乳腺癌中HER2基质金属蛋白酶-2和9的表达及其相互关系

目的　研究乳腺癌中HER2基因、基质金属蛋白酶 (MMP) 2、基质金属蛋白酶(MMP) 9的表达情况、与临床病理指标之间的关系以及它们之间的相互关系。方法　采用免疫组织化学的方法对 114例乳腺癌组织标本中HER2、MMP 2、MMP 9的表达情况进行检测。结果　乳腺癌组织中HER2、MMP 2、MMP 9的表达阳性率分别是 46.49%、78.95 %、68.42 %。HER2表达与淋巴结转移相关。原发肿瘤 >2cm或有淋巴结转移的患者中 ,其MMP 2、MMP 9表达明显高于原发肿瘤≤ 2cm或无淋巴结转移的患者 (P <0 .0 5 ) ,且MMP 2表达与临床分期相关 (P <0 .0 5 )。HER2表达与MMP 2、MMP 9表达相关 (P <0 .0 5 )。结论　HER2、MMP 2、MMP 9的阳性表达提示乳腺癌有较强的浸润转移能力 ,这 3种蛋白的表达在乳腺癌浸润转移过程中可能起协同作用。     

Elevation of serum levels of metalloproteinase-1, tissue inhibitor of metalloproteinase-1 and type IV collagen, and plasma levels of metalloproteinase-9 in polycystic kidney disease

Several studies on polycystic kidney disease (PKD) have revealed a number of extracellular matrix (ECM) abnormalities, suggesting that an abnormal ECM plays a role in the development of tubular cysts. Cystic kidney tubules synthesize and secrete high levels of metalloproteinases (MMP), which may participate in the restructuring of the tubular basement membrane. The aim of the present study was to determine whether serum MMP-1, tissue inhibitor of metalloproteinase (TIMP)-1, and type IV collagen levels, and plasma MMP-9 levels were altered in patients with PKD. Sixteen patients with autosomal dominant polycystic kidney disease, and 20 healthy controls were included in this study. Specific enzyme immunoassays were used to measure MMP-1, MMP-9, TIMP-1, and type IV collagen levels. Serum MMP-1 (14.8 +/- 3.6 ng/ml), TIMP-1 (288.6 +/- 48.6 ng/ml), and type IV collagen (192.6 +/- 38.8 ng/ml) concentrations, and plasma MMP-9 (90.2 +/- 26.8 ng/ml) concentrations in patients with PKD were significantly higher than those in healthy controls (MMP-1; 6.6 +/- 0.9 ng/ml, p < 0.01, MMP-9; 36.4 +/- 12.2 ng/ml, p < 0.01, TIMP-1; 164.6 +/- 22.8 ng/ml, p < 0.01, and type IV collagen; 86.6 +/- 14.2 ng/ml, p < 0.001). The present results suggest that ECM abnormalities associated with cystic kidney may result from aberrant degradation as well as from abnormal synthesis of ECM components.     

血清基质金属蛋白酶2和抑制因子与绝经后骨质疏松症的相关性

目的探讨绝经后妇女血清基质金属蛋白酶2（MMP-2）和抑制因子（TIMP-2）水平及其与绝经骨质疏松症指标的关系。方法将202名48～65岁绝经后妇女分为正常组、低骨量组和骨质疏松组，用酶联免疫吸附试验（EIJSA）测定的血清MMP-2、TIMP-2以及骨保护蛋白（OPG）、骨保护蛋白配体（OPGL），计算MMP-2／TIMP-2和OPG／OPGL比值，用双能X线吸收法（DEXA）测定腰椎正位、股骨颈、华氏区和大粗隆的骨密度（BMD）。结果①骨质疏松组中血清MMP-2的数值（1392±121）μg／L高于正常组（1123±141）μg／L（P〈0．05），而TIMP-2的数值（44．3±36．2）ng/ml低于正常组（47．8±30．2）ng/ml。②骨质疏松组中血清MMP-2和MMP-2／TIMP-2比值与骨密度、血精OPGL数值存在明显负相关性（P〈0．05），和OPG和OPG／OPGL比值存在明显正相关性（P〈0．05），TIMP-2和华氏区骨密度和OPG存在明显正相关性（P〈0．05）。结论血清MMP-2和MMP-2／TIMP-2比值与绝经后骨质疏松症妇女骨密度和骨代谢指标OPG、OPGL和OPG／OPGL比值具有关联性。血清MMP-2水平升高和MMP-2／TIMP-2比值降低可能为绝经后骨质疏松症伴随骨代谢转换过程增快的表现。     

Matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 and tumour necrosis factor alpha release during cardiopulmonary bypass

An inflammatory response occurs during cardiac surgery involving cardiopulmonary bypass. Matrix metalloproteinase-9 is an enzyme involved in cytokine processing and leucocyte extravasation. It is secreted as a pro-enzyme in response to several inflammatory mediators and is inhibited by endogenous tissue inhibitor of metalloproteinase-1. The interaction between matrix metalloproteinase-9 and its inhibitor during cardiopulmonary bypass is not known. We measured tumour necrosis factor alpha, and matrix metalloproteinase-9 and its inhibitor using enzyme immunoassay at three time points in 20 patients undergoing elective coronary artery bypass grafting with cardiopulmonary bypass. Tumour necrosis factor and matrix metalloproteinase concentrations increased in all patients during bypass (both p < 0.0001), whereas the inhibitor in contrast, decreased (p < 0.0001). We conclude that matrix metalloproteinase-9 is released as part of the inflammatory response during cardiac surgery. Levels of the endogenous inhibitor of metalloproteinase, however, show a different pattern of release, suggesting independent regulation.     

绝经后妇女血清基质金属蛋白酶-2、-9与骨转换生化指标及骨密度的关系

目的 探讨绝经后妇女血清成骨细胞分泌的基质金属蛋白酶-2(MMP-2)和破骨细胞分泌的基质金属蛋白酶-9(MMP-9)与骨转换生化指标及骨密度(BMD)之间的关系.方法 选择绝经后妇女80例.采用Challenge双能X线骨密度仪(DXA)测量腰椎(L2-L4)侧位和左侧髋部(股骨颈、大转子、Ward三角区)6个骨骼区域的骨密度(BMD).分为正常对照组(骨密度正常组,21例)、低骨量组(20例)、骨质疏松组(23例)和严重骨质疏松组(骨质疏松骨折组,16例),用酶联免疫吸附试验(ELISA法)测定各组血清MMP-2、MMP-9、血清骨碱性磷酸酶(BAP)、血清骨钙素(OC)和血清Ⅰ型胶原氨基末端肽(NTx).结果 ①绝经后女性各组MMP-2、MMP-9与血清BAP、OC、NTx的变化水平相一致.②绝经后女性血清MMP-2及MMP-9水平随骨密度的降低呈现升高趋势,以骨质疏松骨折组为著.结论 血清MMP-2、MMP-9与骨转换生化指标相关联.血清MMP-2及MMP-9水平升高可能为绝经后骨质疏松症发生的重要影响因素.     

Mitogenic bovine whey extract modulates matrix metalloproteinase-2, -9, and tissue inhibitor of matrix metalloproteinase-2 levels in chronic leg ulcers

Matrix metalloproteinases (MMPs) and their tissue inhibitors play important roles in the wound-healing process. An imbalance in the expression of these molecules is thought to contribute to the failure of chronic ulcers to heal. We investigated whether a mitogenic bovine whey extract enriched with growth factors modulated the expression and activity of MMP-2 and -9, and the tissue inhibitor of MMP-2 (TIMP-2) in chronic leg ulcers. Wound fluids and biopsies were collected from chronic leg ulcer patients whose ulcers were treated topically for 4 weeks with placebo or mitogenic bovine whey extract at concentrations of 2.5, 10, and 20 mg/mL. The levels of MMP-2 and -9 in wound fluid samples was assessed by gelatin zymography and showed a decrease in active MMP-2 in the 2.5 and 10.0 mg/mL mitogenic bovine whey extract-treated ulcers compared with placebo (p<0.05). Immunohistochemical analysis of ulcer biopsies for MMP-2, -9, and TIMP-2 expression showed a reduction in the number of MMP-2-positive dermal fibroblasts in the mitogenic bovine whey extract-treated ulcers compared with pretreatment biopsies (p<0.05) that persisted over the course of the study. In contrast, a transient increase in the number of MMP-9- and TIMP-2-positive cells was observed in mitogenic bovine whey extract treated ulcer biopsies compared with pretreatment levels (p<0.05). These results show that topical application of mitogenic bovine whey extract was able to modulate the expression of MMP-2, -9, and TIMP-2 in chronic leg ulcers and that its constituent growth factors may have the potential to redress the proteolytic imbalance observed in nonhealing chronic ulcers.     

