Insulin-like growth factor binding protein (IGFBP-1) involvement in intrauterine growth retardation: study on IGFBP-1 overexpressing transgenic mice.
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.
Ben Lagha
Nadia
N
Laboratoire de Biologie Oro-faciale et Pathologie, Institut National de la Santé et de la Recherche Médicale Unité 714, Institut biomédical des Cordeliers, 15/21 rue de l'école de Médecine, 75006 Paris, France.
Seurin
Danielle
D
Le Bouc
Yves
Y
Binoux
Michel
M
Berdal
Ariane
A
Menuelle
Pierrette
P
Babajko
Sylvie
S
D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000378:metabolism; D002113:Calcification, Physiologic / Q000502:physiology; D050260:Carbohydrate Metabolism / Q000502:physiology; D002356:Cartilage / Q000254:growth & development; D005260:Female; D005317:Fetal Growth Retardation / Q000503:physiopathology*; D005838:Genotype; D006128:Growth / Q000502:physiology; D006801:Humans; D018970:Insulin-Like Growth Factor Binding Protein 1 / Q000097:blood / Q000235:genetics* / Q000502:physiology*; D008112:Liver Glycogen / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D010012:Osteogenesis / Q000502:physiology; D011247:Pregnancy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013002:Somatomedins / Q000096:biosynthesis; D013534:Survival
D001786:Blood Glucose; D018970:Insulin-Like Growth Factor Binding Protein 1; D008112:Liver Glycogen; D013002:Somatomedins