Schatz F, Papp C, Toth-Pal E, Lockwood C J
Department of Obstetrics, Gynecology, and Reproductive Sciences, Mount Sinai School of Medicine, New York, New York 10029.
J Clin Endocrinol Metab. 1994 Jun;78(6):1467-72. doi: 10.1210/jcem.78.6.8200951.
This study examined steroid-regulated expression of the metalloproteinase stromelysin-1 in primary human endometrial stromal and decidual cells. Immunoblot analysis using a specific polyclonal antibody against stromelysin-1 revealed that the progestin medroxyprogesterone acetate (MPA) produced a time-dependent reduction in a band at 50,000 mol wt. Although the cells were refractory to estradiol (E2) alone, E2 plus MPA further reduced the intensity of this stromelysin-1 zone. By 6 days of incubation, MPA inhibited levels of secreted stromelysin-1 by one third, and E2 plus MPA inhibited stromelysin-1 levels by two thirds compared with the control values. This differential responsiveness of the stromal cells to the two steroids is reported for several biochemical end points of decidualization. Northern analysis indicated pronounced inhibition of stromelysin-1 messenger ribonucleic acid (mRNA) by E2 plus MPA over a concentration range that simulated circulating progesterone levels of the luteal phase (10(-8) mol/L) through pregnancy (10(-6) mol/L). After suppression of stromelysin-1 expression in the stromal cell monolayers by E2 plus MPA, steroid withdrawal led to a several-fold enhancement of stromelysin-1 mRNA by 4 days and of the stromelysin-1 protein by 7 days. Given its actions in degrading several extracellular matrix components and activating other MMP zymogens, steroid withdrawal-enhanced stromelysin-1 activity could mediate a proteolytic cascade that promotes the rapid tissue destruction and vascular disruption associated with menstruation. Stromelysin-1 expression by cultured decidual cells isolated from first trimester endometrium was also reduced by MPA and synergistically reduced by E2 plus MPA. As activation of the 92-kilodalton gelatinase/type IV collagenase, a crucial mediator of trophoblast invasiveness, is stromelysin-1 dependent, reduced decidual stromelysin-1 production could help to limit trophoblast invasion.
本研究检测了金属蛋白酶基质溶解素-1在原代人子宫内膜基质细胞和蜕膜细胞中受类固醇调节的表达。使用针对基质溶解素-1的特异性多克隆抗体进行免疫印迹分析显示，孕激素醋酸甲羟孕酮（MPA）使50,000道尔顿分子量处的条带出现时间依赖性减少。尽管细胞对单独的雌二醇（E2）无反应，但E2加MPA进一步降低了该基质溶解素-1区域的强度。培养6天时，MPA使分泌的基质溶解素-1水平降低了三分之一，与对照值相比，E2加MPA使基质溶解素-1水平降低了三分之二。蜕膜化的几个生化终点均报道了基质细胞对这两种类固醇的这种差异反应性。Northern分析表明，在模拟黄体期（10^(-8)摩尔/升）至孕期（10^(-6)摩尔/升）循环孕酮水平的浓度范围内，E2加MPA对基质溶解素-1信使核糖核酸（mRNA）有明显抑制作用。在E2加MPA抑制基质细胞单层中基质溶解素-1的表达后，撤除类固醇导致4天时基质溶解素-1 mRNA增加数倍，7天时基质溶解素-1蛋白增加。鉴于其在降解多种细胞外基质成分和激活其他基质金属蛋白酶原方面的作用，撤除类固醇增强的基质溶解素-1活性可能介导一种蛋白水解级联反应，促进与月经相关的快速组织破坏和血管破裂。从孕早期子宫内膜分离的培养蜕膜细胞中，MPA也可降低基质溶解素-1的表达，E2加MPA则协同降低其表达。由于92千道尔顿明胶酶/IV型胶原酶（滋养层侵袭的关键介质）的激活依赖于基质溶解素-1，蜕膜基质溶解素-1产生的减少可能有助于限制滋养层侵袭。
