿瘤组织和正常粘膜中均有高表达 ;(2 )肿瘤组织中MMP 7mRNA的表达水平与大肠癌患者的Dukes′分期相关 (P <0 0 1) ;(3)淋巴结阳性患者的肿瘤组织TIMP 2表达水平为 (1 2 5± 0 46 )明显高于淋巴结阴性患者的 (0 75± 0 41) ,差异有显著性意义 (P <0 0 1) ;(4)大肠癌患者癌周正常粘膜TIMP 3mRNA表达随患者Duke′s分期的进展和肿瘤浸润深度的增加而降低 (P <0 0 1) ;(5 )TIMPs与MMPs之间无明显相关关系 (P >0 1)。　结论　MMP 7可望成为诊断大肠癌的敏感指标 ;人工诱导TIMP 2、TIMP 3或阻断MMP 7、MMP 2、MT1 MMP的表达可能抑制肿瘤的浸润和转移 ,成为肿瘤治疗的新途径。     

Differential regulation of matrix metalloproteinase activities in abdominal aortic aneurysms

BACKGROUND: The increased synthesis of matrix metalloproteinases (MMPs) by aortic smooth muscle cells (SMCs) is thought to be involved in the etiopathogenesis of abdominal aortic aneurysms (AAAs), but the functional regulation and the activation states of these MMPs remain unclear. In this study, we assessed the expression levels and the functional regulation of several MMPs in the pathogenesis of AAAs. METHODS: Human healthy aorta and AAA specimens were homogenized, and the proteolytic activities of MMP-2 and MMP-9 and of the macrophage metalloelastase (MMP-12) were assessed with zymography. Protein expression of MMP-1, MMP-12, membrane-type 1 MMP (MT1-MMP), tissue inhibitor of MMP 1 (TIMP-1), TIMP-2, TIMP-3, alpha-actin, and beta-actin was analyzed with electrophoresis on sodium dodecyl sulfate gels and immunoblotting. RESULTS: MMP-1, MMP-9, and MMP-12 zymogen levels and proteolytic activities were increased in AAAs when compared with healthy aorta. A severe reduction in alpha-actin--positive vascular SMCs was observed in all the AAA specimens and was correlated with an increase in TIMP-3 but not TIMP-1 or TIMP-2 potential activities. Although pro--MMP-2 activity was decreased, the extent of activated MMP-2 remained unaffected in the AAAs. In accordance with this result, a highly activated MT1-MMP form was also observed in AAAs. CONCLUSION: These data suggest that chronic aortic wall inflammation is mediated by macrophage infiltration, which may account for the destruction of medial elastin, as reflected by SMC down regulation, through increased levels of active MMP-1 and MMP-12. Moreover, altered MT1-MMP proteolytic turnover and differential regulation of TIMP expression in AAAs suggest that tight regulatory mechanisms are involved in the molecular regulation of MMP activation processes in the pathogenesis of AAAs.     

Significance of matrix metalloproteinases and tissue inhibitors of metalloproteinase expression in the recurrence of superficial transitional cell carcinoma of the bladder

PURPOSE: We determined whether expression levels of matrix metalloproteinase (MMP)-2, MMP-9, membrane-type MMP-1 (MT1-MMP), tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 messenger (m) RNA in superficial transitional cell carcinoma of the bladder may be used as predictors of tumor recurrence. MATERIALS AND METHODS: Total RNA was extracted from 51 superficial transitional cell carcinomas of the bladder, and expression levels of MMP-2, MMP-9, MT1-MMP, TIMP-1 and TIMP-2 messenger mRNA in these specimens were measured by Northern blot analysis. Results were evaluated in regard to tumor recurrence. RESULTS: Mean MMP-9 and TIMP-2 mRNA expression in the tumors of patients with recurrence were 2.5 and 3-fold higher, respectively, than in those of patients without recurrence despite no significant differences in MMP-2, MT1-MMP or TIMP-1 expression. The recurrence-free survival rate of patients with elevated MMP-9 and TIMP-2 mRNA expression was significantly lower than that of patients with normal MMP-9 and TIMP-2 expression, respectively. In addition, Cox's multivariate analysis revealed that elevated MMP-9 and TIMP-2 were strongly associated with a high incidence of intravesical recurrence of superficial bladder cancer. CONCLUSIONS: These results indicate that MMP-9 and TIMP-2 are strongly expressed in the tumors of patients with recurrence compared with those without recurrence and elevated MMP-9 and TIMP-2 may be used as predictors of recurrence in patients with superficial transitional cell carcinoma.     

