An experimental model of partial insulin-like growth factor-1 deficiency in mice
Tóm tắt
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 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.
Tài liệu tham khảo
Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D, Pfaffle R, Raile K, Seidel B, Smith RJ, Chernausek SD, Intrauterine Growth Retardation Study G (2003) IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 349:2211–2222. doi:10.1056/NEJMoa010107
Akanji AO, Smith RJ (2012) The insulin-like growth factor system, metabolic syndrome, and cardiovascular disease risk. Metab Syndr Relat Disord 10:3–13. doi:10.1089/met.2011.0083
Bailey-Downs LC, Mitschelen M, Sosnowska D, Toth P, Pinto JT, Ballabh P, Valcarcel-Ares MN, Farley J, Koller A, Henthorn JC, Bass C, Sonntag WE, Ungvari Z, Csiszar A (2012) Liver-specific knockdown of IGF-1 decreases vascular oxidative stress resistance by impairing the Nrf2-dependent antioxidant response: a novel model of vascular aging. J Gerontol A Biol Sci Med Sci 67:313–329. doi:10.1093/gerona/glr164
Baker J, Hardy MP, Zhou J, Bondy C, Lupu F, Bellve AR, Efstratiadis A (1996) Effects of an Igf1 gene null mutation on mouse reproduction. Mol Endocrinol 10:903–918
Baker J, Liu JP, Robertson EJ, Efstratiadis A (1993) Role of insulin-like growth factors in embryonic and postnatal growth. Cell 75:73–82
Beck KD, Powell-Braxton L, Widmer HR, Valverde J, Hefti F (1995) Igf1 gene disruption results in reduced brain size, CNS hypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neurons. Neuron 14:717–730
Caro JF, Poulos J, Ittoop O, Pories WJ, Flickinger EG, Sinha MK (1988) Insulin-like growth factor I binding in hepatocytes from human liver, human hepatoma, and normal, regenerating, and fetal rat liver. J Clin Invest 81:976–981. doi:10.1172/JCI113451
Castilla-Cortazar I, Diez N, Garcia-Fernandez M, Puche JE, Diez-Caballero F, Quiroga J, Diaz-Sanchez M, Castilla A, Casares AD, Varela-Nieto I, Prieto J, Gonzalez-Baron S (2004) Hematotesticular barrier is altered from early stages of liver cirrhosis: effect of insulin-like growth factor 1. World J Gastroenterol 10:2529–2534
Castilla-Cortazar I, Garcia M, Muguerza B, Quiroga J, Perez R, Santidrian S, Prieto J (1997) Hepatoprotective effects of insulin-like growth factor I in rats with carbon tetrachloride-induced cirrhosis. Gastroenterology 113:1682–1691
Castilla-Cortazar I, Garcia M, Quiroga J, Diez N, Diez-Caballero F, Calvo A, Diaz M, Prieto J (2000) Insulin-like growth factor-I reverts testicular atrophy in rats with advanced cirrhosis. Hepatology 31:592–600
Castilla-Cortazar I, Picardi A, Tosar A, Ainzua J, Urdaneta E, Garcia M, Pascual M, Quiroga J, Prieto J (1999) Effect of insulin-like growth factor I on in vivo intestinal absorption of D-galactose in cirrhotic rats. Am J Physiol 276:G37–G42
Castilla-Cortazar I, Prieto J, Urdaneta E, Pascual M, Nunez M, Zudaire E, Garcia M, Quiroga J, Santidrian S (1997) Impaired intestinal sugar transport in cirrhotic rats: correction by low doses of insulin-like growth factor I. Gastroenterology 113:1180–1187
Castilla-Cortazar I, Quiroga J, Prieto J (2000) Insulin-like growth factor-I, liver function, and hypogonadism in rats with experimentally induced cirrhosis. Hepatology 31:1379
Cemborain A, Castilla-Cortazar I, Garcia M, Quiroga J, Muguerza B, Picardi A, Santidrian S, Prieto J (1998) Osteopenia in rats with liver cirrhosis: beneficial effects of IGF-I treatment. J Hepatol 28:122–131
Conti E, Andreotti F, Sestito A, Riccardi P, Menini E, Crea F, Maseri A, Lanza GA (2002) Reduced levels of insulin-like growth factor-1 in patients with angina pectoris, positive exercise stress test, and angiographically normal epicardial coronary arteries. Am J Cardiol 89:973–975
