TIMP-2、MMP-2和MT1-MMP在活化肝星状细胞中的表达及对细胞外基质合成分泌的影响

目的 研究金属蛋白酶组织抑制剂-2(TIMP-2)、基质金属蛋白酶-2(MMP-2)和膜型基质金属蛋白酶-1(MT1-MMP)在活化肝星状细胞(HSCs)中的表达,观察其对细胞外基质(ECM)合成分泌的影响.方法 原代分离培养大鼠HSCs活化后,分别给予40～160 pmol化学合成经修饰抗TIMP-2 siRNA进行干预,检测培养细胞上清液透明质酸(HA)、Ⅲ型前胶原(PCⅢ)和羟脯氨酸(Hyp)的含量,采用荧光实时定量PCR法检测TIMP-2、MMP-2、MT1-MMP、MMP-13、COL Ⅰ和COL Ⅲ mRNA的表达,western印迹检测TIMP-2、MT1-MMP和MMP-13蛋白表达及明胶酶谱法检测MMP-2蛋白表达.结果 应用化学合成经修饰抗TIMP-2 siRNA后,TIMP-2、MMP-2、MT1-MMP、COL Ⅰ和COL Ⅲ的表达明显降低,而MMP-13的表达则明显增加,培养细胞上清液中HA、PCⅢ和Hyp的含量也明显减少.结论 TIMP-2通过MT1-MMP介导MMP-2的活化,抑制TIMP-2的表达,MT1-MMP和MMP-2的表达随之降低,而HSCs合成分泌ECM也相应减少.     

The prognostic value of metalloproteinases and angiogenic factors in ovarian carcinoma

The objective of this study was to analyze the correlation between matrix metalloproteinases (MMPs) and angiogenic genes and survival in advanced-stage ovarian carcinomas. Primary and metastatic ovarian carcinomas from patients diagnosed with FIGO stage III-IV disease and followed up to 20 years were studied using mRNA in situ hybridization (ISH). Expression of MMP-2, MMP-9, membrane-type 1-MMP (MT1-MMP), the MMP inhibitor TIMP-2, vascular endothelial growth factor (VEGF), interleukin-8 (IL-8) and basic fibroblast growth factor (bFGF) was studied. MMP-2, MMP-9 and TIMP-2 mRNA was detected in both tumor and stromal cells, while MT1-MMP was largely confined to tumor cells. In univariate analysis of primary tumors, TIMP-2 and MMP-9 mRNA expression correlated with poor outcome. In metastatic lesions, mRNA expression of TIMP-2, MMP-2, and MT1-MMP correlated with poor survival. In a multivariate analysis of primary tumors, TIMP-2 expression in stromal cells (P=0.006) and MMP-9 expression in tumor cells (P=0.011) retained their predictive value. Intense expression of bFGF mRNA and weak expression of IL-8 mRNA was detected in both stromal and tumor cells in most cases, while VEGF mRNA expression was limited to a few cases. Angiogenic mRNA expression showed no correlation with disease outcome in survival analysis (P>0.05). We conclude that bFGF is the major angiogenic factor expressed in ovarian carcinoma at the mRNA level. MMP-2, MMP-9, MT1-MMP and TIMP-2 are valid markers of poor survival in advanced-stage ovarian carcinoma.     

Matrix metalloproteinase (MMP) expression by differentiated thyroid carcinoma of children and adolescents

The factor(s) that control metastasis of thyroid carcinoma are unknown, but the matrix metalloproteinases (MMPs) are excellent candidates. MMP-1, membrane-type-1 MMP (MT1-MMP), and tissue inhibitor of MMP-1 (TIMP-1) have all been implicated, but the site of production and importance are disputed. In vitro, normal thyroid cells secrete TIMP-1, while thyroid cancer cells secrete TIMP-1 and MMP-1. However, previous pathological studies identified MMP-1 and TIMP-1 only in the stroma surrounding thyroid carcinoma. These data suggest that thyroid carcinoma or tumor-associated inflammatory cells might secrete a factor(s) which stimulates MMP-1 or TIMP-1 expression by surrounding tissues. We hypothesized that MMP-1, MT1-MMP, and TIMP-1 would be directly expressed by thyroid carcinoma and might promote invasion or metastasis. We used immunohistochemistry to determine the expression of MMP-1, MT1-MMP, and TIMP-1 in 32 papillary thyroid carcinoma (PTC), 10 follicular thyroid carcinoma (FTC) and 13 benign thyroid lesions from children and adolescents. The intensity of staining was graded from absent (grade 0) to intense (grade 3). Average MMP-1 expression (mean relative intensity units+/-SE) was significantly greater among PTC (1.97+/-0.15; p=0.004) and FTC (2.2+/-0.25; p=0.006) compared to benign lesions (1.30+/-0.15); but there was no relationship between MMP-1 expression and invasion, metastasis, or recurrence. Expression of MT1-MMP and TIMP-1 was similar for benign and malignant lesions; but recurrent PTC expressed lower levels of TIMP-1 when compared to non-recurrent PTC (p=0.049). Only the expression of TIMP-1 correlated with the presence of tumor-associated lymphocytes (r=0.35, p=0.032). We conclude that MMP-1, MT1-MMP and TIMP-1 are all expressed by thyroid carcinoma and could be important in promoting recurrence.     

