Masanobu Fujimoto1,2, Jane C Khoury1,3, Philip R Khoury4, Bhanu Kalra5, Ajay Kumar5, Patrick Sluss5, Claus Oxvig6, Vivian Hwa1, Andrew Dauber1,7,8. 1. Cincinnati Center for Growth Disorders, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. 2. Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Yonago, Japan. 3. Division of Biostatistics and Epidemiology, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. 4. Heart Institute Research Core, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. 5. Ansh Labs, Webster, Texas, USA. 6. Department of Molecular Biology and Genetics, Aarhus University, Aarhus C, Denmark. 7. Division of Endocrinology, Children's National Hospital, Washington, District of Columbia, USA. 8. Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, District of Columbia, USA.
Abstract
OBJECTIVE: Pregnancy-associated plasma protein-A2 (PAPP-A2) is a metalloproteinase that cleaves IGFBP-3 and IGFBP-5. Human mutations in PAPPA2 result in short stature with a low percentage of free IGF-I. Little is known about PAPP-A2 levels and the regulation of free IGF-I throughout childhood. We examined PAPP-A2 and intact IGFBP-3 levels in childhood and explored associations between PAPP-A2, free and total IGF-I, and total and intact IGFBP-3 and their relationship to the percentage of free to total IGF-I and anthropometric factors. DESIGN: Cross-sectional study at a single center. METHODS: PAPP-A2, free IGF-I, and intact IGFBP-3 levels were measured in childhood (3-18 years old) and an evaluation of the relationship between these proteins and anthropometric factors. RESULTS: In 838 children, PAPP-A2 consistently decreased throughout childhood. In contrast, free IGF-I increased. A pubertal peak in free IGF-I was present in females but was less evident in males. Intact and total IGFBP-3 increased throughout childhood; however, intact IGFBP-3 had a more marked rise than total IGFBP-3. Percent free IGF-I decreased with no distinct pubertal peak. PAPP-A2 levels positively correlated with the percent free IGF-I (Male, Female; r = 0.18, 0.38; P < 0.001) and negatively with intact IGFBP-3 (Male, Female; r = -0.58, -0.65; P < 0.0001). CONCLUSIONS: This is the first study to describe serum PAPP-A2 and intact IGFBP-3 in children between 3 and 18 years of age. Our correlative findings suggest that PAPP-A2 is an important regulator of the percent free IGF-I which can be a marker of perturbations in the GH/IGF-I axis.
OBJECTIVE: Pregnancy-associated plasma protein-A2 (PAPP-A2) is a metalloproteinase that cleaves IGFBP-3 and IGFBP-5. Human mutations in PAPPA2 result in short stature with a low percentage of free IGF-I. Little is known about PAPP-A2 levels and the regulation of free IGF-I throughout childhood. We examined PAPP-A2 and intact IGFBP-3 levels in childhood and explored associations between PAPP-A2, free and total IGF-I, and total and intact IGFBP-3 and their relationship to the percentage of free to total IGF-I and anthropometric factors. DESIGN: Cross-sectional study at a single center. METHODS: PAPP-A2, free IGF-I, and intact IGFBP-3 levels were measured in childhood (3-18 years old) and an evaluation of the relationship between these proteins and anthropometric factors. RESULTS: In 838 children, PAPP-A2 consistently decreased throughout childhood. In contrast, free IGF-I increased. A pubertal peak in free IGF-I was present in females but was less evident in males. Intact and total IGFBP-3 increased throughout childhood; however, intact IGFBP-3 had a more marked rise than total IGFBP-3. Percent free IGF-I decreased with no distinct pubertal peak. PAPP-A2 levels positively correlated with the percent free IGF-I (Male, Female; r = 0.18, 0.38; P < 0.001) and negatively with intact IGFBP-3 (Male, Female; r = -0.58, -0.65; P < 0.0001). CONCLUSIONS: This is the first study to describe serum PAPP-A2 and intact IGFBP-3 in children between 3 and 18 years of age. Our correlative findings suggest that PAPP-A2 is an important regulator of the percent free IGF-I which can be a marker of perturbations in the GH/IGF-I axis.
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