Deficiency of pregnancy-associated plasma protein-A2 (PAPP-A2), a regulator of IGF-1 availability, causes postnatal growth failure in humans and mice, at least in part through dysregulation of bone size and density. The present study aimed to determine the effects of Pappa2 gene deletion and the response to recombinant murine IGF-1 (rmIGF-1) on femur microstructure and composition. Hydroxyapatite-related crystallography and ionic substitutions were analyzed by X-ray powder diffraction (XRD) and Attenuated Total Reflection-Fourier Transform Infra-Red (ATR-FTIR) spectroscopy. Gene expression of members of the IGF-1 system was measured in tibia. Male and female Pappa2 knock-out (ko/ko) mice had reduced body length in the peripubertal and adult periods. In adulthood, the femurs and tibias were shorter in Pappa2ko/ko mice of both sexes and weighed relatively less in Pappa2ko/ko males compared to same-sex controls. Pappa2ko/ko male bone had: 1) Altered hydroxyapatite-(CaOH)-related crystallinity and crystallite size; 2) Increased content of phosphates (PO43-) and carbonates (CO32; C-O); 3) Increased expression of Igfbp3, Igfbp5 and Igfals; and 4) Dynamic increases in phosphate (PO43-) and carbonate (C-O) content, and decreases in amide (OH-, C=O) content after a single administration of rmIGF-1 (0.3 mg/kg). Pappa2ko/ko female bone had: 1) No change in crystallinity or ionic content; 2) Reduced expression of Igfbp3 and Igfbp5; and 3) Increased content of phosphates (PO43-), carbonates (CO32; C-O) and amides (OH) and 4) Higher expression of Igfbp3 and Igfbp5 after rmIGF-1 administration. In summary, acute treatment with recombinant IGF-1 modifies hydroxyapatite-related ionic substitutions and local IGF-1 system in the bones of mice with Pappa2 deficiency. These effects depend on sex and provide important insights into IGF-1 efficacy as potential therapy for growth failure.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology