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 8

Schematic presentation of the dual role of fibulin-5 in prevention of POP.

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Schematic presentation of the dual role of fibulin-5 in prevention of PO...
In WT mice, fibulin-5 controls assembly of elastic fibers (in an RGD-independent manner) and MMP-9 activity (in an RGD-dependent manner) in the vaginal wall and prevents development of POP. In the absence of fibulin-5 (Fbln5–/–), elastic fibers are disrupted and MMP-9 activity is upregulated through increased fibronectin-integrin (FN-β1) interactions and generation of ROS in vaginal stromal cells. Upregulation of MMP-9 activity is important in the pathogenesis of prolapse because deletion of MMP-9 results in significant rescue of the prolapse phenotype. In the presence of RGE mutation (Fbln5RGE/RGE), upregulation of MMP-9 itself was not sufficient to cause POP due to a presence of intact elastic fibers; however, inhibition of LOX activity by BAPN together with the increased MMP-9 led to subclinical POP. Blue and red arrows indicate normal and abnormal conditions, respectively.