An insulin-like growth factor (IGF) binding protein enhances the biologic response to IGF-I

The insulin-like growth factors IGF-I and IGF-II circulate in blood bound to carrier proteins. The higher molecular mass IGF-binding protein complex (150 kDa) is composed of subunits, and one subunit that forms this complex is growth hormone dependent. In addition, many cell types and tissues secrete another form of IGF binding protein that is not growth hormone dependent. Both forms of the IGF binding protein are believed to inactivate the IGFs and to function as delivery systems to tissues. This conclusion was based on studies that determined the effects of impure preparations of these binding proteins or that examined the effect of these proteins only on the insulin-like actions of the IGFs. We report here that a pure preparation of the extracellular form of the IGF binding protein (purified from human amniotic fluid) markedly potentiated replication of several cell types in response to human IGF-I. Secondary cultures of human, mouse, and chicken embryo fibroblasts as well as porcine aortic smooth muscle cells showed marked enhancement of their DNA synthesis response (2.8- to 4.4-fold increases) to IGF-I in the presence of this protein. These responses were synergistic since the sum of the responses to either IGF-I or to the binding protein alone was between 8 and 17% of the increase obtained in cultures exposed to both peptides. The binding protein not only potentiated the DNA synthesis response but also enhanced the increase in cell number in response to IGF-I. This stimulation is specific for growth factors that bind to the binding protein since incubation with insulin, which binds to the type I IGF receptor but not to the binding protein, did not result in potentiation of this response. We conclude that a form of IGF binding protein that is present in extracellular fluids and is secreted by many types of cells can markedly potentiate the cellular response to IGF-I.