Insulin-Like Growth Factor Binding Protein (IGFBP-1) Involvement in Intrauterine Growth Retardation: Study on IGFBP-1 Overexpressing Transgenic Mice

Abstract

In humans, intrauterine growth retardation is correlated to high levels of serum IGF binding protein-1 (IGFBP-1). This present study analyzes in vivo the impact of circulating IGFBP-1 on body growth associated to bone mineralization and carbohydrate resources. Transgenic mice used in this work overexpressed human IGFBP-1 in liver from embryonic day (E)14.5, concomitantly to the appearance of ossification centers, through to adulthood. Growth retardation was observed as early as E17.5 in homozygous (HM) mice being 20% smaller at birth (postnatal d 1). Anatomical analysis of the skeletons by alizarin red and alcian blue staining showed that the mice exhibited pleiotropic defects of several skeletal units. Some bones were small and dysmorphic. Our results showed reduced mineralization in the posterior area of the skull (delayed suture closure), as well as in the appendicular and axial skeleton. Heterozygous crossings showed a loss of HM animals. Moreover, IGFBP-1 overexpression contributed to decreased fetal hepatic glycogen and neonate blood glucose levels which constitute the main reservoir of carbohydrate resources for neonates. Thus, this reduced carbohydrate pool contributed to perinatal mortality. Maternal IGFBP-1 expression was also clearly associated with neonate growth retardation (newborn weights from HM mothers were 20% smaller than newborns from NT mothers) and reduced fetal carbohydrate resources. In conclusion, antenatal growth retardation and delayed mineralization in transgenic mice are related to overexpressed fetal and maternal circulating human IGFBP-1. Similar perturbations could be observed in human intrauterine growth retardation suggesting the IGF/IGFBP system is involved in fetal growth, biomineralization, and energetic status in humans.

Contrasting bone effects of temporary versus permanent IGFBP administration in rodents

“…In a follow-up study [9], intrauterine growth retardation was in fact observed in homozygous IGFBP-1 transgenic mice at embryonic day 17.5. In homozygous mice, increased perinatal mortality was observed, which was probably due to decreased carbohydrate pools in the transgenic mice.…”

Stabilization of IGFBP-1 mRNA by ethanol in hepatoma cells involves the JNK pathway

“…The biological relevance of high levels of IGFBP-1 has been extensively studied using transgenic technology. A dominant feature of the transgenic lines is the fetal and postnatal growth restrictions [10,11] and alterations of female reproductive functions [12,13]. Some transgenic lines also display impaired glucose homeostasis [14].…”

Organ-Specific Defects in Insulin-Like Growth Factor and Insulin Receptor Signaling in Late Gestational Asymmetric Intrauterine Growth Restriction in Cited1 Mutant Mice

“…This is of importance because the activity of secreted IGF ligands is regulated by a variety of IGF-binding proteins in vivo (26), and IGF-binding proteins are also abnormally regulated in different models of IUGR (18 -21). Therefore, our studies establish that alterations in tissue expression of IGF and insulin are associated with decreased activation of their cognate receptors in fetal organs affected by IUGR.…”

“…However, there has been no systematic analysis of IGF-I or IGF-II expression in other organs affected by IUGR. Moreover, complex interactions with a variety of IGF-binding proteins regulate bioavailability and net activity of IGF ligands in vivo (26). Because these factors are also abnormally regulated in different models of IUGR (18 -21), the net effect of decreasing circulating and/or hepatic IGF-I on IGF-IR signaling are unknown.…”