Differential regulation of stromelysin-1 (matrix metalloproteinase-3) and matrilysin (matrix metalloproteinase-7) in baboon endometrium

OBJECTIVE: To investigate in vivo expression of matrix metalloproteinase enzymes (MMP), MMP-3 and MMP-7, by the baboon endometrium in relation to the process of tissue remodeling that accompanies menstruation in the primate. METHODS: Endometrial tissues and uterine fluids obtained from reproductively intact cycling baboons, cycling baboons treated with an anti-progestin, and ovariectomized steroid-treated baboons were evaluated for MMP mRNA expression and protein production by using multiple analytic techniques. RESULTS: The pattern of MMP protein production matched the pattern of MMP mRNA expression. In intact cycling baboons, MMP mRNA expression and protein production were specific to cell type and stage of the menstrual cycle. Endometrial stroma expressed minimal amounts of MMP-3 during the proliferative and secretory stages, whereas endometrial epithelia expressed MMP-7 during the proliferative stage. Expression of stromal MMP-3 and epithelial MMP-7 increased during early menses. Administration of anti-progestin beginning on the day of the LH surge increased MMP-7 but not MMP-3 expression at the mid secretory phase. Expression of MMP-3 and MMP-7 in the ovariectomized steroid-treated animals paralleled that of the intact cycling animals. CONCLUSIONS: These results highlight the similarity of human and baboon endometrial MMP-3 and MMP-7 production, providing further evidence for use of the baboon as a model for studying events associated with hormonally regulated changes during the menstrual cycle. These results also demonstrate that endometrial epithelial MMP-7 is suppressed by progesterone in the baboon endometrium, but endometrial stromal MMP-3 is regulated by a different mechanism.     

基质金属蛋白酶-9及其组织抑制剂TIMP-3在子宫内膜异位症的表达

目的 :探讨基质金属蛋白酶 9(MMP 9)及其抑制剂TIMP 3在子宫内膜异位症发生发展中的作用。方法 :采用免疫组化链霉菌抗生物素蛋白 过氧化物酶染色法 (SP法 )检测 4 3例子宫内膜异位症的异位内膜和在位内膜中MMP 9、TIMP 3的表达 ,以 19例正常子宫内膜为对照组 ,并用银染法观察腺上皮基底膜的完整性。结果 :在异位内膜组织的腺上皮细胞MMP 9呈高表达状态 ,与子宫内膜异位症在位内膜和正常子宫内膜相比 ,差异有高度显著性 (P <0 .0 1)。子宫内膜异位症的在位内膜和异位内膜TIMP 3均呈低表达 ,与正常内膜相比 ,差异有高度显著性 (P <0 .0 1) ,异位内膜较在位内膜TIMP 3的表达降低 ,差异有显著性 (P <0 .0 5 )。子宫内膜腺上皮的基底膜银染结果显示 :MMP 9与TIMP 3的染色强度比值与基底膜的阳性率呈负相关 (P <0 .0 1)。MMP 9、TIMP 3的表达强度与子宫内膜异位症的严重程度无显著相关性。结论 :异位内膜组织中MMP 9过度表达 ,而TIMP 3的表达下降 ,导致MMP 9/TIMP 3的比例增高 ,使子宫内膜异位症患者的异位内膜更具侵袭性 ,在子宫内膜异位症的发生发展中起重要作用     

MMP-2、TIMP-2在子宫内膜异位症组织中的表达及其意义

目的研究基质金属蛋白酶-2(MMP-2)及其抑制因子-2(TIMP-2)mRNA在子宫内膜异位症异位和在位内膜组织中的表达及临床意义。方法分别选取子宫内膜异位症异位内膜组织50例、在位内膜组织26例和对照组正常子宫内膜组织22例为研究对象,应用半定量逆转录聚合酶链反应技术(RT-PCR)检测MMP-2、TIMP-2mRNA的表达。结果(1)MMP-2mRNA在异位症异位内膜组织中相对表达量明显高于正常子宫内膜组织和在位内膜,差异均有显著性(P<0.01,P<0.01);TIMP-2mRNA在子宫内膜异位症异位内膜和在位内膜组织中均低表达,其相对表达量分别明显低于正常子宫内膜,差异均有显著性(P<0.01;P<0.01);(2)异位症异位内膜组织中MMP-2mRNA、TIMP-2的表达与r-AFS临床分期无关,差异无显著性(P>0.05)。结论异位和在位内膜组织中MMP-2高表达,TIMP-2低表达,使MMP-2与TIMP-2平衡失调,异位内膜组织侵袭降解ECM的能力增强,从而在子宫内膜异位症中的发生发展中起了重要作用。     