Effects of hypoxia, hyperoxia on the regulation of expression and activity of matrix metalloproteinase-2 in hepatic stellate cells

AIM To study the effects of hypoxia,hyperoxia on theregulation of expression and activity of matrixmetalloproteinase-2 (MMP-2) in hepatic stellate cells(HSC).METHODS The expressions of MMP-2,tissue inhibitor ofmatrix metalloproteinass-2 (TIMP-2) and membrane typematrix matalloproteinass-1 (MT1-MMP) in cultured rat HSCwere detected by immunocytochemistry (ICC) and in situhybridization (ISH).The contents of MMP-2 and TIMP-2 inculture supernatant were detected with ELISA and theactivity of MMP-2 in supernatant was revealed byzymography.RESULTS In the situation of hypoxia for 12h,theexpression of MMP-2 protein was enhanced (hypoxiagroup positive indexes:5.7±2.0,n=10;control:3.2±1.0,n=7;P<0.05),while TIMP-2 protein was decreasedin HSC (hypoxla group positive indexes:2.5±0.7,n=10;control:3.6±1.0,n=7;P<0.05),and the activity(total A) of MMP-2 in suparnatant declined obviously(hypoxla group:7.334±1.922,n=9;control:17.277±7.424,n=11;P<0.01).Compared the varied duration ofhypoxia,the changes of expressions Including mRNA andprotein level as well as activity of MMP-2 were mostnotable in 6 h group.The highest value (Ahypoxla~-Acontrol) ofthe protein and the most intense signal of mRNA were inthe period of hypoxia for 6 h,along with the lowestactivity of MMP-2.In the situation of hyparoxia for 12 h,the contents (A_(450)) of MMP-2 and TIMP-2 in supernatantwere both higher than those in the control,especially theTIMP-2 (hyperoxla group:0.0499±0.0144,n=16;control:0.0219±0.0098,n=14;P<0.01),and so wasthe activity of MMP-2 (hyperoxia group:5.252±0.771,n=14;control:4.304±1.083,n=12;P<0.05),and the expression of MT1-MMP was increased.CONCLUSION HSC is sensitive to the oxygen,hypoxiaenhances the expression of MMP-2 and the effect is moremarked at the early stage;hyperoxia mainly raises theactivity of MMP-2.     

Long-term overexpression of membrane type-1 matrix metalloproteinase and matrix metalloproteinase-2 in oleic acid-induced pancreatitis in rats

INTRODUCTION: The matrix metalloproteinase (MMP) plays important roles in extracellular matrix turnover. However, little is known about the roles of MMP-2 and type IV collagen, and the relationship between MMP-2 and membrane type-1 matrix metalloproteinase (MT1-MMP) during progressive destruction of acinar cells in pancreatitis. AIMS AND METHODOLOGY: To examine the serial changes in the expression and activity of MMP-2 and expression of MT1-MMP and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) in rats after induction of pancreatitis by intraductal infusion of oleic acid, and to determine protein concentrations by Western blot analysis and localization of type IV collagen by immunostaining. RESULTS: Gelatinolytic activity of pro-and active MMP-2 and concentrations of MT1-MMP protein, as determined by zymography and Western blot analysis, respectively, increased significantly from 6 hours to day 42 after intraductal infusion of oleic acid. TIMP-2 mRNA expression was significantly higher than that at time 0 throughout the study period, and gelatinolytic activity of active MMP-2 increased from day 3 to day 42. In addition, immunoreactivity for type IV collagen was detected as a discontinuous line along the basement membranes of ducts, vessels, tubular complexes, and acinar cells. CONCLUSION: Our findings indicate that long-term increases of gelatinolytic activity of active MMP-2 cause continuous disorganization of type IV collagen in basement membranes during progressive atrophy of pancreatic gland in oleic acid-induced pancreatitis, and that MT1-MMP and TIMP-2 work as activating factors during proMMP-2 activation. Moreover, basement membranes disorganization in the sustentacula of acinar cells and duct epithelia seems to participate in continuous derangement of acinar cells and duct epithelium.     