肝门胆管癌基质金属蛋白酶MMP-2及其组织抑制因子TIMP-2表达及意义的研究

目的：探讨基质金属蛋白酶MMP－2及其组织抑制因子TIMP－2在肝门胆管癌的表达及其与肝门胆管癌浸润、转移及预后间的关系。方法：采用免疫组化S－P法对78例肝门胆管癌的MMP－2及其组织抑制因子TIMP－2的表达进行了检测。对MMP－2及TIMP－2的表达与肝门胆管癌的组织分化程度、浸润转移及预后之间的关系进行分析。结果：MMP－2和TIMP－2表达阳性率分别为72％和76％。MMP－2的阳性表达率有淋巴结浸润的肝门胆管癌高于无淋巴结浸润的肝门胆管癌，低分化的肝门胆管癌高于高分化的肝门胆管癌。TIMP－2阳性表达率与以上相反。MMP－2表达与肝门胆管癌术后生存期呈负相关（γ=-0.713,P＜0．01），TIMP－2表达与肝门胆管癌术后生存期呈正相关（γ=0.652,P＜0．01）。MMP－2与TIMP－2具有负相关关系，（γ=-0.708,P＜0．01）。结论：MMP－2与TIMP－2是反映肝门胆管癌浸润、转移及预后的指标。     

Expression of matrix metalloproteinase-7 and tissue inhibitor of metalloproteinase-2 in human endometrial carcinoma

<正>Objective:To investigate the expression of matrix metalloproteinase-7(MMP-7) and its tissue inhibitor (TIMP-2) in endometrial carcinoma and analyze their significance in endometrial cancer's invasion and metastasis. Methods:Endometrial tissues were collected from 64 patients with endometrial carcinoma,20 patients with endometrial hyperplasia and 20 normal women.The expressions of MMP-7,TIMP-2 in endometrium were measured by immuohistochemistry. Results;Expressions of MMP-7,TIMP-2 in endometrium of patients with endometrial carcinoma were significantly higher than those in normal endometrium(P0.05).MMP-7 expression increased with surgical-pathological staging,depth of myometrial invasion,histologic grades and lymph node metastasis(P0.05),while TIMP-2 expression was related to lymph node metastasis(P0.05).TIMP-2 expression in endometrial cancer was significantly higher than that in hyperplastic endometrium(P0.05).Expressions of TIMP-2 and MMP-7 in endometrium of patients with endometrial carcinoma were positively correlated(r=0.654,P0.001). Conclusion:Highly expressed MMP-7 and TIMP-2 in endometrium may be related to development,invasion and metastasis of endometrial cancers.     

Matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinase-1 in the peripheral blood of patients with various glomerular diseases and their implication in pathogenetic lesions: study based on an enzyme-linked assay and immunohistochemical staining

