Elevated serum levels of IGF-1 are sufficient to establish normal body size and skeletal properties even in the absence of tissue IGF-1

Sebastien Elis, Hayden William Courtland, Yingjie Wu, Clifford J. Rosen, Hui Sun, Karl J. Jepsen, Robert J. Majeska, Shoshana Yakar

Research output: Contribution to journalArticle

Abstract

Use of recombinant insulin-like growth factor 1 (IGF-1) as a treatment for primary IGF-1 deficiency in children has become increasingly common. When untreated, primary IGF-1 deficiency may lead to a range of metabolic disorders, including lipid abnormalities, insulin resistance, and decreased bone density. To date, results of this therapy are considered encouraging; however, our understanding of the role played by IGF-1 during development remains limited. Studies on long-term treatment with recombinant IGF-1 in both children and animals are few. Here, we used two novel transgenic mouse strains to test the long-term effects of elevated circulating IGF-1 on body size and skeletal development. Overexpression of the rat igf1 transgene in livers of mice with otherwise normal IGF-1 expression (HIT mice) resulted in approximately threefold increases in serum IGF-1 levels throughout growth, as well as greater body mass and enhanced skeletal size, architecture, and mechanical properties. When the igf1 transgene was overexpressed in livers of igf1 null mice (KO-HIT), the comparably elevated serum IGF-1 failed to overcome growth and skeletal deficiencies during neonatal and early postnatal growth. However, between 4 and 16 weeks of age, increased serum IGF-1 fully compensated for the absence of locally produced IGF-1 because body weights and lengths of KO-HIT mice became comparable with controls. Furthermore, micro-computed tomography (μCT) analysis revealed that early deficits in skeletal structure of KO-HIT mice were restored to control levels by adulthood. Our data indicate that in the absence of tissue igf1 gene expression, maintaining long-term elevations in serum IGF-1 is sufficient to establish normal body size, body composition, and both skeletal architecture and mechanical function.

Original languageEnglish (US)
Pages (from-to)1257-1266
Number of pages10
JournalJournal of Bone and Mineral Research
Volume25
Issue number6
DOIs
StatePublished - Jun 2010

Fingerprint

Body Size
Somatomedins
Serum
Transgenes
Growth
Liver
Body Composition
Bone Density
Transgenic Mice
Insulin Resistance
Therapeutics
Tomography
Body Weight
Lipids
Gene Expression

Keywords

  • Bone
  • Endocrine IGF-1
  • IGF-1
  • IGF-1KO
  • Mechanical properties
  • Micro-computed tomography
  • Transgenic mice

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism

Cite this

Elevated serum levels of IGF-1 are sufficient to establish normal body size and skeletal properties even in the absence of tissue IGF-1. / Elis, Sebastien; Courtland, Hayden William; Wu, Yingjie; Rosen, Clifford J.; Sun, Hui; Jepsen, Karl J.; Majeska, Robert J.; Yakar, Shoshana.

In: Journal of Bone and Mineral Research, Vol. 25, No. 6, 06.2010, p. 1257-1266.

Research output: Contribution to journalArticle

Elis, Sebastien ; Courtland, Hayden William ; Wu, Yingjie ; Rosen, Clifford J. ; Sun, Hui ; Jepsen, Karl J. ; Majeska, Robert J. ; Yakar, Shoshana. / Elevated serum levels of IGF-1 are sufficient to establish normal body size and skeletal properties even in the absence of tissue IGF-1. In: Journal of Bone and Mineral Research. 2010 ; Vol. 25, No. 6. pp. 1257-1266.
@article{db2e9c69ddaa40b38425aaf4c57021f1,
title = "Elevated serum levels of IGF-1 are sufficient to establish normal body size and skeletal properties even in the absence of tissue IGF-1",
abstract = "Use of recombinant insulin-like growth factor 1 (IGF-1) as a treatment for primary IGF-1 deficiency in children has become increasingly common. When untreated, primary IGF-1 deficiency may lead to a range of metabolic disorders, including lipid abnormalities, insulin resistance, and decreased bone density. To date, results of this therapy are considered encouraging; however, our understanding of the role played by IGF-1 during development remains limited. Studies on long-term treatment with recombinant IGF-1 in both children and animals are few. Here, we used two novel transgenic mouse strains to test the long-term effects of elevated circulating IGF-1 on body size and skeletal development. Overexpression of the rat igf1 transgene in livers of mice with otherwise normal IGF-1 expression (HIT mice) resulted in approximately threefold increases in serum IGF-1 levels throughout growth, as well as greater body mass and enhanced skeletal size, architecture, and mechanical properties. When the igf1 transgene was overexpressed in livers of igf1 null mice (KO-HIT), the comparably elevated serum IGF-1 failed to overcome growth and skeletal deficiencies during neonatal and early postnatal growth. However, between 4 and 16 weeks of age, increased serum IGF-1 fully compensated for the absence of locally produced IGF-1 because body weights and lengths of KO-HIT mice became comparable with controls. Furthermore, micro-computed tomography (μCT) analysis revealed that early deficits in skeletal structure of KO-HIT mice were restored to control levels by adulthood. Our data indicate that in the absence of tissue igf1 gene expression, maintaining long-term elevations in serum IGF-1 is sufficient to establish normal body size, body composition, and both skeletal architecture and mechanical function.",
keywords = "Bone, Endocrine IGF-1, IGF-1, IGF-1KO, Mechanical properties, Micro-computed tomography, Transgenic mice",
author = "Sebastien Elis and Courtland, {Hayden William} and Yingjie Wu and Rosen, {Clifford J.} and Hui Sun and Jepsen, {Karl J.} and Majeska, {Robert J.} and Shoshana Yakar",
year = "2010",
month = "6",
doi = "10.1002/jbmr.20",
language = "English (US)",
volume = "25",
pages = "1257--1266",
journal = "Journal of Bone and Mineral Research",
issn = "0884-0431",
publisher = "Wiley-Blackwell",
number = "6",

