Lack of functional pregnancy-associated plasma protein-A (PAPPA) compromises mouse ovarian steroidogenesis and female fertility

Mette Nyegaard, Michael T. Overgaard, You Qiang Su, Amy E. Hamilton, Jakub Kwintkiewicz, Minnie Hsieh, Nihar R. Nayak, Marco Conti, Cheryl A Conover, Linda C. Giudice

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Abstract

The insulin-like growth factor (IGF) system plays an important role in regulating ovarian follicular development and steroidogenesis. IGF binding proteins (IGFBP) mostly inhibit IGF actions, and IGFBP proteolysis is a major mechanism for regulating IGF bioavailability. Pregnancy-associated plasma protein-A (PAPPA) is a secreted metalloprotease responsible for cleavage of IGFBP4 in the ovary. The aim of this study was to investigate whether PAPPA plays a role in regulating ovarian functions and female fertility by comparing the reproductive phenotype of wild-type (WT) mice with mice heterozygous or homozygous for a targeted Pappa gene deletion (heterozygous and PAPP-A knockout [KO] mice, respectively). When mated with WT males, PAPP-A KO females demonstrated an overall reduction in average litter size. PAPP-A KO mice had a reduced number of ovulated oocytes, lower serum estradiol levels following equine chorionic gonadotropin administration, lower serum progesterone levels after human chorionic gonadotropin injection, and reduced expression of ovarian steroidogenic enzyme genes, compared to WT controls. In PAPP-A KO mice, inhibitory IGFBP2, IGFBP3, and IGFBP4 ovarian gene expression was reduced postgonadotropin stimulation, suggesting some compensation within the ovarian IGF system. Expression levels of follicle-stimulating hormone receptor, luteinizing hormone receptor, and genes required for cumulus expansion were not affected. Analysis of preovulatory follicular fluid showed complete loss of IGFBP4 proteolytic activity in PAPP-A KO mice, demonstrating no compensation for loss of PAPPA proteolytic activity by other IGFBP proteases in vivo in the mouse ovary. Taken together, these data demonstrate an important role of PAPPA in modulating ovarian function and female fertility by control of the bioavailability of ovarian IGF.

Original languageEnglish (US)
Pages (from-to)1129-1138
Number of pages10
JournalBiology of Reproduction
Volume82
Issue number6
DOIs
StatePublished - Jun 2010

Fingerprint

Pregnancy-Associated Plasma Protein-A
Fertility
Insulin-Like Growth Factor Binding Proteins
Somatomedins
Knockout Mice
Chorionic Gonadotropin
Biological Availability
Ovary
FSH Receptors
Equine Gonadotropins
LH Receptors
Follicular Fluid
Litter Size
Gene Deletion
Metalloproteases
Serum
Contraception
Proteolysis
Genes
Oocytes

Keywords

  • Follicle
  • Growth factors
  • Insulin-like growth factor binding protein proteolysis
  • Mechanisms of hormone action
  • Ovary

ASJC Scopus subject areas

  • Cell Biology

Cite this

Nyegaard, M., Overgaard, M. T., Su, Y. Q., Hamilton, A. E., Kwintkiewicz, J., Hsieh, M., ... Giudice, L. C. (2010). Lack of functional pregnancy-associated plasma protein-A (PAPPA) compromises mouse ovarian steroidogenesis and female fertility. Biology of Reproduction, 82(6), 1129-1138. https://doi.org/10.1095/biolreprod.109.079517

Lack of functional pregnancy-associated plasma protein-A (PAPPA) compromises mouse ovarian steroidogenesis and female fertility. / Nyegaard, Mette; Overgaard, Michael T.; Su, You Qiang; Hamilton, Amy E.; Kwintkiewicz, Jakub; Hsieh, Minnie; Nayak, Nihar R.; Conti, Marco; Conover, Cheryl A; Giudice, Linda C.

In: Biology of Reproduction, Vol. 82, No. 6, 06.2010, p. 1129-1138.

Research output: Contribution to journalArticle

Nyegaard, M, Overgaard, MT, Su, YQ, Hamilton, AE, Kwintkiewicz, J, Hsieh, M, Nayak, NR, Conti, M, Conover, CA & Giudice, LC 2010, 'Lack of functional pregnancy-associated plasma protein-A (PAPPA) compromises mouse ovarian steroidogenesis and female fertility', Biology of Reproduction, vol. 82, no. 6, pp. 1129-1138. https://doi.org/10.1095/biolreprod.109.079517
Nyegaard, Mette ; Overgaard, Michael T. ; Su, You Qiang ; Hamilton, Amy E. ; Kwintkiewicz, Jakub ; Hsieh, Minnie ; Nayak, Nihar R. ; Conti, Marco ; Conover, Cheryl A ; Giudice, Linda C. / Lack of functional pregnancy-associated plasma protein-A (PAPPA) compromises mouse ovarian steroidogenesis and female fertility. In: Biology of Reproduction. 2010 ; Vol. 82, No. 6. pp. 1129-1138.
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abstract = "The insulin-like growth factor (IGF) system plays an important role in regulating ovarian follicular development and steroidogenesis. IGF binding proteins (IGFBP) mostly inhibit IGF actions, and IGFBP proteolysis is a major mechanism for regulating IGF bioavailability. Pregnancy-associated plasma protein-A (PAPPA) is a secreted metalloprotease responsible for cleavage of IGFBP4 in the ovary. The aim of this study was to investigate whether PAPPA plays a role in regulating ovarian functions and female fertility by comparing the reproductive phenotype of wild-type (WT) mice with mice heterozygous or homozygous for a targeted Pappa gene deletion (heterozygous and PAPP-A knockout [KO] mice, respectively). When mated with WT males, PAPP-A KO females demonstrated an overall reduction in average litter size. PAPP-A KO mice had a reduced number of ovulated oocytes, lower serum estradiol levels following equine chorionic gonadotropin administration, lower serum progesterone levels after human chorionic gonadotropin injection, and reduced expression of ovarian steroidogenic enzyme genes, compared to WT controls. In PAPP-A KO mice, inhibitory IGFBP2, IGFBP3, and IGFBP4 ovarian gene expression was reduced postgonadotropin stimulation, suggesting some compensation within the ovarian IGF system. Expression levels of follicle-stimulating hormone receptor, luteinizing hormone receptor, and genes required for cumulus expansion were not affected. Analysis of preovulatory follicular fluid showed complete loss of IGFBP4 proteolytic activity in PAPP-A KO mice, demonstrating no compensation for loss of PAPPA proteolytic activity by other IGFBP proteases in vivo in the mouse ovary. Taken together, these data demonstrate an important role of PAPPA in modulating ovarian function and female fertility by control of the bioavailability of ovarian IGF.",
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