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

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 β 1 integrin-dependent, fibronectin-mediated upregulation of MMP-9. Mice in which the integrin-binding motif was mutated to an integrin-disrupting motif (Fbln5 RGE/RGE ) exhibited upregulation of MMP-9 in vaginal tissues. In contrast to fibulin-5 knockouts (Fbln5 -/-), Fbln5 RGE/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. IntroductionPelvic organ prolapse (POP) is characterized by abnormal protrusion of female pelvic organs involving the uterus, bladder, and vagina (reviewed in refs. 1-3). Epidemiologic studies indicate that (a) vaginal birth, aging, and increased body mass index are major risk factors for the development of POP and (b) more than 1 pathology may be involved to exhibit full anatomical loss of support. Although approximately 11% of women have surgery for POP or urinary incontinence in their lifetimes (4), to date, effective therapies to prevent progression of POP have not been established, thereby imposing profound social and financial burden to affected individuals (3).Despite a difference in anatomical position of pelvic organs relative to the body axis and pelvic floor, rodent models of POP have provided important tools to study underlying mechanisms of prolapse. In contrast to an observation that rectal prolapse is frequently associated with the presence of chronic inflammatory bowel disease (5), POP has been found in animals with defective ECM proteins, including fibulin-3, fibulin-5, and lysyl oxidaselike-1 (LOXL-1) (an enzyme that predominantly catalyzes crosslinking of elastin) (6-8). Interestingly, these proteins are abundantly expressed in the vaginal wall and involved in synthesis and assembly of elastic fibers. It is also known that uterosacral ligaments support the vaginal wall and that Hoxa11 is essential for formation of uterosacral ligaments in mice (9). Hoxa11-deficient mice exhibit increased mobility of the uterus; however,

Fibulin-5: two for the price of one maintaining pelvic support

“…Additionally, increased monocytic infiltration in the vaginal wall during labor seen in Fbln5 -/-animals may indicate increased elastolytic activity, further suggesting that both abnormal synthesis and increased degradation are necessary to develop POP (8). Given the aforementioned findings in both Fbln5 -/-and Loxl1 -/-animals, Budatha et al sought to further explain the interactions between fibulin-5 and LOXL1 in the pathogenesis of POP (11).…”

The role of MMP and TIMP genetic polymorphisms in genital prolapse genesis

“…Conclusion: Identifi cation of genetic predictors of pelvic fl oor remodeling with the formation of its insolvency contribute to better understanding of the pathogenesis of the disease and allow to stratify women into risk groups of GP development, progression or recurrence aft er surgery. П ролапс гениталий (ПГ) -серьезная меди-ко-социальная проблема женщин всех воз-растных групп, в большей степени в пери-и постменопаузальном периодах (более половины старше 50 лет), сопряженная со значительными неблагоприят-ными последствиями не только для здоровья, но и для качества жизни, трудоспособности, социального благо-получия [1]. Вызывают обеспокоенность прогнозы об удвоении в ближайшие 30 лет количества обращений за медицинской помощью в связи с проявлениями несосто-ятельности тазового дна, возрастании оперативных вме-шательств в области перинеологии на 45% [2].…”

Histology of the vaginal wall in women with pelvic organ prolapse: a literature review

“…This finding has motivated gene targeting studies of the proteins involved in elastogenesis [20,21]. Elastogenesis starts at midgestation and completes during postnatal development.…”