TY - JOUR
T1 - Dysregulation of Protease and Protease Inhibitors in a Mouse Model of Human Pelvic Organ Prolapse
AU - Budatha, Madhusudhan
AU - Silva, Simone
AU - Montoya, Teodoro Ignacio
AU - Suzuki, Ayako
AU - Shah-Simpson, Sheena
AU - Wieslander, Cecilia Karin
AU - Yanagisawa, Masashi
AU - Word, Ruth Ann
AU - Yanagisawa, Hiromi
PY - 2013/2/20
Y1 - 2013/2/20
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pone.0056376
DO - 10.1371/journal.pone.0056376
M3 - Article
C2 - 23437119
AN - SCOPUS:84874238840
SN - 1932-6203
VL - 8
JO - PloS one
JF - PloS one
IS - 2
M1 - e56376
ER -