Background Various glomerular diseases progress to end-stage renal failure due to an accumulation of the mesangial matrix (MM) and a thickening of the glomerular basement membrane (GBM). Both the MM and GBM are consistently metabolized through the synthesis and destruction of the matrix. Such synthesis is influenced by transforming growth factor-β (TGF-β) and other factors, whereas the destruction is presumed to be mediated by both matrix metalloproteinases (MMPs) and inhibitors of matrix metalloproteinases (TIMPs). Based on such evidence, we tried to detect MMP-2, MMP-9, and TIMP-1 in the peripheral blood of patients with various glomerular diseases. Methods Serum was used to detect MMP-2 and TIMP-1, while plasma was used to detect MMP-9. These enzymes were detected using an enzyme-linked assay. Results The findings showed an increased level of MMP-2 in patients with a alteration of GBM, typically membranous nephropathy (MN), regardless of the differences in their etiological processes. In contrast, MMP-9 did not show a strong association with any specific glomerular abnormalities. However, it mainly tended to increase in patients with MM accumulation. In addition, the localization of MMP-2, MMP-9, and TGF-β1 was studied using immunohistochemical staining. MMP-2 was demonstrated to exist in the glomerular capillary loop (GCL) as well as in the mesangial cells and the mesangial matrix. MMP-9 was found to exist in mesangial cells and the matrix, GCL, infiltrated neutrophils, and some tubular epithelial cells. Positive staining for TGF-β1 in GCL was found to be associated with an increased level of MMP-2 in patients with MN, whereas in MM such positive staining was not necessarily associated with an increased level of MMP-9. Conclusions These results therefore suggest that MMP-2 plays an important role in the degradation of GBM, while MMP-9 only moderately affects the degradation of MM.     

罗格列酮对肝星状细胞基质金属蛋白酶-2和-9基因表达的影响

目的 观察过氧化物酶体增殖物活化受体γ(PPARγ)特异配体罗格列酮对肝星状细胞(HSC)表达基质金属蛋白酶(MMP)-2和MMP-9的影响.方法 在培养的HSC株中加入不同浓度的罗格列酮(终质量浓度为5、10、15、20 μmol/L),于24 h后收取细胞,利用半定量逆转录-聚合酶链反应(RT-PCR)测定MMP-2、MMP-9 mRNA表达.结果 MMP-2表达水平在罗格列酮5、10、15、20 μmol/L组分别为0.5708±0.0609、0.8900±0.0823、1.1348±0.1205、1.4490±0.0832,而空白对照组为0.3237±0.0796.MMP-9表达水平在罗格列酮5、10、15、20 μmol/L组分别为0.5487±0.0770、0.7554±0.0510、0.9497±0.0451、1.1088±0.0777,空白对照组为0.3220±0.0592.结论 罗格列酮可增强HSC对MMP-2、MMP-9的表达,并在一定范围内,呈剂量依赖性.     

The expression of metalloproteinase-2, -9, and -14 and of tissue inhibitors-1 and -2 is developmentally modulated during osteogenesis in vitro, the mature osteoblastic phenotype expressing metalloproteinase-14.

During osteogenesis, in vitro, of tibial-derived rat osteoblasts (ROB) and derived clones, changes occur in the interactions of mature osteoblasts with the endogenous extracellular matrix (ECM) and these culminate in the formation of tridimensional nodules, which become sites of mineral deposition. We investigated if these changes might be mediated by remodeling of ECM, and we focused our study on the neutral metalloproteinases (MMPs), known agents of matrix remodeling, and on their tissue inhibitors (TIMPs). We report that during in vitro differentiation, osteoblasts express the secreted MMP-2 and -9 and the membrane gelatinase MMP-14. These, along with the tissue inhibitors TIMP-1 and -2, are developmentally regulated according to the maturation stage of osteoblasts. Their levels change in a similar association with osteoblast phenotypic maturation in different populations of ROB, which take different times to complete osteogenesis in vitro. MMP-14 expression coincides in both cell populations with the mature osteoblastic phenotype and is localized in the cells forming nodules. MMP-2 and -9 are expressed diffusely in the osteoblast population. Developmentally associated changes in the activation of MMP-2 are detected, associated in their timing with the expression of MMP-14 in both populations of ROB, and MMP-14 activates pro-MMP-2 in vitro. Expression of messenger RNAs (mRNAs) for the three MMPs increases up to the time of nodule formation. At this stage, TIMP-1 mRNA levels are lowest. TIMP-2 mRNA decreases throughout osteogenesis. In situ hybridization in 7-day-old rat tibias shows the strongest expression of MMP-14 among osteogenic cells, in lining osteoblasts on the newly formed trabeculae under the growth plate, and on the endosteal surface of cortical bone. Our data support the concept that the developmentally regulated expression of MMP-14 triggers localized proteolysis within the osteogenic population, concomitant in vitro to nodule formation.     

