Document Detail


Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor.
MedLine Citation:
PMID:  23456957     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Yingjie Wu; Hui Sun; Jelena Basta-Pljakic; Luis Cardoso; Oran D Kennedy; Hector Jasper; Horacio Domené; Liliana Karabatas; Clara Guida; Mitchell B Schaffler; Clifford J Rosen; Shoshana Yakar
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research     Volume:  28     ISSN:  1523-4681     ISO Abbreviation:  J. Bone Miner. Res.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-06-19     Completed Date:  2013-11-04     Revised Date:  2013-12-02    
Medline Journal Info:
Nlm Unique ID:  8610640     Medline TA:  J Bone Miner Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1575-86     Citation Subset:  IM    
Copyright Information:
Copyright © 2013 American Society for Bone and Mineral Research.
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MeSH Terms
Descriptor/Qualifier:
Animals
Bone Development*
Bone and Bones / metabolism*,  pathology
Disease Models, Animal
Female
Hormone Replacement Therapy
Humans
Insulin-Like Growth Factor I / genetics,  metabolism*,  therapeutic use
Laron Syndrome / blood*,  drug therapy,  genetics
Male
Mice
Mice, Mutant Strains
Receptors, Somatotropin / genetics,  metabolism*
Transgenes
Grant Support
ID/Acronym/Agency:
AG034198/AG/NIA NIH HHS; AR041210/AR/NIAMS NIH HHS; AR054919/AR/NIAMS NIH HHS; AR055141/AR/NIAMS NIH HHS; AR057139/AR/NIAMS NIH HHS; AR45433/AR/NIAMS NIH HHS; R01 AR054919/AR/NIAMS NIH HHS; R01 AR055141/AR/NIAMS NIH HHS
Chemical
Reg. No./Substance:
0/Receptors, Somatotropin; 0/insulin-like growth factor-1, mouse; 67763-96-6/Insulin-Like Growth Factor I

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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