Sex-based differences in IGF1 signaling pathways in response to PAPP-A2 deficiency

Abstract

Background. Patients with pregnancy-associated plasma protein-A2 (PAPP-A2) mutations have progressive postnatal growth retardation and high circulating levels of IGF1 bound in ternary complexes. The present study aims to assess whether Pappa2 deficiency is associated with sex-specific differences in the main components of IGF1 ternary complexes and IGF1 signaling pathways in response to low IGF1 bioavailability. Methods. Plasma, hypothalamus, pituitary gland and liver were analyzed in constitutive Pappa2ko/ko mice of both sexes that have reduced skeletal growth and impaired bone composition. Results. The reduction in body and femur length of Pappa2ko/ko mice was associated with increases in total IGF1 and IGFBP5 concentrations in plasma of females, Igfbp5 mRNA levels in the hypothalamus of males, and Igf1, Igfbp3 and Igfals mRNA levels in the liver of females, suggesting sex- and tissue-specific effects of Pappa2 deficiency on IGF ternary/binary complexes. Pappa2 deficiency was also accompanied by increased pituitary GH concentrations in both sexes. Sex-specific dysregulation of IGF1 signaling pathways was found in Pappa2ko/ko mice with higher phosphorylated forms of AKT, mTOR, GSK3β and ERK1/2 in the female hypothalamus, GSK3β in the male pituitary gland, and PI3K and AMPKα in the female liver, suggesting sex-based alterations in regulators of cell proliferation/growth and protein/glucose metabolism. Conclusions. These data suggest that sex-specific differences in IGF ternary complexes and IGF1 signaling pathways are associated with Pappa2 deficiency, pointing to molecular mechanisms that may participate in the physiopathology of postnatal growth retardation in a sex-dependent manner.