Fig. 9
(A) Schematic diagrams summarizing the alterations in the hypothalamus-pituitary-liver axis that result in decreased body and femur length in Pappa2ko/ko mice (males and females) in adulthood. Increased and decreased levels are represented by a blue arrow for males and a red arrow for females. The effect of genotype is indicated by an asterisk (*). Reduced body and femur length of Pappa2ko/ko mice and female-specific increased expressions of components of IGF1 binary/ternary complexes (IGF1 and IGFBP5 in plasma, Igfbp5 in hypothalamus, and Igfbp3 and Igfals in liver) could be consistent with reduced IGF1 availability and signaling in target tissues. Sex-specific modulation of key sensors of IGF1 signaling pathways (phosphorylation of AKT, mTOR, GSK3β and ERK1/2 in the female hypothalamus, phosphorylation of GSK3β and ERK1/2 in the male pituitary gland, and phosphorylation of PI3K and AMPKα in the female liver) may be relevant to explain growth impairment through a dysregulated IGF1 system due to PAPP-A2 deficiency. (B) Schematic diagrams summarizing changes in IGF1 ternary complex components and IGF1 signaling pathways that result in increased body and/or femur length after the pharmacological administration of rhGH, rhIGF1 and rhPAPP-A2 for 30 days (PND5-35) in Pappa2ko/ko mice (males and females) at puberty onset. Increased and decreased levels are represented by a blue arrow for males and a red arrow for females. The effect of treatment is indicated by an asterisk (*). Female-specific increases in body and femur length and female-specific decreases in expressions of components of IGF1 ternary complexes (IGF1 and IGFBP5 in plasma, and Igfbp3 and Igfals in liver) could be consistent with increased IGF1 availability and signaling in target tissues. Female-specific modulation of key sensors of liver IGF1 signaling pathways (reduced phosphorylation of AKT and ERK2, and increased phosphorylation of AMPKα) may be relevant to explain growth improvement through a regulated IGF1 system by rhPAPP-A2 treatment