Published online before print December 18, 2008

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Copyright © 2009 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2009.080212

Accepted for publication October 7, 2008.

Article

Failure of Pelvic Organ Support in Mice Deficient In Fibulin-3

David D. Rahn^*, Jesús F. Acevedo^*, Shayzreen Roshanravan^*, Patrick W. Keller^*, Elaine C. Davis, Lihua Y. Marmorstein, and R. Ann Word^*@

From the Department of Obstetrics and Gynecology,* University of Texas Southwestern Medical Center, Dallas, Texas; the Department of Anatomy and Cell Biology, McGill University, Montreal, Canada; and the Departments of Ophthalmology and Vision Science and Physiology, University of Arizona, Tucson, Arizona

^@ To whom correspondence should be addressed. E-mail: ruth.word{at}utsouthwestern.edu.

	Abstract

Fibulin-5 is crucial for normal elastic fiber synthesis in the vaginal wall; more than 90% of fibulin-5-knockout mice develop pelvic organ prolapse by 20 weeks of age. In contrast, fibulin-1 and -2 deficiencies do not result in similar pathologies, and fibulin-4-knockout mice die shortly after birth. EFEMP1 encodes fibulin-3, an extracellular matrix protein important in the maintenance of abdominal fascia. Herein, we evaluated the role of fibulin-3 in pelvic organ support. Pelvic organ support was impaired significantly in female Efemp1 knockout mice (Fbln3^-[supi]/-), and overt vaginal, perineal, and rectal prolapse occurred in 26.9% of animals. Prolapse severity increased with age but not parity. Fibulin-5 was up-regulated in vaginal tissues from Fbln3^-[supi]/- mice regardless of prolapse. Despite increased expression of fibulin-5 in the vaginal wall, pelvic organ support failure occurred in Fbln3^-[supi]/- animals, suggesting that factors related to aging led to prolapse. Elastic fiber abnormalities in vaginal tissues from young Fbln3^-[supi]/- mice progressed to severe elastic fiber disruption with age, and vaginal matrix metalloprotease activity was increased significantly in Fbln3^-[supi]/- animals with prolapse compared with Fbln3^-[supi]/- mice without prolapse. Overall, these results indicate that both fibulin-3 and -5 are important in maintaining pelvic organ support in mice. We suggest that increased vaginal protease activity and abnormal elastic fibers in the vaginal wall are important components in the pathogenesis of pelvic organ prolapse.

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