D'Ercole AJ, Ye P, Calikoglu AS, Gutierrez-Ospina G (1996) The role of the insulin-like growth factors in the central nervous system. Mol Neurobiol 13:227–255. doi:10.1007/BF02740625
Efstratiadis G, Tsiaousis G, Athyros VG, Karagianni D, Pavlitou-Tsiontsi A, Giannakou-Darda A, Manes C (2006) Total serum insulin-like growth factor-1 and C-reactive protein in metabolic syndrome with or without diabetes. Angiology 57:303–311
Flynn RS, Murthy KS, Grider JR, Kellum JM, Kuemmerle JF (2010) Endogenous IGF-I and alphaVbeta3 integrin ligands regulate increased smooth muscle hyperplasia in stricturing Crohn's disease. Gastroenterology 138:285–293. doi:10.1053/j.gastro.2009.09.003
Gao WQ, Shinsky N, Ingle G, Beck K, Elias KA, Powell-Braxton L (1999) IGF-I deficient mice show reduced peripheral nerve conduction velocities and decreased axonal diameters and respond to exogenous IGF-I treatment. J Neurobiol 39:142–152
Garcia-Fernandez M, Castilla-Cortazar I, Diaz-Sanchez M, Navarro I, Puche JE, Castilla A, Casares AD, Clavijo E, Gonzalez-Baron S (2005) Antioxidant effects of insulin-like growth factor-I (IGF-I) in rats with advanced liver cirrhosis. BMC Gastroenterol 5:7. doi:10.1186/1471-230X-5-7
Garcia-Fernandez M, Delgado G, Puche JE, Gonzalez-Baron S, Castilla Cortazar I (2008) Low doses of insulin-like growth factor I improve insulin resistance, lipid metabolism, and oxidative damage in aging rats. Endocrinology 149:2433–2442. doi:10.1210/en.2007-1190
Giudice LC (1995) The insulin-like growth factor system in normal and abnormal human ovarian follicle development. Am J Med 98:48S–54S
Hankenson FC, Garzel LM, Fischer DD, Nolan B, Hankenson KD (2008) Evaluation of tail biopsy collection in laboratory mice (Mus musculus): vertebral ossification, DNA quantity, and acute behavioral responses. J Am Assoc Lab Anim Sci 47:10–18
Laron Z (1999) Laron syndrome—primary growth hormone resistance. In: Jameson JL (ed) Hormone resistance syndromes. Contemporary endocrinology. Humana Press, Totowa, pp 17–37
Liu JP, Baker J, Perkins AS, Robertson EJ, Efstratiadis A (1993) Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r). Cell 75:59–72
Lupu F, Terwilliger JD, Lee K, Segre GV, Efstratiadis A (2001) Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth. Dev Biol 229:141–162. doi:10.1006/dbio.2000.9975
McAlarney ME, Rizos M, Rocca EG, Nicolay OF, Efstratiadis S (2001) The quantitative and qualitative analysis of the craniofacial skeleton of mice lacking the IGF-I gene. Clin Orthod Res 4:206–219
Mirpuri E, Garcia-Trevijano ER, Castilla-Cortazar I, Berasain C, Quiroga J, Rodriguez-Ortigosa C, Mato JM, Prieto J, Avila MA (2002) Altered liver gene expression in CCl4-cirrhotic rats is partially normalized by insulin-like growth factor-I. Int J Biochem Cell Biol 34:242–252
Mitchell JD, Wokke JH, Borasio GD (2007) Recombinant human insulin-like growth factor I (rhIGF-I) for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev: CD002064. doi: 10.1002/14651858.CD002064.pub2
Muguerza B, Castilla-Cortazar I, Garcia M, Quiroga J, Santidrian S, Prieto J (2001) Antifibrogenic effect in vivo of low doses of insulin-like growth factor-I in cirrhotic rats. Biochim Biophys Acta 1536:185–195
Murillo-Cuesta S, Rodriguez-de la Rosa L, Cediel R, Lassaletta L, Varela-Nieto I (2011) The role of insulin-like growth factor-I in the physiopathology of hearing. Front Mol Neurosci 4:11. doi:10.3389/fnmol.2011.00011
National Institutes of Health (1991) Preparation and maintenance of higher mammals during neuroscience experiments. NIH Publication No. 91–3207. Bethesda: NIH/National Eye Institute
Ohlsson C, Mohan S, Sjogren K, Tivesten A, Isgaard J, Isaksson O, Jansson JO, Svensson J (2009) The role of liver-derived insulin-like growth factor-I. Endocr Rev 30:494–535. doi:10.1210/er.2009-0010
