Mode of growth hormone action in osteoblasts

Douglas J. DiGirolamo, Aditi Mukherjee, Keertik Fulzele, Yujun Gan, Xuemei Cao, Stuart J. Frank, Thomas L. Clemens

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

Growth hormone (GH) affects bone size and mass in part through stimulating insulin-like growth factor type 1 (IGF-1) production in liver and bone. Whether GH acts independent of IGF-1 in bone remains unclear. To define the mode of GH action in bone, we have used a Cre/loxP system in which the type 1 IGF-1 receptor (Igf1r) has been disrupted specifically in osteoblasts in vitro and in vivo. Calvarial osteoblasts from mice homozygous for the floxed IGF-1R allele (IGF-1Rflox/flox) were infected with adenoviral vectors expressing Cre. Disruption of IGF-1R mRNA(>90%) was accompanied by near elimination of IGF-1R protein but retention of GHR protein. GH-induced STAT5 activation was consistently greater in osteoblasts with an intact IGF-1R. Osteoblasts lacking IGF-1R retained GH-induced ERK and Akt phosphorylation and GH-stimulated IGF-1 and IGFBP-3 mRNA expression. GH-induced osteoblast proliferation was abolished by Cre-mediated disruption of the IGF-1R or co-incubation of cells with an IGF-1-neutralizing antibody. By contrast, GH inhibited apoptosis in osteoblasts lacking the IGF-1R. To examine the effects of GH on osteoblasts in vivo, mice wild type for the IGF-1R treated with GH subcutaneously for 7 days showed a doubling in the number of osteoblasts lining trabecular bone, whereas osteoblast numbers in similarly treated mice lacking the IGF-1R in osteoblasts were not significantly affected. These results indicate that although direct IGF-1R-independent actions of GH on osteoblast apoptosis can be demonstrated in vitro, IGF-1R is required for anabolic effects of GH in osteoblasts in vivo.

Original languageEnglish (US)
Pages (from-to)31666-31674
Number of pages9
JournalJournal of Biological Chemistry
Volume282
Issue number43
DOIs
StatePublished - Oct 26 2007

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    DiGirolamo, D. J., Mukherjee, A., Fulzele, K., Gan, Y., Cao, X., Frank, S. J., & Clemens, T. L. (2007). Mode of growth hormone action in osteoblasts. Journal of Biological Chemistry, 282(43), 31666-31674. https://doi.org/10.1074/jbc.M705219200