Low IGF-I bioavailability impairs growth and glucose metabolism in a mouse model of human PAPPA2 p.ALA1033Val mutation

Masanobu Fujimoto, Melissa Andrew, Lihong Liao, Dongsheng Zhang, Gozde Yildirim, Patrick Sluss, Bhanu Kalra, Ajay Kumar, Shoshana Yakar, Vivian Hwa, Andrew Dauber

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)1363-1376
Number of pages14
Issue number6
StatePublished - Jun 1 2019

ASJC Scopus subject areas

  • Endocrinology


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