Circulating levels of IGF-1 directly regulate bone growth and density

Shoshana Yakar, Clifford J. Rosen, Wesley G. Beamer, Cheryl L. Ackert-Bicknell, Yiping Wu, Jun Li Liu, Guck T. Ooi, Jennifer Setser, Jan Frystyk, Yves R. Boisclair, Derek LeRoith

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Abstract

IGF-1 is a growth-promoting polypeptide that is essential for normal growth and development. In serum, the majority of the IGFs exist in a 150-kDa complex including the IGF molecule, IGF binding protein 3 (IGFBP-3), and the acid labile subunit (ALS). This complex prolongs the half-life of serum IGFs and facilitates their endocrine actions. Liver IGF-1-deficient (LID) mice and ALS knockout (ALSKO) mice exhibited relatively normal growth and development, despite having 75% and 65% reductions in serum IGF-1 levels, respectively. Double gene disrupted mice were generated by crossing LID+ALSKO mice. These mice exhibited further reductions in serum IGF-1 levels and a significant reduction in linear growth. The proximal growth plates of the tibiae of LID+ALSKO mice were smaller in total height as well as in the height of the proliferative and hypertrophic zones of chondrocytes. There was also a 10% decrease in bone mineral density and a greater than 35% decrease in periosteal circumference and cortical thickness in these mice. IGF-1 treatment for 4 weeks restored the total height of the proximal growth plate of the tibia. Thus, the double gene disruption LID+ALSKO mouse model demonstrates that a threshold concentration of circulating IGF-1 is necessary for normal bone growth and suggests that IGF-1, IGFBP-3, and ALS play a prominent role in the pathophysiology of osteoporosis.

Original languageEnglish (US)
Pages (from-to)771-781
Number of pages11
JournalJournal of Clinical Investigation
Volume110
Issue number6
DOIs
StatePublished - Sep 2002

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Yakar, S., Rosen, C. J., Beamer, W. G., Ackert-Bicknell, C. L., Wu, Y., Liu, J. L., Ooi, G. T., Setser, J., Frystyk, J., Boisclair, Y. R., & LeRoith, D. (2002). Circulating levels of IGF-1 directly regulate bone growth and density. Journal of Clinical Investigation, 110(6), 771-781. https://doi.org/10.1172/JCI0215463