Differential regulation of pregnancy associated plasma protein (PAPP)-A during pregnancy in human and mouse

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.