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

J Clin Invest. 2002 Sep;110(6):771-81. doi: 10.1172/JCI15463.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Bone Density / physiology*
  • Bone Development / physiology*
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Glycoproteins / genetics*
  • Glycoproteins / metabolism
  • Growth Hormone / blood
  • Insulin-Like Growth Factor Binding Proteins / blood
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism*
  • Liver / metabolism
  • Mice
  • Mice, Inbred Strains
  • Mice, Knockout
  • Tibia / cytology
  • Tibia / metabolism

Substances

  • Carrier Proteins
  • Glycoproteins
  • Insulin-Like Growth Factor Binding Proteins
  • insulin-like growth factor binding protein, acid labile subunit
  • Insulin-Like Growth Factor I
  • Growth Hormone