Urinary incontinence is a major public health problem in the United States, resulting in an 11% lifetime risk of surgery for women with incontinence and/or prolapse. The basic molecular pathophysiology of urinary incontinence is poorly understood and, therefore, the development of medical prophylaxis or therapy for this growing area of disability for older women has lagged. The investigators hypothesize that stress urinary incontinence (SUI) results from abnormal pelvic collagen metabolism as a function of differential expression of the matrix metalloproteinases (MMPs) known to degrade extracellular matrix collagen and the tissue inhibitors of metalloproteinases (TIMPs) which specifically inhibit MMP proteolytic activity. Thus, variations in the expression of MMPs and TIMPs govern the amount and type of collagen in the supporting pelvic structures by controlling proteolysis. They propose to investigate MMP and TIMP expression in vaginal cuff tissue isolated from women with SUI and continent women before and after menopause to delineate differences in proteolytic activity and pelvic collagen content by, first, measuring mRNA and protein expression of MMP-1, MMP-2, MMP-9, TIMP-1, TIMP-2, and TIMP-3 by quantitative, competitive reverse transcription polymerase chain reaction, Western blot analysis, and zymography. Second, they will culture tissue fibroblasts from vaginal cuff samples from control and incontinent women and determine the in vitro mRNA and protein expression of MMPs and TIMPs in response to gonadal steroid, cytokine, and growth factor modulation. Third, to confirm differences in collagenolysis between control and incontinent women, they will measure and compare total collagen content, ratio of type I/type III collagen, amount of the carboxy-terminal epitope, COL2-3/4Cshort, generated by the initial collagen cleavage, and level of pyridinoline crosslinks from both in vivo isolated vaginal cuff tissue and in vitro cultured fibroblasts from control and incontinent patients. Two-thirds of the burden of urinary incontinence is borne by women with prevalence rates of 14 to 41%. The investigators do not believe that any medical therapy for SUI is available. Their fourth goal is to determine the ability of a clinically relevant MMP inhibitor (RS113,456; Roche Bioscience, Inc.) to ablate in vivo MMP proteolysis in fibroblast cultures from women with SUI and control women. Such MMP inhibitors may offer a therapeutic intervention to reverse the pathophysiologc degradation of collagen in women as they age, which results in incontinence.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
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Special Emphasis Panel (ZRG1-UROL (01))
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Sierra, Felipe
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Stanford University
Obstetrics & Gynecology
Schools of Medicine
United States
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Wen, Yan; Whitin, John; Yu, Tom et al. (2012) Identification of protein marker in vaginal wall tissues of women with stress urinary incontinence by protein chip array. J Obstet Gynaecol Res 38:89-96
Wen, Yan; Ho, Jason Yen-Ping; Polan, Mary Lake et al. (2011) Expression of apoptotic factors in vaginal tissues from women with urogenital prolapse. Neurourol Urodyn 30:1627-32
Yen-Ping Ho, Jason; Man, Weng Chi; Wen, Yan et al. (2010) Transforming growth interacting factor expression in leiomyoma compared with myometrium. Fertil Steril 94:1078-83
Man, Weng Chi; Ho, Jason Yen-Ping; Wen, Yan et al. (2009) Is lysyl oxidase-like protein-1, alpha-1 antitrypsin, and neutrophil elastase site specific in pelvic organ prolapse? Int Urogynecol J Pelvic Floor Dysfunct 20:1423-9
Chen, Bertha; Wen, Yan; Yu, Xiao Yun et al. (2009) Relaxin increases elastase activity and protease inhibitors in smooth muscle cells from the myometrium compared with cells from leiomyomas. Fertil Steril 91:1351-4
Wen, Y; Man, W C; Sokol, E R et al. (2008) Is alpha2-macroglobulin important in female stress urinary incontinence? Hum Reprod 23:387-93
Wen, Y; Zhao, Y Y; Li, S et al. (2007) Differences in mRNA and protein expression of small proteoglycans in vaginal wall tissue from women with and without stress urinary incontinence. Hum Reprod 22:1718-24
Chen, Bertha; Wen, Yan; Zhang, Zhaomei et al. (2006) Microarray analysis of differentially expressed genes in vaginal tissues from women with stress urinary incontinence compared with asymptomatic women. Hum Reprod 21:22-9
Chen, Bertha; Wen, Yan; Yu, Xiaoyun et al. (2005) Elastin metabolism in pelvic tissues: is it modulated by reproductive hormones? Am J Obstet Gynecol 192:1605-13
Chen, Bertha; Wen, Yan; Polan, Mary Lake (2004) Elastolytic activity in women with stress urinary incontinence and pelvic organ prolapse. Neurourol Urodyn 23:119-26

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