Characterization of expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in prostate cancer cell lines

Stromal expression of some matrix metalloproteinases (MMPs) has been associated with increasing tumour burden in prostate cancer. We investigated the expression of mRNA (by RT-PCR) and protein (by zymography and western blotting) of MMPs and endogenous inhibitors (tissue inhibitors of metalloproteinases, TIMPs) in two parent epithelial prostate cancer cell lines and sublines of increasing invasive/metastatic potential. Expression of membrane type MMPs, MT1-MMP and MT3-MMP mRNA was higher in PC3-derived than in LNCaP-derived lines, whereas MT2-MMP mRNA expression was higher in the LNCaPderived than in PC3-derived cell lines. Active MT1, MT2 and MT3-MMP protein levels were similar in all lines, but processed MT-MMPs, indicative of latent MMP activation, were increased in more aggressive sublines. Expression of MMP-1, MMP-13 and TIMP-1 was higher in the more aggressive sublines and may be implicated in invasive/metastatic ability. Regulation of MMP-1 and MMP-13 expression may offer important therapeutic options for treating patients with prostate cancer.     

Neutrophil-derived serine proteinases enhance membrane type-1 matrix metalloproteinase-dependent tumor cell invasion

BACKGROUND: Matrix metalloproteinase-2 degrades a variety of basement membrane components and is essential for tumor invasion. We have previously reported that membrane type-1 matrix metalloproteinase (MT1-MMP) cooperates with neutrophil-derived serine proteinases (NDPs; elastase, cathepsin G, protease-3) to activate matrix metalloproteinase-2. We therefore hypothesized that NDPs enhance tumor-cell invasion. METHODS: Clones of human HT1080 fibrosarcoma cells transfected with MT1-MMP sense (HT-SE) or antisense CDNA (HT-AS) were used. These cells express either high (HT-SE) or extremely low levels (HT-AS) of MT1-MMP relative to nontransfected HT1080 cells (HT-WT). The cells were incubated in the presence or absence of purified NDP, with or without alpha 1-antitrypsin or the MMP inhibitor batimastat. Cell invasion was measured with the use of Boyden chambers with polycarbonate membranes coated with a reconstituted extracellular matrix. RESULTS: Under control conditions HT-WT and HT-SE cells were 4-fold more invasive than HT-AS cells. The addition of NDP increased HT-WT and HT-SE cell invasion 60% to 100% but had no effect on HT-AS cells. alpha 1-antitrypsin or batimastat did not decrease the baseline invasiveness of HT-WT and HT-SE cells; however, they abrogated the stimulatory effect of NDP. CONCLUSIONS: HT1080 cell invasion depends on MT1-MMP expression. MT1-MMP overexpression does not increase invasiveness by itself. NDPs increase invasion by MT1-MMP expressing cells by activating matrix metalloproteinase-2.     

