Gupta Madhulika B
Departments of Pediatrics and Biochemistry, Children's Health Research Institute, University of Western Ontario, VRL Room A5-136 (WC) 800 Commissioners Road E., London, ON, N6C 2V5, Canada,
J Cell Commun Signal. 2015 Jun;9(2):111-23. doi: 10.1007/s12079-015-0266-x. Epub 2015 Feb 15.
Fetal growth restriction (FGR) increases the risk of perinatal complications and predisposes the infant to developing metabolic, cardiovascular, and neurological diseases in childhood and adulthood. The pathophysiology underlying FGR remains poorly understood and there is no specific treatment available. Biomarkers for early detection are also lacking. The insulin-like growth factor (IGF) system is an important regulator of fetal growth. IGF-I is the primary regulator of fetal growth, and fetal circulating levels of IGF-I are decreased in FGR. IGF-I activity is influenced by a family of IGF binding proteins (IGFBPs), which bind to IGF-I and decrease its bioavailability. During fetal development the predominant IGF-I binding protein in fetal circulation is IGFBP-1, which is primarily secreted by the fetal liver. IGFBP-1 binds IGF-I and thereby inhibits its bioactivity. Fetal circulating levels of IGF-I are decreased and concentrations of IGFBP-1 are increased in FGR. Phosphorylation of human IGFBP-1 at specific sites markedly increases its binding affinity for IGF-I, further limiting IGF-I bioactivity. Recent experimental evidence suggests that IGFBP-1 phosphorylation is markedly increased in the circulation of FGR fetuses suggesting an important role of IGFBP-1 phosphorylation in the regulation of fetal growth. Understanding of the significance of site-specific IGFBP-1 phosphorylation and how it is regulated to contribute to fetal growth will be an important step in designing strategies for preventing, managing, and/or treating FGR. Furthermore, IGFBP-1 hyperphosphorylation at unique sites may serve as a valuable biomarker for FGR.
胎儿生长受限（FGR）会增加围产期并发症的风险，并使婴儿在儿童期和成年期易患代谢、心血管和神经疾病。FGR的潜在病理生理学仍知之甚少，且尚无特效治疗方法。早期检测的生物标志物也很缺乏。胰岛素样生长因子（IGF）系统是胎儿生长的重要调节因子。IGF-I是胎儿生长的主要调节因子，FGR时胎儿循环中的IGF-I水平会降低。IGF-I的活性受一类IGF结合蛋白（IGFBPs）的影响，这些蛋白与IGF-I结合并降低其生物利用度。在胎儿发育过程中，胎儿循环中主要的IGF-I结合蛋白是IGFBP-1，它主要由胎儿肝脏分泌。IGFBP-1与IGF-I结合，从而抑制其生物活性。FGR时胎儿循环中的IGF-I水平降低，IGFBP-1浓度升高。人IGFBP-1在特定位点的磷酸化显著增加其对IGF-I的结合亲和力，进一步限制IGF-I的生物活性。最近的实验证据表明，FGR胎儿循环中IGFBP-1磷酸化显著增加，提示IGFBP-1磷酸化在胎儿生长调节中起重要作用。了解位点特异性IGFBP-1磷酸化的意义及其如何被调节以促进胎儿生长，将是设计预防、管理和/或治疗FGR策略的重要一步。此外，IGFBP-1在独特位点的过度磷酸化可能成为FGR的一个有价值的生物标志物。
