Hillegass Jedd Michael, Villano Caren Melissa, Cooper Keith Raymond, White Lori Anne
Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, New Brunswick, New Jersey 08901, USA.
Toxicol Sci. 2007 Nov;100(1):168-79. doi: 10.1093/toxsci/kfm192. Epub 2007 Aug 28.
Matrix metalloproteinases (MMPs) are endopeptidases that degrade the proteins of the extracellular matrix (ECM). Expression and activity of the MMPs are essential for embryogenesis, where MMPs participate in the normal ECM remodeling that occurs during tissue morphogenesis and development. Studies have demonstrated that MMP gene expression is inhibited by glucocorticoids in mammalian cell culture systems and that exposure to glucocorticoids causes developmental abnormalities in several species. Therefore, we proposed that glucocorticoids impede normal development through alteration of MMP expression. Zebra fish (Danio rerio) were used as a model to study MMP-13 expression both during normal embryogenesis and following acute exposure to two glucocorticoids, dexamethasone, and hydrocortisone. MMP-13 is one of three collagenases identified in vertebrates that catalyzes the degradation of type I collagens at neutral pH. MMP-13 expression varied during zebra fish development, with peak expression at 48 h post-fertilization (hpf). Morpholino knockdown studies showed that MMP-13 expression is necessary for normal zebra fish embryogenesis. Acute exposure to dexamethasone and hydrocortisone resulted in abnormal zebra fish development including craniofacial abnormalities, altered somitogenesis, blood pooling and pericardial and yolk sac edema as well as increased MMP-13 mRNA and activity at 72 hpf. In situ hybridization experiments were used to confirm the increase in MMP-13 expression following glucocorticoid treatment and showed elevated MMP-13 expression in the rostral trunk, brain, eye, heart, and anterior kidney of treated embryos. These data demonstrate that normal zebra fish embryogenesis requires MMP-13 and that dexamethasone and hydrocortisone modulate the expression of this gene, leading to increased activity and potentially contributing to subsequent dysmorphogenesis.
基质金属蛋白酶（MMPs）是降解细胞外基质（ECM）蛋白质的内肽酶。MMPs的表达和活性对于胚胎发育至关重要，在胚胎发育过程中，MMPs参与组织形态发生和发育期间发生的正常ECM重塑。研究表明，在哺乳动物细胞培养系统中，糖皮质激素会抑制MMP基因的表达，并且接触糖皮质激素会导致多个物种出现发育异常。因此，我们提出糖皮质激素通过改变MMP的表达来阻碍正常发育。斑马鱼（Danio rerio）被用作模型，以研究正常胚胎发育过程中以及急性暴露于两种糖皮质激素地塞米松和氢化可的松后MMP-13的表达。MMP-13是在脊椎动物中鉴定出的三种胶原酶之一，它在中性pH值下催化I型胶原蛋白的降解。MMP-13的表达在斑马鱼发育过程中有所变化，在受精后48小时（hpf）达到峰值。吗啉代敲低研究表明，MMP-13的表达对于斑马鱼的正常胚胎发育是必需的。急性暴露于地塞米松和氢化可的松会导致斑马鱼发育异常，包括颅面异常、体节发生改变、血液淤积以及心包和卵黄囊水肿，同时在72 hpf时MMP-13 mRNA和活性增加。原位杂交实验用于确认糖皮质激素处理后MMP-13表达的增加，并显示处理后的胚胎在吻部躯干、脑、眼、心脏和前肾中MMP-13表达升高。这些数据表明，正常的斑马鱼胚胎发育需要MMP-13，地塞米松和氢化可的松调节该基因的表达，导致活性增加，并可能导致随后出现畸形发生。
