Insulin-like growth factor I (IGF-I) replacement during growth hormone receptor antagonism normalizes serum IGF-binding protein-3 and markers of bone formation in ovariectomized rhesus monkeys.
Previous work from this laboratory has shown that the constant sc infusion of insulin-like growth factor I (IGF-I) to normal pituitary monkeys results in a sustained elevation in circulating concentrations of IGF-binding protein-3 (IGFBP-3), whereas the acute administration of IGF-I to monkeys pretreated with a GH receptor antagonist produces a brief, but significant, elevation in serum IGFBP-3. The present study tested the hypothesis that the constant infusion of IGF-I would normalize serum concentrations of IGFBP-3 in females treated with the GH receptor antagonist. To assess the biological significance of these effects, serum levels of the acid-labile subunit (ALS) and biomarkers for bone formation, osteocalcin, and collagen type I C-terminal propeptide, were also examined. Five female rhesus monkeys were studied over 21 consecutive days involving 7 days of baseline, 7 days of treatment with the GH receptor antagonist (1.0 mg/kg-week, sc), and 7 days of treatment with the GH receptor antagonist supplemented with IGF-I (120 microg/kg x day, sc infusion with osmotic minipump). Within 48 h of the initiation of treatment with the GH receptor antagonist, serum IGF-I and IGFBP-3 were decreased by 40% and 18% from baseline, respectively, and levels continued to decline through the remainder of treatment. However, within 48 h of the initiation of IGF-I administration during GH receptor antagonist treatment, both serum IGF-I and IGFBP-3 were elevated and normalized to baseline values. Serum concentrations of ALS were also decreased by GH antagonism, but levels increased in some (n = 2), but not all, subjects upon administration of IGF-I. Size exclusion ultrafiltration indicated that the amount of IGF-I found in the high molecular mass complex (>100 kDa) decreased significantly during GH antagonism, but was similar during the baseline and IGF-I infusion phases. Finally, treatment with the GH receptor antagonist also significantly reduced serum levels of osteocalcin and collagen type I C-terminal propeptide, an effect reversed by the addition of IGF-I. These data support the hypothesis that IGF-I increases serum concentrations of IGFBP-3 when endogenous GH action is compromised and that such treatment produces biologically active IGF-I, as evidenced by normalization of biomarkers for bone formation. These results indicate that IGF-I administration during GH receptor antagonism restores circulating levels of IGFBP-3 and the amount of IGF-I found in the high molecular mass complex to levels observed during baseline conditions. It remains to be determined whether IGF-I directly affects hepatic synthesis and secretion of IGFBP-3 and what role IGF-I has in the direct regulation of ALS in the monkey.
Wilson
M E
ME
Yerkes Primate Research Center, Emory University, Lawrenceville, Georgia 30043, USA. markw@rmy.emory.edu
D000818:Animals; D015415:Biomarkers / Q000097:blood*; D001846:Bone Development; D002352:Carrier Proteins / Q000097:blood; D003094:Collagen / Q000097:blood; D024042:Collagen Type I; D005260:Female; D006023:Glycoproteins / Q000097:blood; D013006:Growth Hormone / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors*; D019382:Human Growth Hormone / Q000031:analogs & derivatives; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood*; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage*; D008253:Macaca mulatta; D015675:Osteocalcin / Q000097:blood; D010052:Ovariectomy; D010455:Peptides / Q000097:blood
D015415:Biomarkers; D002352:Carrier Proteins; D024042:Collagen Type I; D006023:Glycoproteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D010455:Peptides; C052929:collagen type I trimeric cross-linked peptide; C075944:insulin-like growth factor binding protein, acid labile subunit; D015675:Osteocalcin; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D003094:Collagen; C406545:pegvisomant