基质金属蛋白酶-2及9与子宫内膜腺癌临床及预后的关系

目的探讨基质金属蛋白酶-2(MMP-2)和9(MMP-9)在正常子宫内膜组织、子宫内膜腺癌组织中的表达,及其与子宫内膜腺癌临床和预后的关系。方法2005年10月至2009年3月在中山大学附属中山医院采用免疫组织化学EnVision法,检测100例子宫内膜腺癌组织中MMP-2、MMP-9蛋白的表达,以30例正常子宫内膜组织作为对照组。结果MMP-2、MMP-9在正常子宫内膜增生期表达增加而在早中分泌期几乎无表达(P>0.05)。MMP-2、MMP-9蛋白在子宫内膜腺癌组织中的表达为74.0%和78.0%,显著高于正常子宫内膜组织(50.0%、56.7%)(P<0.05);随着子宫内膜腺癌临床分期、病理组织学分级的提高,MMP-2、MMP-9的表达也随之增强,且有统计学意义(P<0.05);在伴有淋巴结转移的子宫内膜腺癌组织中,两者表达(90.0%、60.0%)高于无淋巴结转移组(28.6%、23.8%)(P<0.05)。子宫内膜组织中MMP-2与MMP-9蛋白的表达呈正相关(r=0.545,P<0.001)。MMP-2和MMP-9的表达与患者生存率相关(P<0.05)。结论MMP-2、MMP-9在子宫内膜腺癌发...     

Difference in expression of matrix metalloproteinase-2 and matrix metalloproteinase-9 in patients with persistent ovarian cysts

Matrix metalloproteinase-1 (MMP-1), MMP-2, and MMP-9 expression with real-time quantitative polymerase chain reaction were analyzed in endometriotic and nonendometriotic ovarian cysts. Although MMP-1 was not detected, MMP-9 and MMP-2 were expressed in all of the cysts. In particular, in five of six nonendometriotic cysts (83.3%) MMP-2 expression was higher than in endometriotic cysts. These data may represent new molecular elements helpful in differential diagnosis of endometriotic lesions.     

Mechanisms of matrix metalloproteinase-9 and matrix metalloproteinase-2 inhibition by N-acetylcysteine in the human term decidua and fetal membranes

OBJECTIVE: The purpose of this study was to evaluate the effect of N-acetylcysteine on the activity and secretion of the matrix metalloproteinases in the decidua, amnion, and chorion and the secretion of the tissue inhibitor of matrix metalloproteinase-1. STUDY DESIGN: Samples from eight nonlaboring women were taken at elective cesarean section and incubated in an in vitro organ culture in the absence or presence of N-acetylcysteine. Matrix metalloproteinase-2 and matrix metalloproteinase-9 activity was measured with the use of gel zymography. Western blot analysis was used to measure matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase-1 secretion. Data were analyzed with the paired Student t test. RESULTS: N-acetylcysteine had a direct inhibitory effect on matrix metalloproteinase-2 and matrix metalloproteinase-9 activity, regardless of tissue origin, starting at 1.0 mmol/L. In cultured media, 20 mmol/L N-acetylcysteine inhibited matrix metalloproteinase-2 and matrix metalloproteinase-9 activity in all three tissues. A differential response was demonstrated for matrix metalloproteinase-2 secretion, depending on the tissue that was studied. Its secretion was decreased in decidua at 10 mmol/L and 20 mmol/L; in amnion, the secretion was inhibited at 0.1 mmol/L and not affected at all in chorion. Matrix metalloproteinase-9 secretion was not affected in a statistically significant manner in any tissue. In the chorion, matrix metalloproteinase-9 showed a trend toward increased secretion. Tissue inhibitor of matrix metalloproteinase-1 secretion significantly decreased in the decidua at 20 mmol/L. CONCLUSION: N-acetylcysteine, at higher concentrations, has an inhibitory effect on matrix metalloproteinase-2 and matrix metalloproteinase-9 activity, regardless of the tissue origin and the differential effect on secretion depending on the tissue and N-acetylcysteine concentration.     

