Effects of the nuclear localization sequence and C-terminus of Parathyroid hormone-related protein on the growth Hormone-IGF-1 axis

Abstract

Parathyroid hormone–related protein (PTHrP) is a polyhormone consisting of an N-terminus, a mid-region, a nuclear localization sequence (NLS), and a C-terminus. The NLS and C-terminus of PTHrP regulate endochondral bone formation, craniofacial development, hematopoiesis, and survival. Our laboratory has developed Pthrp Δ/Δ mice lacking the NLS and C-terminus of PTHrP, which exhibit severe growth delay and early mortality within the first week of life. This study investigates the growth hormone (GH)-IGF-1 axis in Pthrp Δ/Δ mice. PTHrP is expressed by various endocrine cells, including pituitary endocrine epithelial cells of the adenohypophysis. Histopathological, biochemical, ultrastructural, and gene expression analyses were performed on the pituitary from Pthrp Δ/Δ and age-matched control mice. Pituitary glands from Pthrp Δ/Δ mice had normal cellularity; however, the pituitary somatotrophs had increased Gh mRNA expression with a decrease in the number and size of cytoplasmic secretory granules containing GH. Plasma GH concentrations were either normal or increased, and plasma ACTH concentrations were increased. Western blot analysis of the pituitary glands revealed reduced GH in Pthrp Δ/Δ mice. The plasma concentrations of IGF-1 and liver Igf1 mRNA expression and glycogen content were decreased in Pthrp Δ/Δ mice. Western blot analysis of liver from Pthrp Δ/Δ mice showed a significant reduction in both total and phosphorylated Janus Kinase 2 (JAK2) proteins and total and tyrosine-phosphorylated STAT5b proteins compared to controls. In conclusion, the lack of the NLS and C-terminus of PTHrP disrupted the normal GH-IGF-1 axis, leading to impaired IGF-1 production by the liver.