The expression and localization of membrane type-1 matrix metalloproteinase in human abdominal aortic aneurysms

BACKGROUND AND OBJECTIVE: Matrix metalloproteinase-2 (MMP-2) degrades both fibrillar collagens and elastin. MMP-2 is secreted as a latent 72-kd proenzyme that must be proteolytically processed to the 62-kd active form. In our laboratory we demonstrated a significant increase of active, matrix-bound MMP-2 in abdominal aortic aneurysmal (AAA) tissue compared with nonaneurysmal aorta with arteriosclerotic occlusive disease and normal aortic tissue. This increase in active MMP-2 is considered to be important in aneurysm pathogenesis, but the mechanism of its activation in aortic tissue is unknown. Membrane type-1 MMP (MT-1 MMP) is known to be an activator of MMP-2. The purpose of this study was to determine MT-1 MMP expression and its involvement in pro-MMP-2 activation in human aneurysmal tissue. METHODS: Infrarenal aortic tissue was obtained during the surgical repair of AAAs or the bypass of aortoiliac occlusive disease, or from nondiseased aorta, and the expression of MT-1 MMP messenger RNA was determined with Northern blot analysis. MT-1 MMP protein was determined with immunoblot and immunohistochemistry. The ability of aortic tissue to activate pro-MMP-2 was analyzed by incubating aortic tissue with exogenous radiolabeled pro-MMP-2. RESULTS: MT-1 MMP messenger RNA and protein are increased in AAA (P <.05) compared with arteriosclerotic occlusive disease and normal aortic tissue. Immunohistochemical analysis localized MT-1 MMP to aortic smooth muscle cells and macrophages in aneurysmal tissue. AAA tissue demonstrated a greater capacity to activate exogenous pro-MMP-2 compared with atherosclerotic and normal aortic tissue (P <.05). CONCLUSION: These studies demonstrate that MT-1 MMP is increased in AAA tissue and suggest that it may be important in AAA pathogenesis through its ability to activate pro-MMP-2     

Modulation of matrix gelatinases and metalloproteinase-activating process in acute kidney rejection

Changes in matrix metalloproteinase (MMP) activities would contribute to the accumulation of extracellular matrix during acute kidney allograft rejection. MMP-2 and MMP-9 and other gelatinolytic activities were examined in the rejected graft and the urine of a rat model of acute kidney rejection (orthotopic allotransplantation from a Buffalo donor to a Wistar-Furth recipient) by either zymography or fluorescence assay. MMP-2, membrane type 1 (MT1)-MMP, and tissue inhibitor of metalloproteinase (TIMP)-2 were also examined by immunodetection. The proMMP-2 activity and protein level increased in the graft during rejection when compared with normal Buffalo kidney, whereas activated MMP-2 decreased. TIMP-2 protein levels were markedly decreased and MT1-MMP proteolytic fragments (44-40 kDa) were undetectable. This suggests an altered MT1-MMP-dependent processing of proMMP-2 into active MMP-2 due to a diminished TIMP-2 level in acute kidney rejection. In the urine the overall gelatinolytic activity decreased considerably, although activity associated with an as yet unidentified 78-kDa protein appeared 6 days after transplantation.     

Presence of matrix metalloproteinases and tissue inhibitor of matrix metalloproteinase in human sperm

The matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that degrade protein components of the extra-cellular matrix. The necessity of breakdown of physical barriers in the fertilization process suggests that MMPs, along with their tissue inhibitors (TIMPs), might be involved in this task. We have examined the presence of MMP and TIMP in normal and abnormal human sperm samples by gel zymography and Western blot analysis. Thirty-five normal sperm samples and 35 abnormal sperm samples were examined in this study. Gel zymography showed 92-, 72-, 62-, and 28-kd molecular-weight bands exhibiting gelatin-degrading activity in both normal and abnormal sperm samples. The 92-, 72-, and 62-kd bands with gelatinolytic activity are consistent with pro-MMP-9, pro-MMP-2, and active MMP-2, respectively (pro-MMP being the zymogen of MMP). Western blot analysis showed the presence of TIMP-1 in both normal and abnormal sperm samples. A higher 28-kd activity and a lower 92-kd MMP activity in normal sperm samples relative to abnormal samples were detected. No marked difference in TIMP-1, 72-kd, and 62-kd release was observed between normal and abnormal sperm samples. In conclusion, this is the first report of MMP activity in normal and abnormal human sperm samples and of TIMP presence in sperm samples. The data indicate a different MMP profile between normal and abnormal sperm samples, with a higher 28-kd activity and a lower 92-kd MMP activity in normal relative to abnormal samples.     