Expression of matrix metalloproteinase-26 and tissue inhibitors of metalloproteinase-3 and -4 in normal ovary and ovarian carcinoma

The objective of this study was to determine the spatial expression of matrix metalloproteinases (MMPs) and their physiologic inhibitors, the tissue inhibitor of MMP (TIMP)-3 and TIMP-4, in ovarian carcinoma compared to normal ovaries. Immunohistochemistry was carried out in this study. Tissue sections prepared from normal ovarian tissues from throughout the menstrual cycle (N = 20) and ovarian carcinomas (N = 45) characterized as stage I (N = 5), stage III/IV (N = 40) were immunostained using polyclonal antibodies to the latent and the active form of MMP-26, TIMP-3, and a monoclonal antibody to TIMP-4. Immunoreactive MMP-26, TIMP-3, and TIMP-4 were detected in all the ovarian cell types in normal and tumor tissues. In normal ovarian tissues, theca externa and luteal cells immunostained with high intensity for MMP-26 and TIMPs while theca/granulosa cell staining intensity increased as lutenization progressed. There was low immunostaining of the ovarian stromal and surface epithelial cells for MMP-26, with moderate staining for TIMPs. In the carcinoma specimens, cancer cells and vascular endothelial cells displayed the highest staining intensity compared to adjacent nontumor areas. The immunostaining intensity of MMP-26 and TIMP-3 increased with stage of tumor with the invading tumor cells displaying the strongest immunostaining. MMP-26, TIMP-3, and TIMP-4 are expressed in normal ovarian as well as ovarian tumors with elevated expression in the invasive tumor cells suggesting a potential role for MMP-26 in normal ovary and ovarian cancer biologic function.     

压力性尿失禁患者阴道壁结缔组织MMP-2及其抑制物的表达

目的:探讨女性压力性尿失禁(SUI)患者阴道壁结缔组织中基质金属蛋白酶-2(MMP-2)和基质金属蛋白酶组织抑制物-2(TIMP-2)mRNA表达与SUI发病的关系。方法:7例无SUI妇女为对照组(A组),24例有完整随访资料的女性SUI患者的阴道壁结缔组织标本为研究组,分为<60岁组(B组)和>60岁组(C组)。应用逆转录-聚合酶链反应分别检测MMP-2和TIMP-2表达量。结果:SUI组患者的MMP-2均较非SUI组显著升高,差别有显著性(P<0.01),TIMP-2均显著下降,差异有统计学意义(P<0.01)。MMP-2在B组和C组之间的差异无显著性(P>0.05),TIMP-2的mRNA表达量C组较B组显著下降,差别有统计学意义(P<0.01)。MMP-2/TIMP-2从A组到B组再到C组显著升高,A组相似文献   

基质金属蛋白酶9及其组织抑制剂1在子宫内膜异位症组织中的表达

目的探讨基质金属蛋白酶9(MMP-9)及其组织抑制剂1(TTMP-1)在子宫内膜异位症(内异症)患者异位内膜及在位内膜中的表达,及其在内异症发病中的作用。方法选取38例根据美国生育学会修订的内异症分期法,诊断为内异症患者的卵巢内膜异位囊肿标本38份、腹膜红色病变标本16份及同期在位内膜35份组织作为研究组,以及非内异症患者的子宫内膜标本20份作为对照组。采用RT-PCR半定量技术,检测上述不同组织中MMP-9mRNA及TIMP-1mRNA的表达率及表达强度。结果两组所有标本均有TIMP-1mRNA表达,部分标本有MMP-9mRNA表达。研究组中,卵巢异位囊肿及腹膜红色病变组织MMP-9mRNA表达率分别为45%及56%,表达强度分别为0·46±0·22及0·33±0·12;同期在位内膜MMP-9mRNA表达率为57%,表达强度为0·49±0·28。卵巢异位囊肿、腹膜红色病变及同期在位内膜组织TIMP-1mRNA表达强度分别为1·67±0·79、1·45±0·68及2·31±1·21,前两者与后者比较,差异有统计学意义(P<0·05)。研究组在位内膜及对照组MMP-9的表达率分别为57%及45%;表达强度分别为0·49±0·28及0·29±0·12,两组比较,差异有统计学意义(P<0·05)。研究组在位内膜及对照组TIMP-1mRNA的表达强度分别为2·31±1·21及2·40±0·89。结论内异症患者在位内膜MMP-9mRNA的表达增强,促进了内膜的异位种植。异位内膜TIMP-1mRNA的表达减弱,可促使内异症病变的发展。     

