Ternary Complex Formation and IGFBP-3 Proteolytic Activity During Childhood: Age-Dependent Changes

• Published in: The journal of clinical endocrinology and metabolism 2014-10, Vol.99 (10), p.E1988-E1996
• Main Authors: Renes, J. S, van Doorn, J, Hokken-Koelega, A. C. S
• Format: Article
• Language: English
• Subjects: Adolescent; Adolescent Development - physiology; Age Factors; Child; Child Development - physiology; Child, Preschool; Chromatography - methods; Female; Humans; Infant; Infant, Small for Gestational Age - metabolism; Insulin-Like Growth Factor Binding Protein 3 - metabolism; Insulin-Like Growth Factor I - metabolism; Insulin-Like Growth Factor II - metabolism; Iodine Radioisotopes; Male; Ternary Complex Factors - metabolism; Young Adult
• ISSN: 0021-972X; 1945-7197
• DOI: 10.1210/jc.2013-3814

Background: IGF-I is mainly sequestered in a 150-kDa ternary complex with IGF binding protein (IGFBP)-3 and the acid-labile subunit. Data on complex formation and factors influencing formation have not been established. Dissociation of IGF-I from the ternary complex is in part regulated by proteolysis of IGFBP-3, which reduces its affinity for IGF-I. Short small for gestational age (SGA) children have lower IGF-I and IGFBP-3 levels compared with healthy peers. Objective: The objective of the study was to determine complex formation in healthy normal-statured children and assess variables influencing complex formation. Second, we determined complex formation in short SGA children. Design/Methods: Complex formation was assessed using 125I-hIGF-I column chromatography in 70 controls (40 boys), median age 10.6 years, and 40 short SGA children (25 boys), median age 8.6 years. IGFBP-3 was determined by Western immunoblotting. Results: 125I-hIGF-I complex formation showed an age-specific pattern in healthy controls. Variables positively influencing ternary complex formation were higher serum IGF-I levels compared with IGFBP-3 levels (P < .001) and lower serum IGF-II (P < .001) and IGFBP-1 levels (P < .001). In addition, a higher presence of proteolyzed IGFBP-3 negatively influenced 150-kDa complex formation (P = .006). At a young age, healthy children showed considerable IGFBP-3 proteolytic activity, which declined with aging (P < .001). IGFBP-3 proteolytic activity was negatively correlated with IGF-I levels (P < .001). Compared with healthy controls, short SGA children showed reduced IGF-I levels (−1.3 vs 0.1 SD score) and increased proteolyzed IGFBP-3 (35.1% vs 12.2%). Conclusion: Age-specific normative values for 125I-hIGF-I 150-kDa ternary complex formation are presented. A decrease in IGF-I and an increase in IGF-II, IGFBP-1, and IGFBP-3 proteolytic activity associate with reduced 125I-hIGF-I ternary complex formation. Our results suggest that in conditions in which IGF-I levels are low, such as young age and in short SGA children, IGFBP-3 proteolytic activity is increased to ensure IGF-I bioavailability.