Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans
Madhusudhan Budatha, … , R. Ann Word, Hiromi Yanagisawa
Madhusudhan Budatha, … , R. Ann Word, Hiromi Yanagisawa
Published April 25, 2011
Citation Information: J Clin Invest. 2011;121(5):2048-2059. https://doi.org/10.1172/JCI45636.
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Research Article

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

Madhusudhan Budatha, Shayzreen Roshanravan, Qian Zheng, Cecilia Weislander, Shelby L. Chapman, Elaine C. Davis, Barry Starcher, R. Ann Word, Hiromi Yanagisawa

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Figure 1

Characterization of Fbln5RGE/RGE (RGE) mice.

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Characterization of Fbln5RGE/RGE (RGE) mice. (A) RT-PCR of Fbln5 fro...
(A) RT-PCR of Fbln5 from WT and RGE kidney mRNA. (B) Sequencing confirms a successful mutation of D56E. (C) Western blot analysis showing comparable level of fibulin-5 protein in the WT and mutant kidneys. (D) Representative fibulin-5 immunostaining in the vagina from WT, Fbln5–/– (KO), and RGE mice. Note strong fibulin-5 expression in the vaginal stroma in WT and RGE mice. Asterisks indicate vessels. Scale bars: 50 μm. (E) Histological analysis of vaginal wall from WT, KO, and RGE mice at 4 weeks of age stained with H&E, Hart’s, or Masson’s trichrome. Numerous long branching elastic fibers are seen in WT and RGE vagina, whereas abnormal elastic fibers are present in KO mouse (arrow). Scale bars: 50 μm (H&E); 20 μm (Hart’s and Masson’s trichrome). ep, epithelium; s, stroma.