肿瘤坏死因子α及孕酮对异位子宫内膜间质细胞分泌基质金属蛋白酶-3的调节

目的 :探讨细胞因子、性激素与基质金属蛋白酶 (MMPs)在子宫内膜异位症(EMs)发病机制中的作用及相关性。方法 :以EMs患者 15例作研究组 ,分别取其在位与异位内膜 ,以非EMs患者 10例的正常内膜为对照组。原代培养子宫内膜间质细胞 ,在研究组和对照组内分别设置空白对照组、孕酮组与肿瘤坏死因子 α(TNF α)组。孕酮组分别加入孕酮 10 - 7mol/L、10 - 5mol/L ,各孵育 2 4h ;TNF α组中加入TNF α 10 0ng/L ,分别孵育2 4h、4 8h。ELISA法检测MMP 3含量。结果 :空白对照组MMP 3含量 ,异位组显著高于在位内膜组与对照组 (P <0 .0 1)。加入孕酮后各组MMP 3含量均呈下降趋势 ,异位组下降程度更为显著 (P <0 .0 1) ,高浓度孕酮具有更强的抑制作用 (P <0 .0 5 )。TNF α干扰后 ,各组MMP 3含量均升高 (P <0 .0 1) ,以异位组显著 (P <0 .0 1) ,不同作用时间对MMP 3含量的影响各组间无显著差异 (P >0 .0 5 )。结论 :EMs患者子宫内膜间质细胞分泌MMP 3较正常人高 ,异位病灶分泌能力更强。TNF α和孕酮对MMP 3的分泌分别有升调与降调的作用 ,二者可能通过此途径参与了EMs的发生发展过程。     

Regulation of uterine matrix metalloproteinase-9 and the role of microRNAs

Controlled expression of matrix metalloproteinase-9 (MMP9) is vital for normal uterine physiology, whereas abnormal expression of MMP9 is associated with uterine disease. Despite the importance of MMP9 within the uterus, its regulation is poorly understood. In this review, the complex regulation of MMP9 within the uterus is highlighted, and the potential novel role of microRNAs in the regulation of this protease is discussed. Emphasis is placed on the necessity to enhance our understanding of the regulation of MMP9 expression, which may lead to the establishment of novel approaches to counteract misexpression of this protease and the diseases associated with it.     

Amniotic fluid matrix metalloproteinase-8 and the development of cerebral palsy

AIMS: To examine if increased concentrations of matrix metalloproteinase-8 (MMP-8) in amniotic fluid are associated with the development of cerebral palsy at the age of three years. METHODS: The relationship between amniotic fluid concentrations of MMP-8 and the development of cerebral palsy was examined in 116 preterm singleton newborns (gestational age at birth < 35 weeks) born to mothers who underwent amniocentesis and were followed for at least 3 years. Amniotic fluid was cultured for aerobic and anaerobic bacteria and mycoplasmas. MMP-8 concentrations were measured by specific immunoassays. Cerebral palsy was diagnosed by neuro developmental assessment at the age of three years. RESULTS: Median amniotic fluid concentration of MMP-8 was significantly higher in mothers whose newborns developed cerebral palsy than in mothers whose newborns did not develop cerebral palsy (median 153.9 [range < 0.3-1535.9] ng/ml vs median 6.4 [range < 0.3-3836.8] ng/ml; p < 0.01). Neonates who developed cerebral palsy were delivered at earlier gestational age than those without cerebral palsy. After adjustment for the gestational age at birth and the results of amniotic fluid culture, elevated concentrations of amniotic fluid MMP-8 significantly increased the odds of development of cerebral palsy (odds ratio, 6.0; 95% confidence interval, 1.1-33.0; p < 0.05). CONCLUSION: Increased concentrations of amniotic fluid MMP-8 are associated with the subsequent development of cerebral palsy at the age of 3 years.     

