HOXA11 is critical for development and maintenance of uterosacral ligaments and deficient in pelvic prolapse

Abstract

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

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

“…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, POP was not reported.…”

The Scientific Rationale for Using Biomaterials in Stress Urinary Incontinence and Pelvic Organ Prolapse

“…Collagen metabolism is largely regulated by matrix metalloproteinases (MMPs), which are zinc-dependent endopeptidases that degrade collagen; over 20 different MMPs have been identified [9]. Multiple studies have revealed higher MMP activity in patients with SUI and POP as compared to control patients [6,[10][11][12][13]. With increasingly more information available regarding the etiologies of pelvic floor dysfunction, there is a need for treatment strategies to incorporate this knowledge and translate it into clinical practice.…”

The contribution of mouse models to the understanding of constitutional thrombocytopenia

“…Heterozygous and homozygous Hoxa11-deficient mice have malformations in the lower and hind limbs, consistent with the observations in patients, but thrombocytopenia has never been reported. 73,74 At present, it is not known whether the megakaryocytopoietic defects present in patients result from a dominant negative effect of the point mutations or not. 75 …”