Pregnancy Associated Plasma Protein A2 (PAPP-A2) Affects Bone Size and Shape and Contributes to Natural Variation in Postnatal Growth in Mice

Abstract

Pregnancy associated plasma protein A2 (PAPP-A2) is a protease of insulin-like growth factor binding protein 5 and is receiving increasing attention for its roles in pregnancy and postnatal growth. The goals of the present study were to characterize the effects of PAPP-A2 deletion on bone size and shape in mice at 10 weeks of age, and to determine whether Pappa2 is the gene responsible for a previously-identified quantitative trait locus (QTL) contributing to natural variation in postnatal growth in mice. Mice homozygous for constitutive PAPP-A2 deletion were lighter than wild-type littermates, and had smaller mandible dimensions and shorter skull, humerus, femur, tibia, pelvic girdle, and tail bone. Furthermore, PAPP-A2 deletion reduced mandible dimensions and the lengths of the skull, femur, pelvic girdle, and tail bone more than would be expected due to the effect on body mass. In addition to its effects on bone size, PAPP-A2 deficiency also altered the shape of the mandible and pelvic girdle, as assessed by geometric morphometrics. Mice homozygous for the PAPP-A2 deletion had less deep mandibles, and pelvic girdles with a more feminine shape. Using a quantitative complementation test, we confirmed that Pappa2 is responsible for the effects of the previously-identified QTL, demonstrating that natural variation in the Pappa2 gene contributes to variation in postnatal growth in mice. If similar functional variation in the Pappa2 gene exists in other species, effects of this variation on the shape of the pelvic girdle might explain the previously-reported associations between Pappa2 SNPs and developmental dysplasia of the hip in humans, and birthing in cattle.

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].…”

Papp-a2 modulates development of cranial cartilage and angiogenesis in zebrafish embryos

“…The knockout mice also display disproportionally reduced dimensions of specific bones, including skull and mandible, with size reductions being more severe than would be expected from the decrease in total body mass and length (Christians et al, 2013;Conover et al, 2011). Whereas similar phenotypes of the skeleton were not reported in IGFBP-3-and IGFBP-5-knockout, or transgenic mice overexpressing IGFBP-3 or IGFBP-5 (Ning et al, 2006;Salih et al, 2005;Silha et al, 2003), addition of purified IGFBP-5 to metatarsal bones in culture reduced longitudinal growth (Mukherjee and Rotwein, 2008).…”

Pregnancy-Associated Plasma Protein A2 in Hemodialysis Patients: Significance for Prognosis

“…They are responsible for proteolytic cleavage of insulin like growth factor binding proteins (IGFBPs), thus increasing insulin like growth factor (IGF) bioavailability [1, 2]. Both are expressed predominantly by placenta in pregnancy [1, 3] and required for normal growth and development [4-6]. …”

“…On the other hand, PAPP-A knockout mice are born as proportional dwarfs [21]. PAPP-A2 deficiency altered both the size as well as the shape of bones [6]. PAPP-A2 also modulates angiogenesis in zebrafish embryos [22].…”