STUDIES ON THE MECHANISMS BY WHICH INSULIN-LIKE GROWTH-FACTOR (IGF) BINDING PROTEIN-4 (IGFBP-4) AND IGFBP-5 MODULATE IGF ACTIONS IN BONE-CELLS

The growth potentiating effects of the insulin-like growth factor (IGF )-I and IGF-II are modulated by a family of six insulin-like growth fa ctor binding proteins (IGFBPs). Despite the similarity in amino acid s equences of the IGFBPs, their effects on the growth of bone cells diff er. Studies on the molecular mechanisms for IGFBP-4 actions revealed t hat coincubation of bone cells with IGFBP-4 and I-125-IGF-I or I-125-I GF-II decreased the binding of both of these ligands in a dose-depende nt manner. In addition, IGFBP-4 decreased the binding of IGF-I tracer to purified type I IGF receptor. These data in conjunction with data s howing that IGFBP-4 had no effect on cell proliferation induced by ana logs of IGF-I or IGF-II, which exhibited > 100-fold reduced affinity f or binding to IGFBP-4 suggest that IGFBP-4 may inhibit IGF action by p reventing the binding of ligand to its membrane receptor. In contrast to IGFBP-4, IGFBP-5 treatment increased the binding of IGF tracer to b one cells but did not increase the binding of I-125-IGF-I to, type I I GF receptor. Studies on the mechanism by which IGFBP-5 increased the b inding of I-125-IGF tracer to bone cells suggest that IGFBP-5 could fa cilitate IGF binding by a mechanism in which IGFBP-5 has cell surface binding sites independent of IGF receptors. These data in conjunction with the findings that IGFBP-5 potentiated cell proliferation even in the presence of those same IGF analogs that exhibited > 200-fold reduc ed affinity for binding to IGFBP-5, suggest that IGFBP-5 may in part s timulate bone cell proliferation by an IGF-independent mechanism invol ving IGFBP-5 specific cell surface binding sites.