Expression of membrane type 1 matrix metalloproteinase, matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 in human cartilaginous tumors with special emphasis on mesenchymal and dedifferentiated chondrosarcoma

Membrane type 1 matrix metalloproteinase (MT1-MMP) has been identified as an activator of the proenzyme of matrix metalloproteinase 2 (MMP-2: gelatinase A), and has also been shown to play a crucial role in tumor invasion by activating proMMP2 in both lung and gastric carcinoma. The tissue inhibitor of metalloproteinase 2 (TIMP-2) plus the MT1-MMP complex also plays an important role in the activation of proMMP-2. In this study, the expressions of MT1-MMP, MMP-2 and TIMP-2 were evaluated in 10 enchondromas, 34 conventional chondrosarcomas, 5 clear-cell chondrosarcomas, 7 mesenchymal chondrosarcomas and 8 dedifferentiated chondrosarcomas. The expressions were immunohistochemically visualized on paraffin sections and the levels of expression were assessed semiquantitatively. The extent of staining was assessed by the extent score in order to determine the overall level of expression. The extent scores of MT1-MMP, MMP-2 and TIMP-2 in grade 2 chondrosarcoma were significantly higher than those in either enchondroma or grade 1 chondrosarcoma (P < 0.05). In conventional chondrosarcoma, significant correlations were found between the extent scores of MT1-MMP and MMP-2 (P < 0.001), MT1-MMP and TIMP-2 (P < 0.01), and MMP-2 and TIMP-2 (P < 0.01). The undifferentiated small round tumor cells of mesenchymal chondrosarcoma showed lower positive rates and extent scores for MT1-MMP (2/7, 0.7 ± 0.5) and MMP-2 (3/7, 0.7 ± 0.4) than for cartilaginous components of mesenchymal chondrosarcoma [MT1-MMP (4/7, 1.3 ± 0.5) and MMP-2 (7/7, 1.9 ± 0.3)] or conventional chondrosarcoma. In dedifferentiated chondrosarcoma, the extent scores of MT1-MMP, MMP-2 and TIMP-2 in low-grade cartilaginous components were not significantly different from those in conventional chondrosarcoma; however, the high-grade anaplastic components showed high extent scores for MT1-MMP, MMP-2 and TIMP-2, compared with the low-grade cartilaginous components of dedifferentiated chondrosarcoma or conventional chondrosarcoma. According to our results, the expression of MT1-MMP as well as that of MMP-2 or TIMP-2 demonstrated a significant correlation with the tumor grade in human cartilaginous tumors. Furthermore, the expressions of MT1-MMP, MMP-2 and TIMP-2 were also found to play a crucial role in invasion in the high-grade components of dedifferentiated chondrosarcoma. Received: 17 February 1999 / Accepted: 21 April 1999     

Aging increases aortic MMP-2 activity and angiotensin II in nonhuman primates

To seek evidence that the nonhuman primate arterial wall, as it ages in the absence of atherosclerosis, exhibits alterations in pathways that are involved in the pathogenesis of experimental atherosclerosis, we assessed aortic matrix metalloproteinase-2 (MMP-2) and its regulators, ie, membrane type-1 of matrix metalloproteinase (MT1-MMP) and tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), and the expression of angiotensin II (Ang II), angiotensin-converting enzyme (ACE), and chymase in young (6.4+/-0.7 years) and old (20.0+/-1.9 years) male monkeys. With advancing age, (1) the intimal thickness increased 3-fold and contained numerous vascular smooth muscle cells and matrix, but no inflammatory cells; (2) the intimal MMP-2 antibody-staining fraction increased by 80% (P<0.01); (3) in situ zymography showed that MMP-2 activity, mainly confined to the intima, increased 3-fold (P<0.01); (4) the MT1-MMP antibody-staining fraction increased by 150% (P<0.001), but the TIMP-2 antibody-staining fraction did not significantly change; (5) steady levels of the mRNA-staining fraction (via in situ hybridization) for MMP-2 increased 7-fold, for MT1-MMP increased 9-fold, and for TIMP-2 increased 2-fold (all P<0.001); and (6) intimal Ang II and ACE immunofluorescence were increased 5-fold and 5.6-fold, respectively, and colocalized with MMP-2. Thus, age-associated arterial remodeling and the development and progression of experimental atherosclerosis in young animals share common mechanisms, ie, MMP-2 activation and increased Ang II signaling. This might explain, in part, the dramatically exaggerated prevalence and severity of vascular diseases with aging.     