The impact of differential expression of extracellular matrix metalloproteinase inducer, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-2 and PDGF-AA on the chronicity of venous leg ulcers.

INTRODUCTION: Alteration in the expression of extracellular matrix metalloproteinase inducer (EMMPRIN), matrix metalloproteinase-2 (MMP-2), tissue inhibitors of matrix metalloproteinases (TIMP-2) and platelet derived growth factor (PDGF-AA) may contribute to poor healing in venous leg ulcers. AIM: The aim of this study is to determine the expression of EMMPRIN, MMP-2, TIMP-2 and PDGF-AA in the ulcer exudates and perivascular tissue of healing and non-healing chronic venous ulcers. PATIENTS, MATERIALS AND METHODS: Forty patients with chronic venous ulcers were included in this study, with a mean age of 60 years. Eleven patients were males and 29 were females. All patients had normal ankle brachial index and a venous ulcer of at least 8 weeks duration. Immuno-histochemistry using monoclonal antibodies to PDGF-AA, MMP-2, TIMP-2 and EMMPRIN was carried out on paraffin embedded punch biopsy skin specimens from the ulcer edge. Enzyme linked immunosorbent assay for PDGF, MMP-2 and TIMP-2 were carried out on wound fluids collected from patients. The ulcer size and character at the initial assessment and after 8 weeks were assessed to determine the status of ulcer healing. RESULTS: No significant difference was seen in the expression of TIMP-2, MMP-2 and EMMPRIN between the two groups. However, in the non-healing group high levels of MMP-2 and low levels of TIMP-2 in the wound fluid suggest a strong correlation of these two markers in the state of healing. Analysis of wound fluid by ELISA demonstrated high PDGF-AA in the healing group (p = 0.021). Significantly increased levels of PDGF-AA (p<0001) was noted in the perivascular area on immuno-histochemistry of healing ulcers. These data suggest that PDGF-AA plays an important role in healing of venous ulcers. CONCLUSION: Non-healing venous ulcers are associated with greater activity MMP-2 activity. The ratio of MMPs to their inhibitors TIMPs, dictate the rate of healing of the ulcers. PDGF-AA activity is associated with ulcer healing, though the mechanism is unclear. EMMPRIN expression in chronic venous ulcers probably parallels the chronicity of the condition rather than propagate it. However, further studies with larger samples are needed.     

结肠直肠癌病人血浆金属蛋白酶及其组织抑制物的表达及意义

目的：探讨结肠直肠癌病人血浆中基质金属蛋白酶-9（MMP-9）及其组织抑制因子-1（TIMP-1）的表达与结肠直肠癌浸润、转移及预后的关系,以及手术、化疗对其表达的影响,以期在分子水平上更准确地判断结肠直肠癌的预后。方法：选取结肠直肠癌病人50例,于手术前、术后10d、6次化疗后2周,分别抽取病人4mL外周静脉血,采用酶联免疫分析法检测MMP-9、TIMP-1血浆浓度的变化。结果：低分化结肠直肠癌病人血浆MMP-9及TIMP-1水平高于高、中分化者（P〈0．01、P〈0．05）;TNMⅢ、Ⅳ期病人高于TNMⅠ、Ⅱ期者（P〈0．01）。手术后血浆MMP-9、TIMP-1水平显著下降,有统计学意义（P〈0．01、P〈0．05）,化疗后其浓度变化无显著性差异（P〉0．05）。结论：MMP-9和TIMP-1与肿瘤恶性程度有关;术前检测外周血MMP-9和TIMP-1浓度有可能成为结肠直肠癌辅助诊断及病情评估的较好血清学标志。MMP-9可能与肿瘤复发或转移存在一定关系,术后动态检测外周血MMP-9浓度可反映肿瘤负荷。从而对监测肿瘤复发提供一定帮助。     

