title: Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans.
abstract: Pelvic organ prolapse (POP) is a common condition affecting almost half of women over the age of 50. The molecular and cellular mechanisms underlying this condition, however, remain poorly understood. Here we have reported that fibulin-5, an integrin-binding matricellular protein that is essential for elastic fiber assembly, regulated the activity of MMP-9 to maintain integrity of the vaginal wall and prevented development of POP. In murine vaginal stromal cells, fibulin-5 inhibited the β1 integrin-dependent, fibronectin-mediated upregulation of MMP-9. Mice in which the integrin-binding motif was mutated to an integrin-disrupting motif (Fbln5RGE/RGE) exhibited upregulation of MMP-9 in vaginal tissues. In contrast to fibulin-5 knockouts (Fbln5-/-), Fbln5RGE/RGE mice were able to form intact elastic fibers and did not exhibit POP. However, treatment of mice with β-aminopropionitrile (BAPN), an inhibitor of matrix cross-linking enzymes, induced subclinical POP. Conversely, deletion of Mmp9 in Fbln5-/- mice significantly attenuated POP by increasing elastic fiber density and improving collagen fibrils. Vaginal tissue samples from pre- and postmenopausal women with POP also displayed significantly increased levels of MMP-9. These results suggest that POP is an acquired disorder of extracellular matrix and that therapies targeting matrix proteases may be successful for preventing or ameliorating POP in women.
authors.affiliation: Department of Molecular Biology, University of Texas, Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: Madhusudhan
authors.initials: M
authors.lastname: Budatha
authors.forename: Shayzreen
authors.initials: S
authors.lastname: Roshanravan
authors.forename: Qian
authors.initials: Q
authors.lastname: Zheng
authors.forename: Cecilia
authors.initials: C
authors.lastname: Weislander
authors.forename: Shelby L
authors.initials: SL
authors.lastname: Chapman
authors.forename: Elaine C
authors.initials: EC
authors.lastname: Davis
authors.forename: Barry
authors.initials: B
authors.lastname: Starcher
authors.forename: R Ann
authors.initials: RA
authors.lastname: Word
authors.forename: Hiromi
authors.initials: H
authors.lastname: Yanagisawa
mesh_terms: D000629:Aminopropionitrile / Q000494:pharmacology; D000818:Animals; D003432:Cross-Linking Reagents / Q000494:pharmacology; D018450:Disease Progression; D005109:Extracellular Matrix / Q000201:enzymology* / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005260:Female; D006801:Humans; D019012:Integrin beta1 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D056887:Pelvic Organ Prolapse / Q000473:pathology*; D010447:Peptide Hydrolases / Q000737:chemistry*; D011994:Recombinant Proteins / Q000096:biosynthesis; D014621:Vagina / Q000378:metabolism
chemical_list: D003432:Cross-Linking Reagents; D016326:Extracellular Matrix Proteins; C492373:FBLN5 protein, human; C120769:Fbln5 protein, mouse; D019012:Integrin beta1; D011994:Recombinant Proteins; D000629:Aminopropionitrile; D010447:Peptide Hydrolases; D020780:Matrix Metalloproteinase 9