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From The Berman-Gund Laboratory for the Study of Retinal Degenerations,* Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts; the Department of Biomedical Engineering, Lerner Research Institute and Glickman Urological Institute, Cleveland Clinic Foundation, Cleveland, Ohio; and the Research Service, Louis Stokes Cleveland Veteran’s Administration Medical Center, Cleveland, Ohio
Pelvic floor disorders, a group of conditions affecting adult women, include pelvic organ prolapse and urinary incontinence. Vaginal childbirth and aging are risk factors, and weakening of the pelvic support structures is a major aspect of the pathology. However, the underlying molecular mechanism remains unknown. Female reproductive organs are rich in elastic fibers that turn over slowly in most adult tissues but undergo massive remodeling in the reproductive organs through pregnancy and birth. Here we show that a failure to maintain elastic fiber homeostasis in mice causes pelvic floor disorders. Lysyl oxidase-like-1 (LOXL1), a protein essential for the postnatal deposition of elastic fibers, was highly expressed and regulated in the reproductive tract of the mouse, and its expression was diminished during aging. LOXL1 deficiency caused an inability of reproductive tissues to replenish elastic fibers after parturition, leading to pelvic organ prolapse, weakening of the vaginal wall, paraurethral pathology, and lower urinary tract dysfunction. These data demonstrate the importance of elastic fibers for maintaining structural and functional integrity of the female pelvic floor. Our findings raise the possibility that a failure of elastic fiber homeostasis, either due to genetic predisposition or advancing age, could underlie the etiology of pelvic floor dysfunction in women.
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