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.

A large lung gene expression study identifying fibulin-5 as a novel player in tissue repair in COPD

“…Two studies have now demonstrated that the FBLN5 protein can be cleaved by serine proteases23 24 and increased levels of this cleaved form of FBLN5 protein were demonstrated in the skin of aged mice 23. This is intriguing as on the one hand COPD has been regarded as an aging lung disease25 26 and on the other hand increased serine protease activity is present in COPD lungs, which is thought to play an important role in emphysematous lung tissue destruction 27 28.…”

Neurovascular alterations of muscularis propria in the human anterior vaginal wall in pelvic organ prolapse

“…It has been demonstrated that a switch from phenotypic smooth muscle cells (SMCs) to myofibroblast differentiation could be the underlying cause of structural modifications in the tunica muscularis of the anterior vaginal wall. Indeed, SMCs undergo an aberrant switch from a contractile to a synthetic extracellular matrix, producing a phenotype consequent to their trans-differentiation into myofibroblasts (Smith et al 1990;Budatha et al 2013;Severi et al 2014;Vetuschi et al 2016). Therefore, the switch from type I to type III occurring in POP entails a greater distensibility, but at the same time fragility, of the wall itself (Tremollieres, 2010;Kannan et al 2011;Kerkhof et al 2013).…”

“…Changes in muscularis propria in POP also include a reduction in the concentration of elastic fibres and an imbalance in the extracellular matrix turnover, due to the overexpression of MMPs and a simultaneous reduction in their inhibitors (Budatha et al 2013;Shynlova et al 2013;Yucel et al 2013;De Landsheere et al 2014;Vetuschi et al 2018).…”

Expression changes in pelvic organ prolapse: a systematic review and in silico study

“…Usage of (iii) as an evidence was based on the rationale that heart valve, cartilage, tendon, and bone development share common regulatory pathways 26 . The genes ADAMTS1 12 , MYH3 27 and SERPINE1 28 were up-regulated in POP tissues. Polymorphic variants in the genes LIN28B 29 and AGT 30 were associated with POP and mitral valve prolapse (MVP) respectively.…”