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Pediatr Nephrol (2005) 20:269278 DOI 10.1007/s00467-004-1657-z
REVIEW
Eckhard Wolf Marlon R. Schneider Rui Zhou Thomas M. Fisch Nadja Herbach Maik Dahlhoff R diger Wanke Andreas Hoeflich
Functional consequences of IGFBP excess lessons from transgenic mice
Received: 3 June 2004 / Revised: 26 July 2004 / Accepted: 26 July 2004 / Published online: 16 December 2004 IPNA 2004
Abstract The functions of insulin-like growth factor-binding proteins (IGFBPs) have been studied extensively in vitro, revealing IGF-dependent and also IGF-independent effects on cell growth, differentiation, and survival. In contrast, the biological relevance of IGFBPs in vivo is only partially understood. In the past decade, mouse models lacking or overexpressing specific IGFBPs have been generated by transgenic technology. Phenotypic analysis revealed features that are common for most IGFBPs (growth inhibition), but also effects that appear to be specific for some but not all IGFBPs, such as disturbed glucose homeostasis (IGFBP-1 and -3) or impaired fertility (IGFBP-1, -5, and -6). Future systematic comparison of IGFBP functions in transgenic mice will be facilitated by targeted insertion of IGFBP expression vectors and by standardized phenotype assessment. Furthermore, analysis of IGFBP expression in growth-selected mouse lines or pedigrees segregating for growth phenotypes will be important to understand the roles of IGFBPs in multigenic growth regulation.
Keywords Insulin-like growth factor-binding protein Mouse Growth Metabolism Fertility
Introduction
The actions of the six high-affinity insulin-like growth factor-binding proteins (IGFBP-1 to -6) have been extensively characterized in many cellular models. IGFBPs are capable of sequestering IGFs from their receptors, thus inhibiting the actions of IGFs such as induction of an increase in cell size or proliferation, or inhibition of apoptosis. The effects of IGFBPs can be modulated by proteolysis through specific proteases or by association with the cell surface. In addition, IGF-independent effects of IGFBPs have been discovered in in vitro systems (re-viewed in [1]).
Although circulating and/or tissue levels of IGFBPs show changes in normal growth physiology and particularly under pathological conditions, it is unclear whether altered IGFBP levels have intrinsic effects or merely represent an epiphenomenon of developmental processes or diseases. Transgenic technology in rodent models provides the unique possibility to alter the abundance of specific IGFBPs in the circulation or at the tissue level and to study consequences for growth and other physiological functions....