Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)1575-1586
Number of pages12
JournalJournal of Bone and Mineral Research
Volume28
Issue number7
DOIs
StatePublished - Jul 2013

Keywords

  • BETA-ISLET
  • BONE
  • GLUCOSE TOLERANCE
  • GROWTH HORMONE RECEPTOR
  • IGF-1
  • MICRO-COMPUTED TOMOGRAPHY

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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