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

Journal of Bone and Mineral Research

John Wiley & Sons, Inc.

Lugar: Hoboken, NJ 07030; Año: 2013 vol. 28 p. 1575 - 1586

1523-4681

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.