MMP-2, MT1-MMP, and TIMP-2 are essential for the invasive capacity of human mesenchymal stem cells: differential regulation by inflammatory cytokines

Human mesenchymal stem cells (hMSCs) represent promising tools in various clinical applications, including the regeneration of injured tissues by endogenous or transplanted hMSCs. The molecular mechanisms, however, that control hMSC mobilization and homing which require invasion through extracellular matrix (ECM) barriers are almost unknown. We have analyzed bone marrow-derivedhMSCs and detected strong expression and synthesis of matrix metalloproteinase 2 (MMP-2), membrane type 1 MMP (MT1-MMP), tissue inhibitor of metalloproteinase 1 (TIMP-1), and TIMP-2. The ability of hMSCs to traverse reconstituted human basement membranes was effectively blocked in the presence of synthetic MMP inhibitors. Detailed studies by RNA interference revealed that gene knock-down of MMP-2, MT1-MMP, or TIMP-2 substantially impaired hMSC invasion, whereas silencing of TIMP-1 enhanced cell migration, indicating opposing roles of both TIMPs in this process. Moreover, the inflammatory cytokines TGF-beta1, IL-1beta, and TNF-alpha up-regulated MMP-2, MT1-MMP, and/or MMP-9 production in these cells, resulting in a strong stimulation of chemotactic migration through ECM, whereas the chemokine SDF-1alpha exhibited minor effects on MMP/TIMP expression and cell invasion. Thus, induction of specific MMP activity in hMSCs by inflammatory cytokines promotes directed cell migration across reconstituted basement membranes in vitro providing a potential mechanism in hMSC recruitment and extravasation into injured tissues in vivo.     

Apoptosis of human hepatic myofibroblasts promotes activation of matrix metalloproteinase-2

Liver fibrosis is potentially reversible after removal of the injurious agent. Fibrosis resolution is characterized by apoptosis of hepatic myofibroblasts and degradation of extracellular matrix components. Matrix metalloproteinase-2 (MMP-2) is involved in matrix remodeling. In the liver, it is synthesized by myofibroblasts, secreted as a proenzyme, and activated by membrane type-MMPs (MT-MMP) such as MT1-MMP. The goal of this work was to determine whether apoptosis induction in human hepatic myofibroblasts modulates the gene expression of MMP-2 and/or its activation by MT1-MMP. Induction of apoptosis by cytochalasin D or C(2)-ceramide did not modulate MMP-2 mRNA expression. In contrast, apoptosis was associated with marked activation of pro-MMP-2, as shown by gelatin zymography, which revealed the presence of the 59-kd active form, whereas untreated cells only expressed the 66-kd proform. SB-203580, a specific inhibitor of p38 (MAPK), selectively abrogated both C(2)-ceramide-induced apoptosis and pro-MMP-2 activation. Apoptosis-induced pro-MMP-2 activation was inhibited by the tissue inhibitors of metalloproteinases (TIMP)-2 but not by TIMP-1, implying involvement of an MT-MMP-mediated process. Induction of apoptosis by cytochalasin D and C(2)-ceramide upregulated MT1-MMP protein expression and MT1-MMP mRNA expression. In conclusion, apoptosis of hepatic myofibroblasts induces pro-MMP-2 activation through increased MT1-MMP expression. HEPATOLOGY 2002;36:615-622.)     

