Pregnancy-Associated Plasma Protein-A2 (PAPP-A2): Tissue Expression and Biological Consequences of Gene Knockout in Mice

Abstract

Pregnancy-associated plasma protein-A2 (PAPP-A2) is a novel homolog of PAPP-A in the metzincin superfamily. However, compared with the accumulating data on PAPP-A, very little is known about PAPP-A2. In this study, we determined the tissue expression pattern of PAPP-A2 mRNA in wild-type (WT) mice and characterized the phenotype of mice with global PAPP-A2 deficiency. Tissues expressing PAPP-A2 in WT mice were more limited than those expressing PAPP-A. The highest PAPP-A2 mRNA expression was found in the placenta, with abundant expression in fetal, skeletal, and reproductive tissues. Heterozygous breeding produced the expected Mendelian distribution for the pappa2 gene and viable homozygous PAPP-A2 knockout (KO) mice that were normal size at birth. The most striking phenotype of the PAPP-A2 KO mouse was postnatal growth retardation. Male and female PAPP-A2 KO mice had 10 and 25-30% lower body weight, respectively, than WT littermates. Adult femur and body length were also reduced in PAPP-A2 KO mice, but without significant effects on bone mineral density. PAPP-A2 KO mice were fertile, but with compromised fecundity. PAPP-A expression was not altered to compensate for the loss of PAPP-A2 expression, and proteolysis of PAPP-A2's primary substrate, IGF-binding protein-5, was not altered in fibroblasts from PAPP-A2 KO embryos. In conclusion, tissue expression patterns and biological consequences of gene KO indicate distinct physiological roles for PAPP-A2 and PAPP-A in mice.

PAPP-A2 nowy regulator procesu wzrastania

“…The dysmorphic features observed in affected members of both families were similar to those observed in PAPP-A2 knockout mice [33,34].…”

“…The knockout mice also displayed disproportionally reduced dimensions of specific bones, including skull, mandible, humerus, femur, tibia, pelvic girdle, and tailbone, with size reductions being more severe than would be expected from the decrease in total body mass and length [32][33][34][35]. The mice with PAPP-A2 gene deletion had shallower mandible and pelvic girdles with a more feminine shape [35].…”

Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes

“…In this context, it has been proposed that cell-associated PAPPA, enhancing local IGF actions, could amplify atherosclerosis plaque formation (Conover, 2010). Little is known on PAPPA1 homologue, PAPPA2, even though in a recent study the analysis of tissue expression patterns and biological consequences of KO gene indicate distinct physiological roles for PAPP-A2 and PAPP-A in mice (Conover et al, 2011).…”

PAPPA2 is increased in severe early onset pre-eclampsia and upregulated with hypoxia

“…Pregnancy-associated plasma protein A2 (PAPPA2) is a homologue of the well known first-trimester serum marker of pathological pregnancies, namely PAPPA, sharing 46% sequence identity (Conover et al 2011). Importantly, recent reports demonstrate a link between PAPPA2 and PE (Nishizawa et al 2008;Winn et al 2009;Paiva et al 2011).…”