Differential regulation of pregnancy associated plasma protein (PAPP)-A during pregnancy in human and mouse
Differential regulation of pregnancy associated plasma protein (PAPP)-A during pregnancy in human and mouse
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DOI：
10.1016/s1096-6374(02)00046-1
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发表时间：
2002-10-01
影响因子：
1.4
通讯作者：
Mohan, S
中科院分区：
文献类型：
--
作者：
Qin, XZ;Sexton, C;Mohan, S
妊娠期血清IGFBP-4蛋白水解酶活性显著升高，其主要来源是妊娠相关血浆蛋白-A(PAPP-A)。为了了解PAPP-A在体内的调节和作用，我们评估了一个小鼠模型系统的实用性。以重组小鼠IGFBP-4为底物，检测妊娠第9天和第17天小鼠血清和年龄匹配的对照组血清中IGFBP-4的蛋白水解性。令人惊讶的是，IGFBP-4在小鼠妊娠血清(MPS)和非妊娠血清(MNPs)中的蛋白分解活性没有显著差异。将IGF-II添加到MPS或mNPs中，以足够的剂量促进人PS对IGFBP-4的蛋白降解，但不能促进IGFBP-4的蛋白降解。PAPP-A中和抗体不能抑制MPS或mNPs对IGFBP-4的蛋白降解，但能完全阻断人PS(HPS、小鼠成骨细胞条件培养液和小鼠羊水)对IGFBP-4的降解活性。为了确定MPS中PAPP-A活性的缺乏是否是由于胎盘中PAPP-A的低表达所致，我们克隆了小鼠基因组DNA，该DNA包含1kb的完整外显子2编码序列和2.5kb的侧翼内含子序列。外显子2编码的小鼠和人PAPP-A的氨基酸序列有86%的同源性。RT-PCR分析表明，与人胎盘相比，小鼠胎盘中PAPP-A的mRNA水平至少低了两个数量级。PAPP-A在小鼠胎盘中的表达也低于在小鼠肾脏、成骨细胞和骨髓基质细胞中的表达。结论：(1)人和小鼠血清IGFBP-4蛋白水解酶活性受妊娠的影响不同。(2)小鼠妊娠期血清IGFBP-4蛋白水解酶活性未见升高是由于胎盘中PAPP-A表达水平较低所致。(C)2002爱思唯尔科学有限公司。保留所有权利。
Serum IGFBP-4 proteolytic activity increases dramatically during human pregnancy and is mainly attributed to the pregnancy-associated plasma protein-A (PAPP-A). To understand the regulation and actions of PAPP-A in vivo, we evaluated the utility of a mouse model system. Serum from day-9 and day-17 pregnant mice and age-matched controls was tested for IGFBP-4 proteolytic activity using recombinant mouse IGFBP-4 as the substrate. Surprisingly, IGFBP-4 proteolytic activity in mouse pregnancy serum (mPS) was not significantly different from that of non-pregnancy serum (mNPS). Addition of IGF-II to mPS or mNPS at a dose sufficient to increase IGFBP-4 proteolysis by human PS failed to enhance IGFBP-4 proteolysis. PAPP-A neutralization antibody did not inhibit IGFBP-4 proteolysis by mPS or mNPS, but completely blocked IGFBP-4 proteolytic activity in human PS (hPS, mouse osteoblast conditioned medium, and mouse amniotic fluid). To determine whether the lack of PAPP-A activity in mPS was due to low expression of PAPP-A in the placenta, we cloned a mouse genomic DNA, which contained 1 kb of the entire exon 2 coding sequence and 2.5 kb of the flanking intron sequences. The exon 2-coded mouse and human PAPP-A shared 86% amino acid sequence identity. RT-PCR analysis revealed that the PAPP-A mRNA level in mouse placenta was lower compared to that in human placenta by at least two orders of magnitude. PAPP-A expression was also lower in mouse placenta compared to those in mouse kidney, osteoblasts, and bone marrow stromal cells. Conclusions: (1) Serum IGFBP-4 proteolytic activity is differentially regulated by pregnancy in human and mouse. (2) The lack of an increase in serum IGFBP-4 proteolytic activity during mouse pregnancy is due to the low level of PAPP-A expression in the placenta. (C) 2002 Elsevier Science Ltd. All rights reserved.