CEDIE   05498
CENTRO DE INVESTIGACIONES ENDOCRINOLOGICAS "DR. CESAR BERGADA"
Unidad Ejecutora - UE
congresos y reuniones científicas
Título:
Unbound/Bio-Available IGF-I Enhances Somatic Growth
Autor/es:
HÉCTOR G. JASPER; HORACIO M. DOMENÉ; LILIANA KARABATAS; CLARA GUIDA; SHOSHANA YAKAR
Lugar:
Boston, Massachusetts
Reunión:
Congreso; 93th Annual Meeting of the Endocrine Society; 2011
Institución organizadora:
The Endocrine Society
Resumen:
Endocr Rev, Vol. 32 (03_MeetingAbstracts): P1-128Copyright © 2011 by The Endocrine Society Unbound/Bio-Available IGF-I Enhances Somatic Growth Hector Jasper, MD1, Horacio Domene, PhD1, Liliana Karabatas, PhD1, Clara Guida, PhD1 and Shoshana Yakar, PhD2 Endocrinology Research Center (HJ,HD,LK,CG), Children´s Hospital, Buenos Aires ArgentinaEndocrinology/Medicine (SY), Mount Sinai School of Medicine, New York, NY IGF-I bioactivity is modulated by its binding to serum and tissues IGF binding proteins (IGFBPs). Des1-3-IGF-I (DES) is an IGF-I analog with normal affinity for the IGF-I receptor but much lower affinity to IGFBPs. To determine whether IGF-I binding to IGFBPs is necessary to facilitate normal growth, we generated a knock-in mouse model of DES-IGF-I (KID), where the native Igf1 gene was replaced by des-Igf1,and therefore expressed under the endogenous Igf1 promoter. IGF-1 concentrations in serum of KID mice, measured by radio-immunoassay (National Hormone and Peptide Program, NIH), were reduced significantly as compared to controls. Similarly, IGFBP-3 levels reduced by 40%, likely due to decreased protein stability in the absence of binding to IGF-I, while the levels of the acid-labile subunit (ALS) remained unchanged. Formation of ternary complexes (IGF-I/IGFBP-3/ALS) in serum of KID mice was significantly reduced when WT-IGF-I was used as a tracer, (28.8±3.9 vs 14.6±2.0, % total binding, p< 0.01). Likewise, bound IGF-I cpm/total cpm was significantly reduced in KID mice (57.23±3.76 vs 29,26±4,29, p=0.0008) when DES IGF-I was used as tracer. Despite significant reductions (60%) in serum IGF-I levels and reduced IGF-I ternary complex formation, KID mice exhibited increased body weight and body length in both males and females as compared to controls. We found that not all organs responded equally to DES-IGF-I. Relative weights (% BW) of kidney, pancreas, uterus and ovaries increased at all ages studied, while other tissues showed no difference when compared to controls. In summary, despite lower concentrations in serum, Des-IGF-I was more potent in promoting growth than native IGF-I. The lower affinity of DES for IGFBPs, resulting in a reduction of bound-IGFs in KID mice, suggests that an increase in bioactive DES (free plus that loosely bound to IGFBPs) at the target organ is responsible for increased body size and selective organ growth in KID mice. The KID model supports the important roles of IGFBPs in modulating IGFs bioavailability. Nothing to Disclose: HJ, HD, LK, CG, SY