Pelvic organ prolapse (POP) is a common, debilitating disorder affecting millions of women. Uterosacral ligaments (USLs) are the main supportive structures of the uterus and vagina and are often attenuated in women with POP. Although the mechanical strength of USLs is known to be dependent on collagen synthesis and catabolism and the degradation protein MMP2 has been implicated in POP, the molecular mechanisms involved in the development of POP are currently unknown. Homeobox (HOX) genes are transcriptional regulators that orchestrate embryonic development of the urogenital tract. We demonstrated here that HOXA11 was essential for organogenesis of the USL by showing that USLs were absent in Hoxa11-null mice. We compared expression of HOXA11, collagen type I, collagen type III, MMP2, and MMP9 in USLs of women with and without POP. Expression of HOXA11 and both collagens was dramatically decreased while MMP2 was increased in women with POP. Constitutive expression of Hoxa11 in murine fibroblasts resulted in significantly increased expression of collagen type III and decreased expression of MMP2. These results identified HOXA11 as an essential gene for the development of the USL and suggested that women with POP might have weakened connective tissue due to changes in a signaling pathway involving HOXA11, collagen type III, and MMP2. IntroductionPelvic organ prolapse (POP) is a common, costly, and debilitating disorder that negatively impacts the quality of life in many women. It entails the downward descent of the pelvic organs (uterus, vagina, bladder, and rectum) in women, causing symptoms including urinary and fecal incontinence, pelvic pain, and sexual dysfunction (1). The prevalence of POP has been estimated at 30%-50% of the population and increases with advancing age (2). It has been cited as one of the most common diagnoses for performing a hysterectomy, and over 300,000 procedures for POP are performed yearly in the United States (3, 4). Unfortunately, the recurrence rate for POP is very high, and approximately 30% of women undergoing surgical repair of POP will require reoperation for recurrent prolapse (4). Direct costs of this surgery exceed 1 billion dollars annually in the United States, and it is estimated that the rate of women seeking treatment for POP will double over the next 30 years as the elderly population rapidly expands (5, 6).While increasing age, parity, menopause, and BMI have been consistently implicated as risk factors for the development of POP, the molecular mechanisms responsible for the maintenance of the pelvic organ support structures are poorly characterized (1, 7-9). It has been proposed that alterations in remodeling of the pelvic floor after childbirth trauma, compounded by the risk factors cited above, lead to gradual weakening of the pelvic support system. In women with POP, biochemical analyses of the supportive structures of the pelvic floor (endopelvic fascia and uterosacral ligaments [USLs]) have demonstrated alterations in

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The uterosacral ligaments (USLs) are key support structures of the uterus and upper vagina. Previously, we have shown that HOXA11 is necessary for the development of the USLs, is deficient in women with pelvic organ prolapse (POP) and regulates expression of extracellular matrix (ECM) proteins. Here we sought to determine if HOXA11 regulates cell proliferation in the USLs in women. Like others, we have found that, there is decreased cellularity in prolapsed USLs compared to USLs in women with normal pelvic support. We have also demonstrated that HOXA11 promotes cell proliferation in murine fibroblasts and primary human USL cells in vitro. These findings support a relationship between HOXA11 expression, rates of proliferation and phenotypic abnormalities in the USL. Based on these findings, we sought to determine if HOXA11 regulates p53, a tumor suppressor gene which controls progression through the cell cycle and regulates ECM genes. We have demonstrated that expression of HOXA11 represses expression of p53, suggesting a mechanism by which HOXA11 regulates of the morphology and integrity of the USLs. A better understanding of the influence of these genes on the homeostasis of the ECM and interactions with each other may prove beneficial in defining the underlying etiologies of the development of POP and aid in the development of new treatment options for women with this disorder.

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Percutaneous tibial nerve stimulation was not cost-effective for treating overactive bladder vs tolterodine ER under a wide range of clinical circumstances.