1,25-二羟维生素D3对人成骨细胞基质金属蛋白酶及其抑制因子的作用

目的　研究 1, 25 二羟维生素D3 [ 1α, 25 (OH)2D3 ]对人成骨细胞基质金属蛋白酶(MMP) 1、MMP 2、膜型基质金属蛋白酶 1 (MT1 MMP)、基质金属蛋白酶抑制因子 1 (TIMP 1 )的影响,探讨 1α, 25(OH)2D3 调节骨代谢作用机制。方法　人成骨细胞用 1α, 25 (OH)2D3 干预。Western杂交检测MT1 MMP蛋白质表达。MMP 1、MMP 2、TIMP 1的分泌及MMP 2的活性用ELISA检测。Northern杂交检测维生素D受体、MT1 MMPmRNA表达。结果　 1α, 25 (OH)2D3 对人成骨细胞MMP 1、MMP 2、TIMP 1表达无影响, 10-10 ~ 10-8 mol/L 1α, 25 (OH)2D3 干预诱导成骨细胞MT1 MMP表达呈剂量依赖性 (P值均 <0 05);促进MMP 2激活呈剂量依赖性 [MMP 2活性分别为(42 3 ± 8 6)、(64 4 ±11 4)、(93 5 ±9 9)μg/L, P值均<0 05]。结论　由于MT1 MMP在骨吸收过程中起着关键作用, 1α, 25(OH)2D3 可通过诱导成骨细胞MT1 MMP表达刺激骨吸收。     

MT1-MMP、MMP-2和TIMP-2基因在去卵巢大鼠成骨细胞中的表达

目的　通过观察去卵巢 (OVX)骨质疏松模型大鼠成骨细胞膜型基质金属蛋白酶 1(MT1 MMP)基因的表达 ,探讨绝经后骨质疏松的发病机制。　方法　对OVX大鼠与假手术大鼠进行骨密度和骨组织形态计量学测定。股骨远端行原位杂交检测骨组织MT1 MMP、MMP 2和TIMP 2mRNA表达 ,免疫组化检测骨组织MT1 MMP、MMP 2和TIMP 2蛋白质表达。　结果　OVX大鼠第 3、4腰椎骨密度 (0 14 4± 0 0 11) g cm2 、(0 14 3± 0 0 15 ) g cm2 较对照组 (0 15 8± 0 0 18)g cm2 、(0 16 2± 0 0 17) g cm2 明显减少 ,OVX组骨小梁面积 (9 5 8± 3 39) %、厚度 (40 85± 8 0 4 ) μm和数目 (2 30± 0 4 8)个 mm分别较对照组 (2 0 6 3± 4 8) %、(44 73± 6 8) μm、(4 6± 0 7)个 mm明显下降 ,OVX组骨小梁间隔 (5 85 8± 115 1) μm较对照组 (2 5 4 6± 4 8 0 ) μm明显增宽 ;成骨细胞MT1 MMPmRNA与蛋白质表达下调 ,而MMP 2和TIMP 2之间表达无差异。　结论　雌激素不足可使成骨细胞MT1 MMP基因表达减少 ,可能为绝经后骨质疏松的发病机制之一。     

EMMPRIN、MT1-MMP蛋白在原发胃癌和胃癌转移淋巴结中的表达及意义

目的:探讨细胞外基质金属蛋白酶诱导因子-EMMPRIN(extracellular matrix metalloproteinase inducer,EMMPRIN)、膜型基质金属蛋白酶-1(membrane-type matrix metalloproteinase-1,MT1-MMP)蛋白在原发胃癌和胃癌转移淋巴结中的表达差异及与人胃癌临床病理特征的关系,以及二者之间是否有协同作用.方法:应用量子点免疫荧光组织化学技术检测人胃癌组织芯片(包括204例胃癌组织,21例非癌性胃黏膜组织)和20例胃癌转移淋巴结组织中EMMPRIN和MT1-MMP的蛋白表达并评分.结果:在正常胃黏膜组织、慢性萎缩性胃炎伴肠上皮化生、胃癌和胃癌转移淋巴结组织中,EMMPRIN和MT1-MMP蛋白表达呈逐渐递增的趋势,正常胃黏膜组分别与胃癌组、胃癌转移淋巴结组相比,2种蛋白表达的差异均有显著性.EMMPRIN蛋白表达与浸润深度、高TNM分期和淋巴结转移之间均呈显著正相关,而与其他临床病理参数均无关.MT1-MMP蛋白表达仅与高TNM分期和伴有淋巴结转移呈显著正相关.EMMPRIN和MT1-MMP蛋白表达之间呈显著正相关(r=0.584,P=0.001).结论:EMMPRIN与MT1-MMP蛋白在胃癌的发生与进展中有协同作用;在胃癌转移淋巴结中的表达高于原发胃癌,但差异无显著性.     

