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

46 Scopus citations

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 1 2010

Keywords

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

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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