Dysregulation of protease and protease inhibitors in a mouse model of human pelvic organ prolapse

PLoS One. 2013;8(2):e56376. doi: 10.1371/journal.pone.0056376. Epub 2013 Feb 20.


Mice deficient for the fibulin-5 gene (Fbln5(-/-)) develop pelvic organ prolapse (POP) due to compromised elastic fibers and upregulation of matrix metalloprotease (MMP)-9. Here, we used casein zymography, inhibitor profiling, affinity pull-down, and mass spectrometry to discover additional protease upregulated in the vaginal wall of Fbln5(-/-) mice, herein named V1 (25 kDa). V1 was a serine protease with trypsin-like activity similar to protease, serine (PRSS) 3, a major extrapancreatic trypsinogen, was optimum at pH 8.0, and predominantly detected in estrogenized vaginal epithelium of Fbln5(-/-) mice. PRSS3 was (a) localized in epithelial secretions, (b) detected in media of vaginal organ culture from both Fbln5(-/-) and wild type mice, and (c) cleaved fibulin-5 in vitro. Expression of two serine protease inhibitors [Serpina1a (α1-antitrypsin) and Elafin] was dysregulated in Fbln5(-/-) epithelium. Finally, we confirmed that PRSS3 was expressed in human vaginal epithelium and that SERPINA1 and Elafin were downregulated in vaginal tissues from women with POP. These data collectively suggest that the balance between proteases and their inhibitors contributes to support of the pelvic organs in humans and mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Caseins / metabolism
  • Demography
  • Disease Models, Animal
  • Extracellular Matrix Proteins / deficiency
  • Extracellular Matrix Proteins / metabolism
  • Female
  • Humans
  • Matrix Metalloproteinases / metabolism
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Organ Specificity
  • Pelvic Organ Prolapse / enzymology*
  • Pelvic Organ Prolapse / pathology*
  • Peptide Hydrolases / genetics
  • Peptide Hydrolases / metabolism*
  • Protease Inhibitors / metabolism*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Recombinant Proteins / metabolism
  • Serine Endopeptidases / metabolism
  • Serpins / metabolism
  • Trypsin / genetics
  • Trypsin / metabolism
  • Vagina / enzymology
  • Vagina / pathology


  • Caseins
  • Extracellular Matrix Proteins
  • Fbln5 protein, mouse
  • Protease Inhibitors
  • RNA, Messenger
  • Recombinant Proteins
  • Serpins
  • Peptide Hydrolases
  • PRSS35 protein, mouse
  • Serine Endopeptidases
  • PRSS3 protein, human
  • Trypsin
  • Matrix Metalloproteinases