基质金属蛋白酶及其抑制因子在脑胶质瘤侵袭性中的作用

目的分析基质金属蛋白酶(MM P)及其抑制因子(T IM P)的表达与脑胶质瘤恶性程度和侵袭性之间的关系。方法采用免疫组化SP法,测定76例不同级别胶质瘤(观察组)和10例正常脑组织对照组中MM P-2、MM P-3和T IM P-2蛋白表达。结果MM P-2蛋白表达水平与肿瘤的恶性程度呈正相关(P<0.01),不同级别的胶质瘤与正常脑组织比较,均有显著的差异(P<0.01)。胶质瘤中MM P-2和T IM P-2的表达水平之间呈明显负相关(r=-0.562,P<0.01)。MM P-3在正常脑组织与胶质瘤之间有显著差异性(P<0.05)。结论MM P-2的高表达与胶质瘤的恶性程度呈正相关;MM P-2与T IM P-2的平衡失调与胶质瘤的恶性程度和侵袭性密切相关,两者之间协同作用在胶质瘤的侵袭中有重要的意义。     

Membrane-type matrix metalloproteinase-1 (MT1-MMP) is down-regulated in estrogen-deficient rat osteoblast in vivo

Our previous study showed that estrogen stimulates membrane-type matrix metalloproteinases-1 (MT1-MMP) production in osteoblastic cells culture, but has no effect on MMP-2 and TIMP-2 synthesis. Osteoblast-derived MT1-MMP have been recently implied to play a role in bone metabolism by degrading tumor necrosis factor-alpha (TNF-alpha), resolving extracellular matrix and activating proMMP-2, which requires the process of activation mediated by MT1-MMP/tissue inhibitor of metalloproteinase (TIMP-2) complex on the cell surface. To investigate the mechanism of bone loss following estrogen deficiency, we examined the effects of estrogen on osteoblast synthesis of MT1-MMP, MMP-2 and TIMP-2. In situ hybridization and immunohistochemistry of rat bone samples were used to document the synthesis of MT1-MMP, MMP-2, and TIMP-2 mRNA and protein. Osteoblasts from distal femoral head showed an increase in the pattern of MT1-MMP mRNA and protein production in sham-operated controls and 17beta-estradiol (E2)-treated rats, compared with the ovariectomized group; the synthesis of MMP-2 and TIMP-2 mRNA and protein was unaffected. Our data show a down-regulation of MT1-MMP synthesis by osteoblast in vivo following estrogen withdrawal, and treatment with E2 resulted in induced MT1-MMP expression in vivo. There is evidence suggesting a role for MT1-MMP in the process of bone loss during the pathogenesis of osteoporosis.     

Glycation cross-links inhibit matrix metalloproteinase-2 activation in vascular smooth muscle cells cultured on collagen lattice

Aims/hypothesis. Extracellular matrix glycation has been proposed to contribute to the arterial stiffness observed in aging and diabetes. We examined whether matrix protein glycation regulates the proleolytic process through the manipulation of matrix metalloproteinases (MMPs) activation, using collagen fibrils model. Methods. Vascular smooth muscle cells were cultured on control or glycated collagen fibrils. Matrix metalloproteinase-2 activation and the production of tissue inhibitors of metalloproteinase (TIMPs) were measured in the conditioned medium by using gelatin zymography and immunoblotting. Membrane type 1 matrix metalloproteinase (MT1-MMP) expression was also measured in cell lysates. Results. When smooth muscle cells were cultured on collagen fibrils, pro-MMP-2 processing to active form was observed in the conditioned medium in coincidence with the increased MT1-MMP expression and the suppressed TIMP-2 production. Culturing smooth muscle cells on glycated collagen fibrils inhibited MMP-2 activation and attenuated MT1-MMP expression without the alteration of TIMP-2 production compared with control fibrils, indicating the possible mechanism of the suppression of MT1-MMP expression for the inhibition of MMP-2 activation on glycated collagen fibrils. Inclusion of aminoguanidine, an inhibitor of cross-linking formation, during collagen glycation restored the MMP-2 activation, suggesting the role of cross-links on the inhibition of MMP-2 activation. Conclusion/interpretation. These observations suggest that glycation-induced cross-linking formation in interstitial collagen contributes to arterial stiffness in aging and diabetes through the manipulation of matrix metalloproteinase activation along with the reduction of the susceptibility to proteolytic enzymes. [Diabetologia (2001) 44: 433–436] Received: 16 October 2000 and in revised form: 18 December 2000     

Expression of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinase-1 in ulcerative colitis

INTRODUCTION Ulcerative colitis (UC) is a chronic, non-specific inflammatory disease of the colonic mucosa with unknown etiology and pathogenesis. Pathologically, it is characterized by ulceration in the mucosal and submucosal areas, and degradation of ex…