}

TY - JOUR

T1 - Elevated serum levels of IGF-1 are sufficient to establish normal body size and skeletal properties even in the absence of tissue IGF-1

AU - Elis, Sebastien

AU - Courtland, Hayden William

AU - Wu, Yingjie

AU - Rosen, Clifford J.

AU - Sun, Hui

AU - Jepsen, Karl J.

AU - Majeska, Robert J.

AU - Yakar, Shoshana

PY - 2010/6

Y1 - 2010/6

N2 - Use of recombinant insulin-like growth factor 1 (IGF-1) as a treatment for primary IGF-1 deficiency in children has become increasingly common. When untreated, primary IGF-1 deficiency may lead to a range of metabolic disorders, including lipid abnormalities, insulin resistance, and decreased bone density. To date, results of this therapy are considered encouraging; however, our understanding of the role played by IGF-1 during development remains limited. Studies on long-term treatment with recombinant IGF-1 in both children and animals are few. Here, we used two novel transgenic mouse strains to test the long-term effects of elevated circulating IGF-1 on body size and skeletal development. Overexpression of the rat igf1 transgene in livers of mice with otherwise normal IGF-1 expression (HIT mice) resulted in approximately threefold increases in serum IGF-1 levels throughout growth, as well as greater body mass and enhanced skeletal size, architecture, and mechanical properties. When the igf1 transgene was overexpressed in livers of igf1 null mice (KO-HIT), the comparably elevated serum IGF-1 failed to overcome growth and skeletal deficiencies during neonatal and early postnatal growth. However, between 4 and 16 weeks of age, increased serum IGF-1 fully compensated for the absence of locally produced IGF-1 because body weights and lengths of KO-HIT mice became comparable with controls. Furthermore, micro-computed tomography (μCT) analysis revealed that early deficits in skeletal structure of KO-HIT mice were restored to control levels by adulthood. Our data indicate that in the absence of tissue igf1 gene expression, maintaining long-term elevations in serum IGF-1 is sufficient to establish normal body size, body composition, and both skeletal architecture and mechanical function.

AB - Use of recombinant insulin-like growth factor 1 (IGF-1) as a treatment for primary IGF-1 deficiency in children has become increasingly common. When untreated, primary IGF-1 deficiency may lead to a range of metabolic disorders, including lipid abnormalities, insulin resistance, and decreased bone density. To date, results of this therapy are considered encouraging; however, our understanding of the role played by IGF-1 during development remains limited. Studies on long-term treatment with recombinant IGF-1 in both children and animals are few. Here, we used two novel transgenic mouse strains to test the long-term effects of elevated circulating IGF-1 on body size and skeletal development. Overexpression of the rat igf1 transgene in livers of mice with otherwise normal IGF-1 expression (HIT mice) resulted in approximately threefold increases in serum IGF-1 levels throughout growth, as well as greater body mass and enhanced skeletal size, architecture, and mechanical properties. When the igf1 transgene was overexpressed in livers of igf1 null mice (KO-HIT), the comparably elevated serum IGF-1 failed to overcome growth and skeletal deficiencies during neonatal and early postnatal growth. However, between 4 and 16 weeks of age, increased serum IGF-1 fully compensated for the absence of locally produced IGF-1 because body weights and lengths of KO-HIT mice became comparable with controls. Furthermore, micro-computed tomography (μCT) analysis revealed that early deficits in skeletal structure of KO-HIT mice were restored to control levels by adulthood. Our data indicate that in the absence of tissue igf1 gene expression, maintaining long-term elevations in serum IGF-1 is sufficient to establish normal body size, body composition, and both skeletal architecture and mechanical function.

KW - Bone

KW - Endocrine IGF-1

KW - IGF-1

KW - IGF-1KO

KW - Mechanical properties

KW - Micro-computed tomography

KW - Transgenic mice

UR - http://www.scopus.com/inward/record.url?scp=77953481694&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77953481694&partnerID=8YFLogxK

U2 - 10.1002/jbmr.20

DO - 10.1002/jbmr.20

M3 - Article

VL - 25

SP - 1257

EP - 1266

JO - Journal of Bone and Mineral Research

JF - Journal of Bone and Mineral Research

SN - 0884-0431

IS - 6

ER -