TGF-β1和TGF-α在膀胱癌侵袭和转移中的作用

目的 探讨转化生长因子-β（TGF-β1）和转化生长因子－α（TGF-α）对膀胱癌细胞株（EJ）生长的影响以及促进膀胱癌侵袭和转移的可能途径。方法 采用MTT、Western Blot和RT－PCR方法,观察TGF－β1和TGF－α对DJ细胞株生长以及在mRNA和蛋白水平上对金属基质蛋白酶（MMPs)和组织特异性金属蛋白酶抑制剂－2（TIMP－2）表达的影响。结果 （1）TGF-β1和TGF－α对EJ细胞生长存在抑制趋势,但差别无显著性意义。（2）TGF－β1和TGF－α作用于EJ细胞48h时 ,MMP－2、TIMP－2、MT1－MMP mRNA表达降低;TGF－β1组MMP-9 mRNA表达增加,而对照组和TGF－α组无MP－9mRNA表达。（3）当TGF－β1浓度为0．1、1．0ng/ml时,增加细胞培养上清液中MMP－2蛋白含量对TIMP－2蛋白水平无影响。当浓度为5．0、10．0ng/ml时对MMP－2无影响而降低TIMP－2表达;TGF－α在浓度为1.0、5.0、10.0ng/ml时,对MMP－2蛋白表达无影响而降低TIMP－2表达;在100．0ng/ml时增加MMP－2蛋白表达而对TIMP－2表达无影响;无论在对照组和实验组均未检测到MMP－9。结论 TGF-β1、TGF-α不能抑制EJ细胞生长,参与肿瘤侵袭和转移作用可能与调节MMPs、TIMP－2表达途径有关。     

Differential localization of MT1-MMP in human prostate cancer tissue: role of IGF-1R in MT1-MMP expression

BACKGROUND: MT1-MMP is a metalloproteinase involved in prostate cancer metastasis. The IGF-1R is a tyrosine kinase receptor involved with tumor progression and metastasis. The purpose of this investigation was to examine MT1-MMP and IGF-1R expression and localization in prostate cancer tissues and explore the role of IGF-1R in regulating MT1-MMP in prostate cancer cell lines. METHODS: Immunohistochemistry was utilized to study MT1-MMP and IGF-1R expression in human prostate tissues. IGF-1R regulation of MT1-MMP expression was determined by gene promoter analysis, quantitative RT-PCR and Western blot analysis following pharmacological inhibition of the receptor in PC-3N cells and treatment of LNCaP cells with androgen and IGF-1. RESULTS: MT1-MMP expression was high in the apical regions of the luminal cells in PIN and prostate cancer and less intense in the basalateral regions of benign tissues. IGF-1R was expressed primarily in the basal cells of normal glands and highly expressed in prostate cancer. Inhibition of IGF-1R in PC-3N cells decreased MT1-MMP expression and treatment of LNCaP cells with a synthetic androgen and IGF-1 increased MT1-MMP expression. CONCLUSIONS: These data demonstrate that MT1-MMP is highly expressed in the apical cytoplasmic regions of the luminal cells in PIN and prostate cancer when compared to basalateral cytoplasmic membrane staining in benign glands. Additionally, we demonstrate that IGF-1R is highly expressed in human prostate carcinoma. These findings suggest that MT1-MMP localization and IGF-1R expression in prostate carcinoma could be predictive biomarkers for aggressive disease and support IGF-1R as a promising therapeutic target to decrease processes of prostate cancer metastasis.     

