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

Section on Cellular and Molecular Physiology, Clinical Endocrinology Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Health, Bethesda, Maryland 20892, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 10/2002; 110(6):771-81. DOI: 10.1172/JCI15463
Source: PubMed


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.

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Available from: Jan Frystyk, Oct 02, 2015
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    • "Congenital GH deficiency in humans and laboratory animals results in decreased bone growth and osteopenia (Kasukawa et al., 2004; Ohlsson et al., 1998). However, genetic and epidemiological evidence suggest that there is a correlation between serum IGF-1 and bone rather than serum GH and bone (Yakar et al., 2002). The mouse deficient for Igf1 or Igf1r in osteoblasts display osteopenia and reduced bone formation despite increased GH levels (Stabnov et al., 2002), whereas the mouse overexpressing Igf1 in osteoblast had increased bone mass (Zhao et al., 2000). "
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    • "Growth hormone (GH) is responsible for longitudinal bone growth. A study elegantly demonstrated that a reduction in IGF-1 levels correlated with interstitial growth of long bones in mice (Yakar et al., 2002). It is also suggested that the localized activity of GH on the growth plate is mediated by elevated levels of IGF-1 production, with subsequent stimulation of chondrocyte proliferation and hypertrophy (Nilsson et al., 2005). "
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    • "In addition, muscle mass appears to play a role in the interplay between adipose and bone tissue, likely by mechanical stimuli and also by myokines and other factors secretion [42]. Indeed, muscle is also source of IGF-1, known to be one of the factors which cooperate in the maintenance of skeletal health [43].In addition, lower levels of IGF-1 [27, 41] have been found in obese individuals (unpublished observation) and IGF-1 might play a pivotal role in the mechanism linking obesity to decreased bone density and bone quality [41], by mechanism due to altered osteoblast homeostasis. Indeed, the recent in vivo results, showing a weak increase in osteoclastogenic factors, go against the hypothesis that production of adipokines and inflammatory cytokines by adipose tissue lead to an increased bone resorption inducing a decrease in bone volume [28, 44]. "
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