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.
Highlights
Insulin-like growth factors (IGFs) play a pivotal role in growth and development [1]
The bioavailability of the IGFs is regulated by six IGF binding proteins (IGFBPs), and the release of IGFs and subsequent IGF signaling is achieved through cleavage of the IGFBPs by proteases [1]
We have shown that deletion of Pregnancy associated plasma protein A2 (PAPP-A2) reduces the lengths of some bones beyond what is expected due to reduced body size, and affects bone shape
Summary
Insulin-like growth factors (IGFs) play a pivotal role in growth and development [1]. Pregnancy associated plasma protein A (PAPP-A) is an IGFBP protease that was initially identified as a circulating protein of placental origin, but has since been shown to play roles outside of pregnancy in cardiovascular disease, the regulation of bone mineral density, skin healing and aging [2,3,4,5,6]. While less work has examined PAPP-A2, this protein is receiving increasing attention for its roles in human pregnancy [2,8], reproductive traits in cattle [9,10,11], and postnatal growth in mice [12,13]. The first indication of a role in postnatal growth was our previous work that identified Pappa as a candidate for the gene responsible for the effects of a quantitative trait locus (QTL) affecting adult body size in mice. Others have reported association between developmental dysplasia of the hip and a Pappa SNP in humans [17], again suggesting an effect of PAPP-A2 on bone shape
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