Pascual M, Castilla-Cortazar I, Urdaneta E, Quiroga J, Garcia M, Picardi A, Prieto J (2000) Altered intestinal transport of amino acids in cirrhotic rats: the effect of insulin-like growth factor-I. Am J Physiol Gastrointest Liver Physiol 279:G319–G324
Payne JF, Tangpricha V, Cleveland J, Lynn MJ, Ray R, Srivastava SK (2011) Serum insulin-like growth factor-I in diabetic retinopathy. Mol Vis 17:2318–2324
Perez R, Garcia-Fernandez M, Diaz-Sanchez M, Puche JE, Delgado G, Conchillo M, Muntane J, Castilla-Cortazar I (2008) Mitochondrial protection by low doses of insulin-like growth factor-I in experimental cirrhosis. World J Gastroenterol 14:2731–2739
Picardi A, de Oliveira AC, Muguerza B, Tosar A, Quiroga J, Castilla-Cortazar I, Santidrian S, Prieto J (1997) Low doses of insulin-like growth factor-I improve nitrogen retention and food efficiency in rats with early cirrhosis. J Hepatol 26:191–202
Puche JE, Castilla-Cortazar I (2012) Human conditions of insulin-like growth factor-I (IGF-I) deficiency. J Transl Med 10:224. doi:10.1186/1479-5876-10-224
Puche JE, Garcia-Fernandez M, Muntane J, Rioja J, Gonzalez-Baron S, Castilla Cortazar I (2008) Low doses of insulin-like growth factor-I induce mitochondrial protection in aging rats. Endocrinology 149:2620–2627. doi:10.1210/en.2007-1563
Rio D, Ares MJ, Hannon G, Nilsen T (2010) Purification of RNA using TRIzol (TRI reagent). Cold Spring Harb Protoc 6:prot5439
Rubin CD, Reed B, Sakhaee K, Pak CY (1994) Treating a patient with the Werner syndrome and osteoporosis using recombinant human insulin-like growth factor. Ann Intern Med 121:665–668
Setia S, Sridhar MG (2009) Changes in GH/IGF-1 axis in intrauterine growth retardation: consequences of fetal programming? Horm Metab Res 41:791–798. doi:10.1055/s-0029-1231026
Sjogren K, Liu JL, Blad K, Skrtic S, Vidal O, Wallenius V, LeRoith D, Tornell J, Isaksson OG, Jansson JO, Ohlsson C (1999) Liver-derived insulin-like growth factor I (IGF-I) is the principal source of IGF-I in blood but is not required for postnatal body growth in mice. Proc Natl Acad Sci U S A 96:7088–7092
Svensson J, Sjogren K, Faldt J, Andersson N, Isaksson O, Jansson JO, Ohlsson C (2011) Liver-derived IGF-I regulates mean life span in mice. PLoS One 6:e22640. doi:10.1371/journal.pone.0022640
Switzer M, Rice J, Rice M, Hardin DS (2009) Insulin-like growth factor-I levels predict weight, height and protein catabolism in children and adolescents with cystic fibrosis. J Pediatr Endocrinol Metab 22:417–424
Torres-Aleman I (2007) Targeting insulin-like growth factor-1 to treat Alzheimer's disease. Expert Opin Ther Targets 11:1535–1542. doi:10.1517/14728222.11.12.1535
Tutau F, Rodriguez-Ortigosa C, Puche JE, Juanarena N, Monreal I, Garcia Fernandez M, Clavijo E, Castilla A, Castilla-Cortazar I (2009) Enhanced actions of insulin-like growth factor-I and interferon-alpha co-administration in experimental cirrhosis. Liver Int 29:37–46. doi:10.1111/j.1478-3231.2008.01770.x
Ungvari Z, Csiszar A (2012) The emerging role of IGF-1 deficiency in cardiovascular aging: recent advances. J Gerontol A Biol Sci Med Sci 67:599–610. doi:10.1093/gerona/gls072
Woods KA, Camacho-Hubner C, Savage MO, Clark AJ (1996) Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med 335:1363–1367. doi:10.1056/NEJM199610313351805
Yakar S, Liu JL, Stannard B, Butler A, Accili D, Sauer B, LeRoith D (1999) Normal growth and development in the absence of hepatic insulin-like growth factor I. Proc Natl Acad Sci U S A 96:7324–7329
Ye P, Li L, Richards RG, DiAugustine RP, D'Ercole AJ (2002) Myelination is altered in insulin-like growth factor-I null mutant mice. J Neurosci 22:6041–6051