Expression of matrix metalloproteinase-26 and tissue inhibitor of matrix metalloproteinase-3 and -4 in endometrium throughout the normal menstrual cycle and alteration in users of levonorgestrel implants who experience irregular uterine bleeding

OBJECTIVE: To determine the expression of matrix metalloproteinase (MMP-26) and tissue inhibitor of MMP (TIMP) in the endometrium of women with normal menstrual cycles compared with users of levonorgestrel implants. DESIGN: Prospective observational study. SETTING: Academic research center. PATIENT(S): Fifty patients with normal menstrual cycles who requested permanent surgical sterilization (tubal ligation) and 35 users of levonorgestrel implants. INTERVENTION(S): Endometrial biopsy. MAIN OUTCOME MEASURE(S): Expression of MMP-26, TIMP-3, and TIMP-4 by immunohistochemistry and semiquantitative analysis of staining intensity by using the H score. RESULT(S): Endometrium from women with a normal menstrual cycle and users of levonorgestrel implants expresses MMP-26, TIMP-3, and TIMP-4. These substances are present in various types of endometrial cells; expression is strongest in surface and glandular epithelial cells, followed by vascular endothelial and endometrial stromal cells. Inflammatory and immune-related cells also stained strongly for MMP-26 and TIMPs. Semiquantitative analysis of the staining intensity of endometrial epithelial and stromal cells indicated that expression of MMP-26, TIMP-3, and TIMP-4 peaks during the early to mid-luteal phase. Expression of MMP-26 is elevated in users of levonorgestrel implants who experienced irregular uterine bleeding. CONCLUSION(S): Endometrial expression of MMP-26 and TIMP-4 is present throughout the menstrual cycle and is elevated during the early to mid-luteal phase in normally cycling women. Further elevations in MMP-26 are seen in users of levonorgestrel implants who experience irregular uterine bleeding. These substances thus seem to play a role in hormonal regulation and endometrial tissue remodeling.     

基质金属蛋白酶9及其抑制剂在异位和在位子宫内膜组织中的表达

目的　探讨基质金属蛋白酶 9(MMP 9)及其抑制剂———金属蛋白酶组织抑制因子(TIMP)在子宫内膜异位症患者的异位和在位内膜组织中的表达。方法　采用免疫组化链霉菌抗生物素蛋白 过氧化物酶连接法 (SP法 ) ,分别检测 4 5例子宫内膜异位症患者 (研究组 )的异位和子宫内膜及 32例子宫肌瘤患者 (对照组 )的子宫内膜组织中MMP 9、TIMP 1的表达。结果　研究组异位和在位内膜及对照组子宫内膜组织中 ,MMP 9的表达分别为 0 381、0 336、0 2 76 ;TIMP 1的表达分别为0 2 39、0 2 5 3、0 2 6 7;研究组异位及在位内膜、对照组子宫内膜组织中MMP 9/TIMP 1的比值分别为1 5 94 ,1 2 93,1 0 34。研究组异位及在位子宫内膜组织中MMP 9、MMP 9/TIMP 1分别与对照组比较 ,差异均有显著性 (P <0 0 1,P <0 0 5 ) ;研究组异位内膜组织中TIMP 1的表达与对照组比较 ,差异也有极显著性 (P <0 0 1) ;整个月经期 ,异位内膜组织中MMP 9表达升高 ,TIMP 1表达降低 ;在位内膜MMP 9表达升高 ,其中异位内膜比在位内膜MMP 9表达升高仅发生于增殖期。结论　异位子宫内膜组织中MMP 9、TIMP 1表达的变化可能与子宫内膜异位症的发生、发展有关。     

基质金属蛋白酶MMP-2 MMP-9及其抑制因子TIMP-1TIMP-2在子宫内膜异位症中的表达及意义

目的　研究基质金属蛋白酶MMP 2、9和组织抑制因子TIMP 1、2在子宫内膜异位症中的表达及意义。方法　 2 0 0 0年 3月至 2 0 0 2年 4月应用免疫组化S P法检测卵巢巧克力囊肿 4 5例的异位内膜和其中 2 0例在位内膜 ,以及 2 2例正常子宫内膜中MMP 2、9及TIMP 1、2的表达。结果　异位内膜组织中MMP 2、9和TIMP 1、2的表达均显著高于在位内膜和正常内膜 (P <0 0 1)。在位内膜和正常子宫内膜组织细胞中的表达率比较 ,差异无显著性 (P >0 0 5 )。子宫内膜异位症组织中MMP 2、9的表达与侵袭程度正相关。TIMP 1、2的表达则与侵袭程度呈负相关。结论　MMP 2、9是检测子宫内膜异位症较好的分子标志 ,人工诱导TIMP 1、2或阻断MMP 2、9的表达可能抑制内异症的发生发展 ,有望成为子宫内膜异位症治疗新的辅助手段