Metalloproteinase pregnancy-associated plasma protein A is a critical growth regulatory factor during fetal development

Cheryl A. Conover, Laurie K. Bale, Michael T. Overgaard, Edward W. Johnstone, Ulla L. Laursen, Ernst Martin Füchtbauer, Claus Oxvig, Jan van Deursen

Research output: Contribution to journalArticlepeer-review

217 Scopus citations


Pregnancy-associated plasma protein A (PAPPA) is a metzincin superfamily metalloproteinase in the insulin-like growth factor (IGF) system. PAPPA increases IGF bioavailability and mitogenic effectiveness in vitro through regulated cleavage of IGF-binding protein 4 (IGFBP4). To determine its function in vivo, we generated PAPPA-null mice by gene targeting. Mice homozygous for targeted disruption of the PAPPA gene were viable but 60% the size of wild-type littermates at birth. The impact of the mutation was exerted during the early embryonic period prior to organogenesis, resulting in proportional dwarfism. PAPPA, IGF2 and IGFBP4 transcripts co-localized in wild-type embryos, and expression of IGF2 and IGFBP4 mRNA was not altered in PAPPA-deficient embryos. However, IGFBP4 proteolytic activity was completely lacking in fibroblasts derived from PAPPA-deficient embryos, and IGFBP4 effectively inhibited IGF-stimulated mitogenesis in these cells. These results provide the first direct evidence that PAPPA is an essential growth regulatory factor in vivo, and suggest a novel mechanism for regulated IGF bioavailability during early fetal development.

Original languageEnglish (US)
Pages (from-to)1187-1194
Number of pages8
Issue number5
StatePublished - Mar 2004


  • Gene targeting
  • Insulin-like growth factor
  • Metalloproteinase
  • Pregnancy associated plasma protein A

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology


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