An experimental model of partial insulin-like growth factor-1 deficiency in mice
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ORIGINAL PAPER
An experimental model of partial insulin-like growth factor-1 deficiency in mice I. Castilla-Cortazar & L. Guerra & J. E. Puche & U. Muñoz & R. Barhoum & E. Escudero & J. L. Lavandera
Received: 16 May 2013 / Accepted: 5 September 2013 / Published online: 18 September 2013 # University of Navarra 2013
Abstract Insulin-like growth factor-1 (IGF-1) is responsible for many systemic growth hormone (GH) functions although it has an extensive number of inherent activities (anabolic, cytoprotective, and anti-inflammatory). The potential options for IGF-1 therapy arise as a promising strategy in a wide list of human diseases. However, deeper studies are needed from a suitable animal model. All human conditions of IGF-1 deficiency consist in partially decreased IGF-1 levels since total absence of this hormone is hardly compatible with life. The aim of this work was to confirm that heterozygous Igf-1+/− mice (Hz) may be considered as an appropriate animal model to study conditions of IGF-1 deficiency, focusing on early ages. Heterozygous Igf-1+/− mice were compared to homozygous Igf-1+/+ by assessing gene expression by quantitative PCR, serum circulating levels by ELISA, and tissue staining. Compared to controls, Hz mice (25 days old) showed a partial but significant reduction of IGF-1 circulating levels, correlating with a reduced body weight and diminished serum IGFBP-3 levels. Hz mice presented a significant decrease of IGF-1 gene expression in related organs (liver, bone, testicles, and I. Castilla-Cortazar : L. Guerra : J. E. Puche : U. Muñoz : R. Barhoum : E. Escudero : J. L. Lavandera Institute of Applied Molecular Medicine (IMMA), Department of Medical Physiology, School of Medicine, Universidad CEU San Pablo, Madrid, Spain I. Castilla-Cortazar (*) School of Medicine, Universidad CEU San Pablo, Room D-201, C/ Boadilla del Monte s/n, km 5.3, 28668 Madrid, Spain e-mail: [email protected]
brain) while IGF-1 receptor showed a normal expression. However, gene expression of growth hormone receptor (GHR) was increased in the liver but reduced in the bone, testicles, and brain. In addition, a significant reduction of cortical bone thickness and histopathological alterations in the testicles were found in Hz mice when compared to controls. Finally, the lifelong evolution of IGF-1 serum levels showed significant differences throughout life until aging in mice. Results in this paper provide evidence for considering heterozygous mice as a suitable experimental model, from early stages, to get more insight into the mechanisms of the beneficial actions induced by IGF-1 replacement therapy. Keywords IGF-1 . IGF-1 receptor . GH receptor . Liver cirrhosis . Laron syndrome . GH/IGF-1 axis . IGF-1 deficiency . IGFBP-3 . Gene expression . Aging Abbreviations Bw Body weight Cat Catalase CO Control group (wild-type mice) ELISA Enzyme-linked immunosorbent assay Gclc Glutamate–cysteine ligase catalytic subunit GH Growth hormone GHR Growth hormone receptor Hspa1b Heat shock protein 1B Hz Heterozygous IGF-1 Insulin-like growth
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