Deficiency of pregnancy-associated plasma protein-A2 (PAPP-A2), a protease that regulates IGF-1 availability, causes postnatal growth failure and changes in bone size and density in humans and mice. The present study aimed to determine the effects of daily administration (from PND5 to PND35) of recombinant murine (rm) PAPP-A2, in comparison to rmGH and rmIGF1, on mouse auxology and bone microarchitecture in homozygous Pappa2 knock-out (ko/ko) mice of both sexes. Hormone treatment increased body weight and length in a drug, genotype and sex-dependent manner, with rmPAPP-A2 resulting in weight and length increases up to 10% and 2%, respectively, in Pappa2ko/ko males and up to 15% and 11%, respectively, in Pappa2ko/ko females. Hormone treatment also increased relative femur density and weight in a drug, genotype and sex-dependent manner, with Pappa2ko/ko males exhibiting a significant increase in relative femur density, and Pappa2ko/ko females showing significant increases in both relative femur density and weight after rmPAPPA2 administration. Morphometric analysis of bone by Microcomputed Tomography (µCT) revealed that rmPAPP-A2 administration in Pappa2ko/ko males increased femur trabecular separation, trabecular thickness and cortical area fraction, and normalized trabecular number and cortical thickness. No effect of treatment on femur microarchitecture was observed in females. In summary, daily administration of recombinant PAPP-A2 from PND5 to PND35 increases body weight and length in Pappa2ko/ko mice, and changes bone morphometry in a manner suggestive of prolonged bone development. These effects depend on sex and provide important insights into PAPP-A2 efficacy as potential therapy for growth failure and the comparison to treatment with rmGH or rmIGF1 will be presented.
Funding: Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades co-funded by ERDF-EU (JS: PI19/00343, JA: PI19/00166), and CIBER Obesity & Nutrition (CIBEROBN).
15 Sep 2022 - 17 Sep 2022