Wu Zhiping, Horgan Casie E, Carr Olivia, Owens Rick T, Iozzo Renato V, Lechner Beatrice E
Department of Pediatrics, Women and Infants Hospital of Rhode Island, The Warren Alpert Medical School of Brown University, 101 Dudley Street, Providence, RI 02905, USA.
Lifecell Corporation, 1 Millennium Way, Branchburg, NJ 08876, USA.
Matrix Biol. 2014 Apr;35:266-75. doi: 10.1016/j.matbio.2013.12.006. Epub 2013 Dec 25.
Preterm birth is the leading cause of newborn mortality in the United States and about one third of cases are caused by preterm premature rupture of fetal membranes, a complication that is frequently observed in patients with Ehlers-Danlos Syndrome. Notably, a subtype of Ehlers-Danlos Syndrome is caused by expression of abnormal biglycan and decorin proteoglycans. As compound deficiency of these two small leucine-rich proteoglycans is a model of preterm birth, we investigated the fetal membranes of Bgn(-/-); Dcn(-/-) double-null and single-null mice. Our results showed that biglycan signaling supported fetal membrane remodeling during early gestation in the absence of concomitant changes in TGFβ levels. In late gestation, biglycan signaling acted in a TGFβ-dependent manner to aid in membrane stabilization. In contrast, decorin signaling supported fetal membrane remodeling at early stages of gestation in a TGFβ-dependent manner, and fetal membrane stabilization at later stages of gestation without changes in TGFβ levels. Furthermore, exogenous soluble decorin was capable of rescuing the TGFβ signaling pathway in fetal membrane mesenchymal cells. Collectively, these findings provide novel targets for manipulation of fetal membrane extracellular matrix stability and could represent novel targets for research on preventive strategies for preterm premature rupture of fetal membranes.
在美国，早产是新生儿死亡的主要原因，约三分之一的病例是由胎膜早破引起的，这是一种在埃勒斯-当洛综合征患者中经常观察到的并发症。值得注意的是，埃勒斯-当洛综合征的一个亚型是由异常的双糖链蛋白聚糖和核心蛋白聚糖蛋白聚糖的表达引起的。由于这两种富含亮氨酸的小蛋白聚糖的复合缺乏是早产的一个模型，我们研究了Bgn(-/-); Dcn(-/-)双敲除和单敲除小鼠的胎膜。我们的结果表明，在不伴随TGFβ水平变化的情况下，双糖链蛋白聚糖信号在妊娠早期支持胎膜重塑。在妊娠晚期，双糖链蛋白聚糖信号以TGFβ依赖的方式发挥作用，以帮助胎膜稳定。相比之下，核心蛋白聚糖信号在妊娠早期以TGFβ依赖的方式支持胎膜重塑，在妊娠后期支持胎膜稳定，而TGFβ水平没有变化。此外，外源性可溶性核心蛋白聚糖能够挽救胎膜间充质细胞中的TGFβ信号通路。总的来说，这些发现为操纵胎膜细胞外基质稳定性提供了新的靶点，并且可能代表胎膜早破预防策略研究的新靶点。
