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

TLDR

IGF‑1 is a growth‑promoting polypeptide essential for normal development, and in serum it circulates mainly in a 150‑kDa complex with IGFBP‑3 and ALS that prolongs its half‑life and facilitates endocrine actions. The authors generated double‑gene disrupted mice by crossing liver IGF‑1‑deficient (LID) and ALS knockout (ALSKO) strains. These LID+ALSKO mice exhibited markedly reduced serum IGF‑1, significant linear growth retardation, smaller tibial growth plates, lower bone mineral density, thinner cortical bone, and IGF‑1 treatment restored growth‑plate height, demonstrating that a threshold level of circulating IGF‑1 is required for normal bone growth and implicating IGF‑1, IGFBP‑3, and ALS in osteoporosis pathophysiology.

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.