Growth Hormone Mediates Pubertal Skeletal Development Independent of Hepatic IGF-1 Production

Growth Hormone Mediates Pubertal Skeletal Development Independent of Hepatic IGF-1 Production

Deficiencies in either growth hormone (GH) or insulin-like growth factor 1 (IGF-1) are associated with reductions in bone size during growth in humans and animal models. Liver-specific IGF-1-deficient (LID) mice, which have 75% reductions in serum IGF-1, were created previously to separate the effec...

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Main Authors: Courtland, Hayden-William, Sun, Hui, Beth-On, Mordechay, Wu, Yingjie, Elis, Sebastien, Rosen, Clifford J, Yakar, Shoshana
Format: Online
Language:English
Published: Wiley Subscription Services, Inc., A Wiley Company 2011
Online Access:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179330/
id pubmed-3179330
recordtype oai_dc
spelling pubmed-31793302012-04-01 Growth Hormone Mediates Pubertal Skeletal Development Independent of Hepatic IGF-1 Production Courtland, Hayden-William Sun, Hui Beth-On, Mordechay Wu, Yingjie Elis, Sebastien Rosen, Clifford J Yakar, Shoshana Original Article Deficiencies in either growth hormone (GH) or insulin-like growth factor 1 (IGF-1) are associated with reductions in bone size during growth in humans and animal models. Liver-specific IGF-1-deficient (LID) mice, which have 75% reductions in serum IGF-1, were created previously to separate the effects of endocrine (serum) IGF-1 from autocrine/paracrine IGF-1. However, LID mice also have two- to threefold increases in GH, and this may contribute to the observed pubertal skeletal phenotype. To clarify the role of GH in skeletal development under conditions of significantly reduced serum IGF-1 levels (but normal tissue IGF-1 levels), we studied the skeletal response of male LID and control mice to GH inhibition by pegvisomant from 4 to 8 weeks of age. Treatment of LID mice with pegvisomant resulted in significant reductions in body weight, femur length (Le), and femur total area (Tt.Ar), as well as further reductions in serum IGF-1 levels by 8 weeks of age, compared with the mean values of vehicle-treated LID mice. Reductions in both Tt.Ar and Le were proportional after treatment with pegvisomant. On the other hand, the relative amount of cortical tissue formed (RCA) in LID mice treated with pegvisomant was significantly less than that in both vehicle-treated LID and control mice, indicating that antagonizing GH action, either directly (through GH receptor signaling inhibition) or indirectly (through further reductions in serum/tissue IGF-1 levels), results in disproportionate reductions in the amount of cortical bone formed. This resulted in bones with significantly reduced mechanical properties (femoral whole-bone stiffness and work to failure were markedly decreased), suggesting that compensatory increases of GH in states of IGF-1 deficiency (LID mice) act to protect against a severe inhibition of bone modeling during growth, which otherwise would result in bones that are too weak for normal and/or extreme loading conditions. © 2011 American Society for Bone and Mineral Research. Wiley Subscription Services, Inc., A Wiley Company 2011-04 2010-10-06 /pmc/articles/PMC3179330/ /pubmed/20928887 http://dx.doi.org/10.1002/jbmr.265 Text en Copyright © 2011 American Society for Bone and Mineral Research http://creativecommons.org/licenses/by/2.5/ Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.
repository_type Open Access Journal
institution_category Foreign Institution
institution US National Center for Biotechnology Information
building NCBI PubMed
collection Online Access
language English
format Online
author Courtland, Hayden-William
Sun, Hui
Beth-On, Mordechay
Wu, Yingjie
Elis, Sebastien
Rosen, Clifford J
Yakar, Shoshana
spellingShingle Courtland, Hayden-William
Sun, Hui
Beth-On, Mordechay
Wu, Yingjie
Elis, Sebastien
Rosen, Clifford J
Yakar, Shoshana
Growth Hormone Mediates Pubertal Skeletal Development Independent of Hepatic IGF-1 Production
author_facet Courtland, Hayden-William
Sun, Hui
Beth-On, Mordechay
Wu, Yingjie
Elis, Sebastien
Rosen, Clifford J
Yakar, Shoshana
author_sort Courtland, Hayden-William
title Growth Hormone Mediates Pubertal Skeletal Development Independent of Hepatic IGF-1 Production
title_short Growth Hormone Mediates Pubertal Skeletal Development Independent of Hepatic IGF-1 Production
title_full Growth Hormone Mediates Pubertal Skeletal Development Independent of Hepatic IGF-1 Production
title_fullStr Growth Hormone Mediates Pubertal Skeletal Development Independent of Hepatic IGF-1 Production
title_full_unstemmed Growth Hormone Mediates Pubertal Skeletal Development Independent of Hepatic IGF-1 Production
title_sort growth hormone mediates pubertal skeletal development independent of hepatic igf-1 production
description Deficiencies in either growth hormone (GH) or insulin-like growth factor 1 (IGF-1) are associated with reductions in bone size during growth in humans and animal models. Liver-specific IGF-1-deficient (LID) mice, which have 75% reductions in serum IGF-1, were created previously to separate the effects of endocrine (serum) IGF-1 from autocrine/paracrine IGF-1. However, LID mice also have two- to threefold increases in GH, and this may contribute to the observed pubertal skeletal phenotype. To clarify the role of GH in skeletal development under conditions of significantly reduced serum IGF-1 levels (but normal tissue IGF-1 levels), we studied the skeletal response of male LID and control mice to GH inhibition by pegvisomant from 4 to 8 weeks of age. Treatment of LID mice with pegvisomant resulted in significant reductions in body weight, femur length (Le), and femur total area (Tt.Ar), as well as further reductions in serum IGF-1 levels by 8 weeks of age, compared with the mean values of vehicle-treated LID mice. Reductions in both Tt.Ar and Le were proportional after treatment with pegvisomant. On the other hand, the relative amount of cortical tissue formed (RCA) in LID mice treated with pegvisomant was significantly less than that in both vehicle-treated LID and control mice, indicating that antagonizing GH action, either directly (through GH receptor signaling inhibition) or indirectly (through further reductions in serum/tissue IGF-1 levels), results in disproportionate reductions in the amount of cortical bone formed. This resulted in bones with significantly reduced mechanical properties (femoral whole-bone stiffness and work to failure were markedly decreased), suggesting that compensatory increases of GH in states of IGF-1 deficiency (LID mice) act to protect against a severe inhibition of bone modeling during growth, which otherwise would result in bones that are too weak for normal and/or extreme loading conditions. © 2011 American Society for Bone and Mineral Research.
publisher Wiley Subscription Services, Inc., A Wiley Company
publishDate 2011
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3179330/
_version_ 1611477135957950464

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