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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

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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 7

Increased MMP-9 activity in human POP patients.

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Increased MMP-9 activity in human POP patients.
(A) MMP2 and MMP9 mRNA l...
(A) MMP2 and MMP9 mRNA levels in vaginal muscularis from women with and without POP. Levels of MMP2 (left) and MMP9 (right) mRNA were quantified in vaginal muscularis from asymptomatic premenopausal (Prem CTL, n = 18) and postmenopausal (Postm CTL, n = 5) controls and premenopausal (Prem prolapse, n = 19) and postmenopausal (Postm prolapse, n = 34) women with POP. Dashed lines represent 95% CI of values from premenopausal controls. Each symbol represents mean determination from a single patient. *P < 0.05 compared with other groups, χ2 analysis. (B) Gelatin zymography of vaginal muscularis from premenopausal women with (Prem prolapse) or without (Prem CTL) POP. Vaginal extracts from Mmp9–/– and Fbln5–/– mice were used as negative and positive controls. (C) Quantification of pro– and active MMP-2 and MMP-9 from premenopausal women with or without POP, respectively. (D) Representative zymogram of vaginal muscularis from postmenopausal with (P) or without (C) prolapse. Coomassie blue staining of the extracts (20 μg/lane) is shown in the lower panel as a control for protein loading. Gelatinolytic activity corresponding to MMP-9 (~105 kDa), proMMP-2 (72 kDa), and active MMP-2 (62 kDa) is seen as clear bands of lysis. Stage of prolapse is noted above each lane. 1 lane (–) was loaded on the Coomassie gel, but not the zymogram. (E) Quantification of proMMP-2, active MMP-2, and MMP-9 in 8 controls and 15 postmenopausal women with prolapse. *P < 0.01.

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