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PAPPA2 as a Therapeutic Modulator of IGF-I Bioavailability: in Vivo and in Vitro Evidence
CONTEXT: Pregnancy-associated plasma protein A2 (PAPPA2) is a protease that cleaves IGF-binding protein (IGFBP)-3 and IGFBP-5, liberating free IGF-I. Five patients from two families with genetic mutations in PAPPA2 presented with growth retardation, elevated total IGF-I, and IGFBP-3 but decreased fr...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Endocrine Society
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009608/ https://www.ncbi.nlm.nih.gov/pubmed/29942928 http://dx.doi.org/10.1210/js.2018-00106 |
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author | Andrew, Melissa Liao, Lihong Fujimoto, Masanobu Khoury, Jane Hwa, Vivian Dauber, Andrew |
author_facet | Andrew, Melissa Liao, Lihong Fujimoto, Masanobu Khoury, Jane Hwa, Vivian Dauber, Andrew |
author_sort | Andrew, Melissa |
collection | PubMed |
description | CONTEXT: Pregnancy-associated plasma protein A2 (PAPPA2) is a protease that cleaves IGF-binding protein (IGFBP)-3 and IGFBP-5, liberating free IGF-I. Five patients from two families with genetic mutations in PAPPA2 presented with growth retardation, elevated total IGF-I, and IGFBP-3 but decreased free IGF-I. OBJECTIVE: To determine whether plasma transfusion or recombinant human (rh)PAPPA2 could increase free IGF-I in patients with PAPPA2 deficiency or idiopathic short stature (ISS). DESIGN: Single patient interventional study combined with in vitro experimentation. SETTING: Academic medical center. PATIENTS: Three siblings with PAPPA2 deficiency and four patients with ISS. INTERVENTIONS: An adult female with PAPPA2 deficiency received a 20 mL/kg plasma transfusion. PAPPA2, intact IGFBP-3, and free and total IGF-I levels were monitored during 2 weeks. rhPAPPA2 was added to serum from patients with PAPPA2 deficiency and ISS in vitro for 4 hours. Intact IGFBP-3 and free IGF-I levels were assayed via ELISA. MAIN OUTCOME MEASURES: Free IGF-I concentrations. RESULTS: Plasma transfusion resulted in a 2.5-fold increase of free IGF-I levels on day 1 posttransfusion with a return to baseline during a 2-week period. In vitro studies demonstrated a dose-dependent increase in free IGF-I and decrease in intact IGFBP-3 after the addition of rhPAPPA2. The increase in free IGF-I was more pronounced in patients with PAPPA2 deficiency compared with those with ISS. CONCLUSIONS: PAPPA2 plays a key role in regulation of IGF-I bioavailability. rhPAPPA2 is a promising therapy to increase free IGF-I levels both in patients with PAPPA2 deficiency as well as in patients with ISS. |
format | Online Article Text |
id | pubmed-6009608 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Endocrine Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-60096082018-06-25 PAPPA2 as a Therapeutic Modulator of IGF-I Bioavailability: in Vivo and in Vitro Evidence Andrew, Melissa Liao, Lihong Fujimoto, Masanobu Khoury, Jane Hwa, Vivian Dauber, Andrew J Endocr Soc Clinical Research Articles CONTEXT: Pregnancy-associated plasma protein A2 (PAPPA2) is a protease that cleaves IGF-binding protein (IGFBP)-3 and IGFBP-5, liberating free IGF-I. Five patients from two families with genetic mutations in PAPPA2 presented with growth retardation, elevated total IGF-I, and IGFBP-3 but decreased free IGF-I. OBJECTIVE: To determine whether plasma transfusion or recombinant human (rh)PAPPA2 could increase free IGF-I in patients with PAPPA2 deficiency or idiopathic short stature (ISS). DESIGN: Single patient interventional study combined with in vitro experimentation. SETTING: Academic medical center. PATIENTS: Three siblings with PAPPA2 deficiency and four patients with ISS. INTERVENTIONS: An adult female with PAPPA2 deficiency received a 20 mL/kg plasma transfusion. PAPPA2, intact IGFBP-3, and free and total IGF-I levels were monitored during 2 weeks. rhPAPPA2 was added to serum from patients with PAPPA2 deficiency and ISS in vitro for 4 hours. Intact IGFBP-3 and free IGF-I levels were assayed via ELISA. MAIN OUTCOME MEASURES: Free IGF-I concentrations. RESULTS: Plasma transfusion resulted in a 2.5-fold increase of free IGF-I levels on day 1 posttransfusion with a return to baseline during a 2-week period. In vitro studies demonstrated a dose-dependent increase in free IGF-I and decrease in intact IGFBP-3 after the addition of rhPAPPA2. The increase in free IGF-I was more pronounced in patients with PAPPA2 deficiency compared with those with ISS. CONCLUSIONS: PAPPA2 plays a key role in regulation of IGF-I bioavailability. rhPAPPA2 is a promising therapy to increase free IGF-I levels both in patients with PAPPA2 deficiency as well as in patients with ISS. Endocrine Society 2018-05-28 /pmc/articles/PMC6009608/ /pubmed/29942928 http://dx.doi.org/10.1210/js.2018-00106 Text en Copyright © 2018 Endocrine Society https://creativecommons.org/licenses/by-nc-nd/4.0/ This article has been published under the terms of the Creative Commons Attribution Non-Commercial, No-Derivatives License (CC BY-NC-ND; https://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Clinical Research Articles Andrew, Melissa Liao, Lihong Fujimoto, Masanobu Khoury, Jane Hwa, Vivian Dauber, Andrew PAPPA2 as a Therapeutic Modulator of IGF-I Bioavailability: in Vivo and in Vitro Evidence |
title | PAPPA2 as a Therapeutic Modulator of IGF-I Bioavailability: in Vivo and in Vitro Evidence |
title_full | PAPPA2 as a Therapeutic Modulator of IGF-I Bioavailability: in Vivo and in Vitro Evidence |
title_fullStr | PAPPA2 as a Therapeutic Modulator of IGF-I Bioavailability: in Vivo and in Vitro Evidence |
title_full_unstemmed | PAPPA2 as a Therapeutic Modulator of IGF-I Bioavailability: in Vivo and in Vitro Evidence |
title_short | PAPPA2 as a Therapeutic Modulator of IGF-I Bioavailability: in Vivo and in Vitro Evidence |
title_sort | pappa2 as a therapeutic modulator of igf-i bioavailability: in vivo and in vitro evidence |
topic | Clinical Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6009608/ https://www.ncbi.nlm.nih.gov/pubmed/29942928 http://dx.doi.org/10.1210/js.2018-00106 |
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