脑膜瘤肿瘤血管形成及瘤周水肿与基质金属蛋白酶-9表达的关系

目的　探讨脑膜瘤中肿瘤血管生成及瘤周水肿与基质金属蛋白酶(MMP) 9表达的关系。方法　采用免疫组织化学法检测5 9例脑膜瘤MMP 9和血小板 内皮细胞黏附因子 1(CD3 1) ,用全自动图像分析系统检测肿瘤组织的CD3 1微血管计数(MVC) ,通过MRI或CT测量瘤周水肿指数,对参数进行综合分析。结果　MMP 9表达强阳性组与弱阳性组、阴性组相比,水肿指数(EI) (分别为2 .86±0 .69、1.2 5±0 .5 3、0 .2 3±0 .18) ,脑水肿发生率(分别为95 .2 %、76.7%、3 7.5 % ) ,微血管计数(MVC分别为2 5 .6±8.5、10 .5±4.6、4.3±1.3 3 )的差异均有统计学意义(P <0 .0 5 )。MMP 9的表达与MVC及瘤周水肿呈正相关(r分别为0 .3 65、0 .5 73 ,P <0 .0 5 )。结论脑膜瘤MMP 9表达、肿瘤血管生成及瘤周水肿形成之间有重要关系;MMP 9能促进脑膜瘤的肿瘤血管生成及瘤周水肿的形成,可能对脑膜瘤瘤周水肿的形成有重要作用     

神经慢性卡压后基质金属蛋白酶及其组织抑制物在神经中的表达

目的 观察大鼠坐骨神经慢性卡压后基质金属蛋白酶-9(MMP-9)和金属蛋白酶组织抑制剂( TIMP-1)在神经中的表达.方法 将90只雄性SD大鼠随机分为对照组和卡压组.根据Mackinnon法建立神经慢性卡压模型,采用逆转录-聚合酶链反应(RT-PCR)和免疫组织化学技术检测神经干内MMP-9和TIMP-1的表达.结果 神经慢性卡压2周时神经纤维脱髓鞘;4周时结缔组织增生;12周后神经内纤维分隔进行性增多,神经纤维化.早期,MMP-9和TIMP-1表达增加,MMP-9mRNA在2周达峰值0.0485,TIMP-1 10周达峰值0.1592,MMP-9/TIMP-1明显升高;后期,MMP-9显著降低,TIMP-1继续升高,MMP-9/TIMP-1显著降低.结论 周围神经慢性卡压后神经纤维化,其机制可能与神经中MMP-9/TIMP-1比值早期增高、晚期降低有关.     

The effects of sodium hyaluronate on mRNA expressions of matrix metalloproteinase-1,-3 and tissue inhibitor of metalloproteinase-1 in cartilage and synovium of traumatic osteoarthritis model

teoarthritis (OA)isadegenerativeprocessofjointscharacterizedbyprogressivedeteriorationanderosionofcartilage .TraumaticOAcausedbyjointsinjuryandoperationiscommonlyobserved .Intra articularinjectionofsodiumhyaluronate (HA )isnowwidelyusedintreatmentofOA .It…     

金属蛋白酶-1和组织金属蛋白酶抑制因子-1在膝关节病理性滑膜皱襞中的表达及意义

目的探讨病理性滑膜皱襞发病机制中对软骨破坏有基质金属蛋白酶的参与。方法关节镜检查确诊为病理性滑膜皱襞和正常滑膜皱襞，分别进行免疫组化染色，观察金属蛋白酶-1（MMP-1）和组织金属蛋白酶抑制因子-1（TIMP-1）的表达及分布。结果MMP-1、TIMP-1在病理性滑膜皱襞和正常皱襞内的阳性表达，差异具有显著性（χ^2=16．014，P=0．000；χ^2=4．059，P=0．044）。MMP-1在滑膜衬里层细胞、单核和淋巴细胞、血管内皮细胞和化生的软骨细胞呈阳性表达，而在正常滑膜皱襞组织中不表达。TIMP-1只在滑膜衬里层细胞和少量的成纤维细胞有表达，而MMP-1免疫组化显示阳性细胞数和着色强度强于TIMP-1。结论病理性滑膜皱襞可产生MMP-1、TIMP-1，而且两者分布不平衡，可能是导致软骨破坏的生物学因素。