ESPE Abstracts (2014) 82 P-D-2-1-409

Ternary Complex Formation and IGFBP3 Proteolytic Activity During Childhood: Age-Dependent Changes

Judith S Renesa, Jaap van Doornc & Anita C S Hokken-Koelegaa,b

aErasmus MC – Sophia Children’s Hospital, Rotterdam, The Netherlands; bDutch Growth Research Foundation, Rotterdam, The Netherlands; cUniversity Medical Center Utrecht, Utrech, The Netherlands

Background: IGF1 is mainly sequestered in a 150 kDa ternary complex with IGFBP3 and the acid-labile subunit (ALS). Dissociation of IGF1 from the ternary complex is in part regulated by proteolysis of IGFBP3, which reduces its affinity for IGF1. Short children born SGA have lower IGF1 and IGFBP3 levels compared to healthy peers.

Objective and hypotheses: To determine complex formation in healthy normal statured children, and assess variables influencing complex formation. Secondly, we determined complex formation in short SGA children. We hypothesized that complex formation is less adequate in these children thus contributing to their short stature.

Method: Complex formation was assessed using 125I-hIGF1 column chromatography in 70 controls (40 boys), median age 10.6 years, and 40 short SGA children (25 boys), median age 8.6 years. IGFBP3 was determined by western immunoblotting.

Results: In controls, 125I-hIGF1 ternary complex formation was strongly positively correlated with age (P<0.001). Variables positively influencing ternary complex formation were higher serum IGF1 levels compared to IGFBP3 levels (P<0.001), and lower serum IGF2 (P<0.001) and IGFBP1 levels (P<0.001). In addition, a higher presence of proteolyzed IGFBP3 negatively influenced ternary complex formation (P=0.006). At a young age, healthy children showed considerable IGFBP3 proteolytic activity which declined with aging (P<0.001). IGFBP3 proteolytic activity was negatively correlated with IGF1 levels (P<0.001). In short SGA children, formation of the ternary complex was positively correlated with height SDS (P=0.01). Compared to healthy controls, short SGA children showed reduced IGF1 levels (−1.3 vs 0.1 SDS) and increased proteolyzed IGFBP3 (35.1 vs 12.2%).

Conclusion: 125I-hIGF1 ternary complex formation is age-dependent. A decrease in IGF1, and an increase in IGF2, IGFBP1 and IGFBP3 proteolytic activity results in reduced 125I-hIGF1 ternary complex formation. In conditions were serum IGF1 levels are low, such as young age and in short SGA children, IGFBP3 proteolytic activity is increased to ensure IGF1 bioavailability.

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