RECOMBINANT HUMAN INSULIN-LIKE GROWTH-FACTOR (IGF)-BINDING PROTEIN-1 INHIBITS SOMATIC GROWTH STIMULATED BY IGF-I AND GROWTH-HORMONE IN HYPOPHYSECTOMIZED RATS

We have examined the effects of exogenously administered recombinant h uman insulin-like growth factor-binding protein-1 (rhIGFBP-1) alone an d in combination with recombinant human insulin-like growth factor-I ( rhIGF-I) or human GH on weight gain and tibial epiphysis enlargement i n hypophysectomized rats, rhIGF-I, given twice daily by sc injection, increased both growth parameters in a dose-dependent manner. Coadminis tration of increasing amounts of rhIGFBP-1 with a constant amount of r hIGF-I (80 mu g/injection, given twice daily) resulted in a dose-depen dent inhibition of the growth-promoting effects of rhIGF-I. A rhIGFBP- 1 dose of 9.8 mu g/injection (an IGFBP-1/IGF-I molar ratio of 0.04:1) caused no significant effect on rhIGF-I-stimulated growth parameters, whereas a rhIGFBP-1 dose of 1200 mu g/injection (IGFBP-1/IGF-I molar r atio of 5:1) resulted in 78% or greater inhibition of rhIGF-I-stimulat ed growth (P < 0.05). rhIGFBP-1 doses of 48 and 240 mu g/injection (IG FBP-1/IGF-I molar ratios of 0.2:1 and 1:1, respectively) had intermedi ate inhibitory effects. None of the rhIGFBP-1 doses potentiated the gr owth-promoting effects of rhIGF-I. Rats treated with rhIGFBP-1 alone ( twice daily injections of 9.8, 48, 240, or 1200 mu g) showed no signif icant differences in growth parameters compared to rats treated with v ehicle. Coadministration of rhIGFBP-1 (1200 mu g/injection, given twic e daily) with GH (15 mU/injection, given twice daily) inhibited weight gain and tibial epiphysis enlargement stimulated by GH by at least 50 % in each of two experiments (P < 0.05). These studies demonstrate tha t nonphosphorylated rhIGFBP-1 can inhibit the growth-promoting effects of rhIGF-I and GH in vivo. The results suggest that in addition to it s proposed role in glucose homeostasis, IGFBP-1 may play a role in inh ibiting somatic growth and other physiological functions stimulated by IGF-I and GH.