title: Dysregulation of protease and protease inhibitors in a mouse model of human pelvic organ prolapse.
abstract: 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.
authors: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors: Madhusudhan
authors: M
authors: Budatha
authors: Simone
authors: S
authors: Silva
authors: Teodoro Ignacio
authors: TI
authors: Montoya
authors: Ayako
authors: A
authors: Suzuki
authors: Sheena
authors: S
authors: Shah-Simpson
authors: Cecilia Karin
authors: CK
authors: Wieslander
authors: Masashi
authors: M
authors: Yanagisawa
authors: Ruth Ann
authors: RA
authors: Word
authors: Hiromi
authors: H
authors: Yanagisawa
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002364:Caseins / Q000378:metabolism; D003710:Demography; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000378:metabolism; D005260:Female; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009928:Organ Specificity; D056887:Pelvic Organ Prolapse / Q000201:enzymology* / Q000473:pathology*; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism*; D011480:Protease Inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012697:Serine Endopeptidases / Q000378:metabolism; D015843:Serpins / Q000378:metabolism; D014357:Trypsin / Q000235:genetics / Q000378:metabolism; D014621:Vagina / Q000201:enzymology / Q000473:pathology
chemical_list: D002364:Caseins; D016326:Extracellular Matrix Proteins; C120769:Fbln5 protein, mouse; D011480:Protease Inhibitors; D012333:RNA, Messenger; D011994:Recombinant Proteins; D015843:Serpins; D010447:Peptide Hydrolases; C517341:PRSS35 protein, mouse; D012697:Serine Endopeptidases; C040749:PRSS3 protein, human; D014357:Trypsin; D020782:Matrix Metalloproteinases