Unbound (bioavailable) IGF1 enhances somatic growth

Sebastien Elis, Yingjie Wu, Hayden William Courtland, Dara Cannata, Hui Sun, Mordechay Beth-On, Chengyu Liu, Hector Jasper, Horacio Domené, Liliana Karabatas, Clara Guida, Jelena Basta-Pljakic, Luis Cardoso, Clifford J. Rosen, Jan Frystyk, Shoshana Yakar

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Understanding insulin-like growth factor-1 (IGF1) biology is of particular importance because, apart from its role in mediating growth, it plays key roles in cellular transformation, organ regeneration, immune function, development of the musculoskeletal system and aging. IGF1 bioactivity is modulated by its binding to IGF-binding proteins (IGFBPs) and the acid labile subunit (ALS), which are present in serum and tissues. To determine whether IGF1 binding to IGFBPs is necessary to facilitate normal growth and development, we used a gene-targeting approach and generated two novel knock-in mouse models of mutated IGF1, in which the native Igf1 gene was replaced by Des-Igf1 (KID mice) or R3-Igf1 (KIR mice). The KID and KIR mutant proteins have reduced affinity for the IGFBPs, and therefore present as unbound IGF1, or 'free IGF1'. We found that both KID and KIR mice have reduced serum IGF1 levels and a concomitant increase in serum growth hormone levels. Ternary complex formation of IGF1 with the IGFBPs and the ALS was markedly reduced in sera from KID and KIR mice compared with wild type. Both mutant mice showed increased body weight, body and bone lengths, and relative lean mass. We found selective organomegaly of the spleen, kidneys and uterus, enhanced mammary gland complexity, and increased skeletal acquisition. The KID and KIR models show unequivocally that IGF1-complex formation with the IGFBPs is fundamental for establishing normal body and organ size, and that uncontrolled IGF bioactivity could lead to pathological conditions.

Original languageEnglish (US)
Pages (from-to)649-658
Number of pages10
JournalDMM Disease Models and Mechanisms
Volume4
Issue number5
DOIs
StatePublished - Sep 1 2011
Externally publishedYes

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ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Elis, S., Wu, Y., Courtland, H. W., Cannata, D., Sun, H., Beth-On, M., Liu, C., Jasper, H., Domené, H., Karabatas, L., Guida, C., Basta-Pljakic, J., Cardoso, L., Rosen, C. J., Frystyk, J., & Yakar, S. (2011). Unbound (bioavailable) IGF1 enhances somatic growth. DMM Disease Models and Mechanisms, 4(5), 649-658. https://doi.org/10.1242/dmm.006775