Protein breakdown contributes to pelvic organ prolapse

Pelvic organ prolapse appears to be caused by a combination of a loss of elasticity and a breakdown of proteins in the vaginal wall, according to a recent multicenter study.

"We found that the protein fibulin-5, which until now simply has been known to be important in generating elastic fibers, actually blocks the enzymes that degrade proteins that support the vaginal wall structure," said co-senior author R. Ann Word, MD, of the University of Texas Southwestern Medical Center, Dallas. "The elastic fibers do play a role, but it’s also the enzymes that degrade the matrix that break down both collagen and elastin over time."

Using mice, researchers tested how fibulin-5, a protein that is essential for elastic fiber assembly, regulated the activity of matrix metalloprotease-9 (MMP-9), a group of enzymes that break down the matrix of collagen and elastic fibers, leading to a loss of the structural support of the vaginal wall.

Researchers used a fibulin-5-deficient rodent model and a new domain-specific mutant of fibulin-5 to demonstrate that fibulin-5-mediated elastogenesis is essential to support the pelvic organs. They also showed that prolapse of the vaginal wall requires an increase in MMP-9, but that fibulin-5 inhibits activation of this protease in a tissue-specific manner.

"Matrix assembly of the vaginal wall is a very complicated process," said co-senior author Hiromi Yanagisawa, PhD, of UT Southwestern. "We need to decode what is necessary in this process, but degrading enzymes are the main therapeutic focus."

"The bottom line is the whole matrix is maintained by a balance between synthesis and degradation," Dr. Word said. "Our goal is to optimize pelvic organ support and target these proteases that degrade the matrix."

Study results were published in the Journal of Clinical Investigation (2011; 121:2048-59).