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 human insulin-like growth factor-binding protein-1 (rhIGFBP-1) alone and in combination with recombinant human insulin-like growth factor-I (rhIGF-I) or human GH on weight gain and tibial epiphysis enlargement in hypophysectomized rats. rhIGF-I, given twice daily by sc injection, increased both growth parameters in a dose-dependent manner. Coadministration of increasing amounts of rhIGFBP-1 with a constant amount of rhIGF-I (80 micrograms/injection, given twice daily) resulted in a dose-dependent inhibition of the growth-promoting effects of rhIGF-I. A rhIGFBP-1 dose of 9.8 micrograms/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 micrograms/injection (IGFBP-1/IGF-I molar ratio of 5:1) resulted in 78% or greater inhibition of rhIGF-I-stimulated growth (P < 0.05). rhIGFBP-1 doses of 48 and 240 micrograms/injection (IGFBP-1/IGF-I molar ratios of 0.2:1 and 1:1, respectively) had intermediate inhibitory effects. None of the rhIGFBP-1 doses potentiated the growth-promoting effects of rhIGF-I. Rats treated with rhIGFBP-1 alone (twice daily injections of 9.8, 48, 240, or 1200 micrograms) showed no significant differences in growth parameters compared to rats treated with vehicle. Coadministration of rhIGFBP-1 (1200 micrograms/injection, given twice 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 that nonphosphorylated rhIGFBP-1 can inhibit the growth-promoting effects of rhIGF-I and GH in vivo. The results suggest that in addition to its proposed role in glucose homeostasis, IGFBP-1 may play a role in inhibiting somatic growth and other physiological functions stimulated by IGF-I and GH.
Cox
G N
GN
Synergen, Inc., Boulder, Colorado 80301.
McDermott
M J
MJ
Merkel
E
E
Stroh
C A
CA
Ko
S C
SC
Squires
C H
CH
Gleason
T M
TM
Russell
D
D
D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006128:Growth / Q000187:drug effects* / Q000502:physiology; D013006:Growth Hormone / Q000494:pharmacology*; D006801:Humans; D007016:Hypophysectomy; D018970:Insulin-Like Growth Factor Binding Protein 1; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology*; D008297:Male; D008969:Molecular Sequence Data; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000494:pharmacology; D015430:Weight Gain / Q000187:drug effects
D002352:Carrier Proteins; D018970:Insulin-Like Growth Factor Binding Protein 1; D011994:Recombinant Proteins; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone