title: Ternary complex formation and IGFBP-3 proteolytic activity during childhood: age-dependent changes.
abstract: 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.
  
  
  METHODS
  Complex formation was assessed using (125)I-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
  (125)I-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%).
  
  
  CONCLUSIONS
  Age-specific normative values for (125)I-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 (125)I-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.
authors.affiliation: Department of Pediatrics (J.S.R., A.C.S.H.-K.), Division of Endocrinology, Erasmus Medical Center/Sophia Children's Hospital, 3015 CN Rotterdam, The Netherlands; Department of Clinical Chemistry and Haematology (J.v.D.), Laboratory of Endocrinology, and Department of Medical Genetics (J.v.D.), Section of Metabolic Diseases, University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands; and Dutch Growth Research Foundation (A.C.S.H.-K.), 3016 AH Rotterdam, The Netherlands.
authors.forename: J S
authors.initials: JS
authors.lastname: Renes
authors.forename: J
authors.initials: J
authors.lastname: van Doorn
authors.forename: A C S
authors.initials: AC
authors.lastname: Hokken-Koelega
mesh_terms: D000293:Adolescent; D041923:Adolescent Development / Q000502:physiology*; D000367:Age Factors; D002648:Child; D002657:Child Development / Q000502:physiology*; D002675:Child, Preschool; D002845:Chromatography / Q000379:methods; D005260:Female; D006801:Humans; D007223:Infant; D007236:Infant, Small for Gestational Age / Q000378:metabolism*; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D007457:Iodine Radioisotopes; D008297:Male; D050801:Ternary Complex Factors / Q000378:metabolism*; D055815:Young Adult
chemical_list: C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; D007457:Iodine Radioisotopes; D050801:Ternary Complex Factors; D007334:Insulin-Like Growth Factor I; D007335:Insulin-Like Growth Factor II