Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans

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

Research output: Contribution to journalArticle

78 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2048-2059
Number of pages12
JournalJournal of Clinical Investigation
Volume121
Issue number5
DOIs
StatePublished - May 2 2011

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Pelvic Organ Prolapse
Extracellular Matrix
Peptide Hydrolases
Matrix Metalloproteinases
Integrins
Elastic Tissue
Aminopropionitrile
Up-Regulation
Stromal Cells
Fibronectins
Carrier Proteins
Collagen
Enzymes
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Budatha, M., Roshanravan, S., Zheng, Q., Weislander, C., Chapman, S. L., Davis, E. C., ... Yanagisawa, H. (2011). Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans. Journal of Clinical Investigation, 121(5), 2048-2059. https://doi.org/10.1172/JCI45636

Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans. / Budatha, Madhusudhan; Roshanravan, Shayzreen; Zheng, Qian; Weislander, Cecilia; Chapman, Shelby L.; Davis, Elaine C.; Starcher, Barry; Word, R. Ann; Yanagisawa, Hiromi.

In: Journal of Clinical Investigation, Vol. 121, No. 5, 02.05.2011, p. 2048-2059.

Research output: Contribution to journalArticle

Budatha, M, Roshanravan, S, Zheng, Q, Weislander, C, Chapman, SL, Davis, EC, Starcher, B, Word, RA & Yanagisawa, H 2011, 'Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans', Journal of Clinical Investigation, vol. 121, no. 5, pp. 2048-2059. https://doi.org/10.1172/JCI45636
Budatha M, Roshanravan S, Zheng Q, Weislander C, Chapman SL, Davis EC et al. Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans. Journal of Clinical Investigation. 2011 May 2;121(5):2048-2059. https://doi.org/10.1172/JCI45636
Budatha, Madhusudhan ; Roshanravan, Shayzreen ; Zheng, Qian ; Weislander, Cecilia ; Chapman, Shelby L. ; Davis, Elaine C. ; Starcher, Barry ; Word, R. Ann ; Yanagisawa, Hiromi. / Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans. In: Journal of Clinical Investigation. 2011 ; Vol. 121, No. 5. pp. 2048-2059.
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