Experimental hindlimb ischemia leads to neutrophil-mediated increases in gastrocnemius MMP-2 and -9 activity: a potential mechanism for ischemia induced MMP activation

INTRODUCTION: Matrix metalloproteinases (MMP)-2 and -9 are Type 4 collagenases instrumental in basement membrane degradation, a process necessary for angiogenesis to occur. Polymorphonuclear leukocytes (PMNs) contain MMP-9, and in the presence of both PMN-derived serine protease and membrane type 1 (MT1)-MMP, are able to activate pro-MMP-2 following hindlimb ischemia. We hypothesized that neutrophil depletion (ND) of animals prior to hindlimb ischemia (HI) would abrogate the activation of pro-MMP-2 and decrease the level of MMP-9 MATERIALS AND METHODS: 12 FVB/N Tie2/LacZ-182 SATO female mice were randomly divided into four blinded groups; HI + PBS, HI + anti-PMN antibody (GR-1), HI + isotype matched control antibody (IgG(2b,K)), and no HI + PBS. PMN depletion was achieved prior to the time of ischemia and maintained until sacrifice. HI was achieved by unilateral femoral artery ligation. Three days postligation the animals were sacrificed and the gastrocnemius muscle from each hindlimb was harvested. MMP-2 and -9 (gelatin zymography) and MT1-MMP (Western blot) expression and activation were quantified by densitometry and NIH Image Analysis software. MMP values were expressed as a ratio of ischemic-to-nonischemic hindlimbs and compared between groups. Statistical significance was determined with analysis of variance (ANOVA) RESULTS: Zymograms revealed a greater than 10-fold increase in active MMP-9 and greater than 4-fold increase in active MMP-2 from HI + PBS compared to no HI + PBS (P < 0.05). HI + anti-PMN antibody demonstrated reduction of both active MMP-2 and -9 levels to that of the nonischemic group. Pro-MMP-2 was constitutively expressed in all four groups with no significant differences between any group (P = NS). There was no difference between the HI + isotype-matched antibody group and the HI + PBS group throughout the experiments (P = NS). ND did not affect MT1-MMP activation or expression CONCLUSIONS: Limb ischemia causes activation of MMP-2 and -9, which is eliminated by ND. ND animals undergoing hindlimb ischemia exhibit identical levels of active MMP-2 and -9 as animals that did not have hindlimb ischemia. Neutrophils may be an important activator of MMP-2 and the suppliers of MMP-9 in the ischemic hindlimb and may be essential for tissue remodeling, basement membrane degradation, and angiogenesis in ischemic limbs     

Decreased collagen-degrading activity could be a marker of prolonged mesangial matrix expansion

Background Mesangial matrix expansion is caused by the overproduction and/or the impaired proteolytic degradation of the extracellular matrix. However, the relative contribution of these changes to the development of prolonged mesangial matrix expansion is still poorly understood. We aimed to elucidate the relative role of the matrix metalloproteinase (MMP)/tissue inhibitors of metalloproteinases (TIMPs) system in the development of prolonged mesangial matrix expansion.Methods We prepared two rat models, showing reversible or prolonged mesangial matrix expansion, induced by a single injection or two consecutive injections of anti-Thy-1.1 monoclonal antibody 1-22-3, respectively. We analyzed the glomerular expression of type I and type IV collagens; MMP-2, -9, and -13; membrane type 1-MMP (MT1-MMP); TIMP-1; and urinary type I collagen-degrading activity in both models.Results There were no differences in glomerular mRNA levels of type I and type IV collagens between the reversible and the prolonged models. MMP-9 mRNA expression and protein level was lower in the prolonged model than in the reversible one, whereas there were no differences in mRNA levels of MMP-2, -13, MT1-MMP, or TIMP-1 between the two models. Urinary type I collagen-degrading activity in the prolonged model was lower than that in the reversible one. Furthermore, there was a significant correlation between the mesangial matrix expansion and urinary type I collagen-degrading activity.Conclusions Impaired expression of MMP-9 may contribute to the development of prolonged mesangial matrix expansion. Analysis of urinary type I collagen-degrading activity may provide additional diagnostic information in mesangial proliferative glomerulonephritis.