title: Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor.
abstract: States of growth hormone (GH) resistance, such those observed in Laron dwarf patients, are characterized by mutations in the GH receptor (GHR), decreased serum and tissue IGF-1 levels, impaired glucose tolerance, and impaired skeletal acquisition. IGF-1 replacement therapy in such patients increases growth velocity but does not normalize growth. Herein we combined the GH-resistant (GHR knockout [GHRKO]) mouse model with mice expressing the hepatic Igf-1 transgene (HIT) to generate the GHRKO-HIT mouse model. In GHRKO-HIT mice, serum IGF-1 levels were restored via transgenic expression of Igf-1, allowing us to study how endocrine IGF-1 affects growth, metabolic homeostasis, and skeletal integrity. We show that in a GH-resistant state, normalization of serum IGF-1 improved body adiposity and restored glucose tolerance but was insufficient to support normal skeletal growth, resulting in an osteopenic skeletal phenotype. The inability of serum IGF-1 to restore skeletal integrity in the total absence of GHR likely resulted from reduced skeletal Igf-1 gene expression, blunted GH-mediated effects on the skeleton that are independent of serum or tissue IGF-1, and poor delivery of IGF-1 to the tissues. These findings are consistent with clinical data showing that IGF-I replacement therapy in patients with Laron syndrome does not achieve full skeletal growth.
authors: David B. Kriser Dental Center, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA.
authors: Yingjie
authors: Y
authors: Wu
authors: Hui
authors: H
authors: Sun
authors: Jelena
authors: J
authors: Basta-Pljakic
authors: Luis
authors: L
authors: Cardoso
authors: Oran D
authors: OD
authors: Kennedy
authors: Hector
authors: H
authors: Jasper
authors: Horacio
authors: H
authors: Domené
authors: Liliana
authors: L
authors: Karabatas
authors: Clara
authors: C
authors: Guida
authors: Mitchell B
authors: MB
authors: Schaffler
authors: Clifford J
authors: CJ
authors: Rosen
authors: Shoshana
authors: S
authors: Yakar
mesh_terms: D000818:Animals; D001846:Bone Development; D001842:Bone and Bones / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D020249:Hormone Replacement Therapy; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D046150:Laron Syndrome / Q000097:blood* / Q000188:drug therapy / Q000235:genetics; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D011986:Receptors, Somatotropin / Q000235:genetics / Q000378:metabolism*; D019076:Transgenes
chemical_list: D011986:Receptors, Somatotropin; C519530:insulin-like growth factor-1, mouse; D007334:Insulin-Like Growth Factor I