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• W2937013003 abstract "Bioactive free IGF-I is critically important for growth. The bioavailability of IGF-I is modulated by the IGF-binding proteins (IGFBPs) and their proteases, such as pregnancy-associated plasma protein-A2 (PAPP-A2). We have created a mouse model with a specific mutation in PAPPA2 identified in a human with PAPP-A2 deficiency. The human mutation was introduced to the mouse genome via a knock-in strategy, creating knock-in mice with detectable protein levels of Papp-a2 but without protease activities. We found that the Pappa2 mutation led to significant reductions in body length (10%), body weight (10% and 20% in males and females, respectively), and relative lean mass in mice. Micro-CT analyses of Pappa2 knock-in femurs from adult mice showed inhibited periosteal bone expansion leading to more slender bones in both male and female mice. Furthermore, in the Pappa2 knock-in mice, insulin resistance correlated with decreased serum free IGF-I and increased intact IGFBP-3 concentrations. Interestingly, mice heterozygous for the knock-in mutation demonstrated a growth rate for body weight and length as well as a biochemical phenotype that was intermediate between wild-type and homozygous mice. This study models a human PAPPA2 mutation in mice. The mouse phenotype closely resembles that of the human patients, and it provides further evidence that the regulation of IGF-I bioavailability by PAPP-A2 is critical for human growth and for glucose and bone metabolism." @default.
• W2937013003 created "2019-04-25" @default.
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• W2937013003 date "2019-04-12" @default.
• W2937013003 modified "2023-10-07" @default.
• W2937013003 title "Low IGF-I Bioavailability Impairs Growth and Glucose Metabolism in a Mouse Model of Human PAPPA2 p.Ala1033Val Mutation" @default.
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• W2937013003 doi "https://doi.org/10.1210/en.2018-00755" @default.
• W2937013003 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6507901" @default.
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