Deficiency of the Circulating Insulin-like Growth Factor System Associated with Inactivation of the Acid-Labile Subunit Gene

Abstract

he growth-promoting actions of growth hormone were originally hypothesized to be mediated through a circulating liver-generated sulfation factor that later came to be known as insulin-like growth factor I (IGF-I). 1 This growth factor is produced in almost every tissue in the body. 2 In the cartilage growth plate, growth hormone-induced IGF-I 3 acts locally through autocrineparacrine mechanisms. 4 Some 80 to 85 percent of IGF-I circulates as a 150-kD ternary complex that includes the ligand itself, IGF-binding protein 3, and an acid-labile subunit. 5 The acid-labile subunit is a glycoprotein found almost exclusively in the circulation and produced in the liver under growth hormone stimulation. 6,7 This subunit stabilizes the IGF-IGF-binding protein 3 complex, reduces the passage of IGF-I to the extravascular compartment, and extends its half-life. 8 Recently, the role of circulating IGF-I in growth has been challenged by the finding that specific disruption of the hepatic igf1 gene in mice, the main source of circulating IGF-I, 9,10 or the inactivation of the gene encoding the acidlabile subunit protein ( igfals ) in mice 11 has a minor effect on growth, despite causing a profound reduction in the serum IGF-I level.