Ben Lagha Nadia, Seurin Danielle, Le Bouc Yves, Binoux Michel, Berdal Ariane, Menuelle Pierrette, Babajko Sylvie
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.
Endocrinology. 2006 Oct;147(10):4730-7. doi: 10.1210/en.2006-0171. Epub 2006 Jun 29.
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.
在人类中，宫内生长迟缓与血清胰岛素样生长因子结合蛋白-1（IGFBP-1）水平升高相关。本研究在体内分析了循环IGFBP-1对与骨矿化和碳水化合物资源相关的身体生长的影响。本研究中使用的转基因小鼠从胚胎第（E）14.5天开始在肝脏中过表达人IGFBP-1，直至成年，此时骨化中心开始出现。早在E17.5时，纯合（HM）小鼠就出现了生长迟缓，出生时（出生后第1天）体型小20%。通过茜素红和阿尔新蓝染色对骨骼进行解剖分析表明，这些小鼠表现出多个骨骼单元的多效性缺陷。一些骨骼小且形态异常。我们的结果显示，颅骨后部区域（缝线闭合延迟）以及附属骨骼和中轴骨骼的矿化减少。杂合子杂交显示HM动物缺失。此外，IGFBP-1过表达导致胎儿肝糖原和新生儿血糖水平降低，而这是新生儿碳水化合物资源的主要储备。因此，这种减少的碳水化合物储备导致了围产期死亡率。母体IGFBP-1表达也与新生儿生长迟缓（HM母亲的新生儿体重比NT母亲的新生儿小20%）和胎儿碳水化合物资源减少明显相关。总之，转基因小鼠的产前生长迟缓和矿化延迟与胎儿和母体循环人IGFBP-1过表达有关。在人类宫内生长迟缓中也可观察到类似的干扰，这表明IGF/IGFBP系统参与了人类胎儿的生长、生物矿化和能量状态。
