Submitted on February 6, 2008
Accepted on May 15, 2008
Lower Urogenital Tract Anatomical and Functional Phenotype in Lysyl Oxidase Like-1 Knockout Mice Resembles Female Pelvic Floor Dysfunction in Humans
Una J Lee1, Arlan Marcus Gustilo-Ashby2, Firouz Daneshgari3, Mei Kuang3, Drina Vurbic4, Dan Li Lin5, Chris A Flask6, Tiansen Li7, and Margot S. Damaser8*
1 Department of Urology, Cleveland Clinic, Glickman Urological and Kidney Institute, Cleveland, Ohio, United States; Research Service, Louis Stokes Cleveland VAMC, Cleveland, Ohio, United States
2 Department of Ob/Gyn, Division of Urogynecology and Reconstructive Pelvic Surgery, Cleveland Clinic, Cleveland, Ohio, United States; Research Service, Louis Stokes Cleveland VAMC, Cleveland, Ohio, United States
3 Department of Urology, Cleveland Clinic, Glickman Urological and Kidney Institute, Cleveland, Ohio, United States
4 Research Service, Louis Stokes Cleveland VAMC, Cleveland, Ohio, United States
5 Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, United States; Research Service, Louis Stokes Cleveland VAMC, Cleveland, Ohio, United States
6 Department of Radiology, Case Western Reserve University, Cleveland, Ohio, United States
7 Department of Opthalmology (Neurosciences), Massachusetts Eye & Ear Institute, Harvard Medical School, Boston, Massachusetts, United States
8 Department of Urology, Cleveland Clinic, Glickman Urological and Kidney Institute, Cleveland, Ohio, United States; Department of Biomedical Engineering, Cleveland Clinic, Cleveland, Ohio, United States; Research Service, Louis Stokes Cleveland VA Medical Center, 10701 East Boulevard, Cleveland, Ohio, 44106, United States
* To whom correspondence should be addressed. E-mail: damasem{at}ccf.org.
Female pelvic floor dysfunction (FPFD) is a complex group of conditions which include urinary incontinence and pelvic organ prolapse (POP). In humans, elastin homeostasis has been implicated in the pathophysiology of FPFD. Lysyl oxidase-like 1 knockout (LOXL1-KO) mice demonstrate abnormal elastic fiber homeostasis and develop FPFD after parturition. We compared the lower urogenital tract (LUT) anatomy and function in LOXL1-KO mice with and without POP. LUT anatomy was assessed in LOXL1-KO mice over 28 weeks. Pelvic visceral anatomy in LOXL1-KO was evaluated with a 7 Tesla MRI scanner. LUT function was assessed using conscious cystometry (CMG) and leak point pressure (LPP) testing. Quantitative histologic analysis of elastic fibers was performed on external urethral sphincter (EUS) cross sections. By 25 weeks of age, 50% of parous LOXL1-KO mice developed POP. LOXL1-KO mice with POP had greater variability in the size and location of the bladder on MRI compared with mice without POP. Parity and POP were associated with lower LPP. Elastin clusters were significantly increased in the EUS of LOXL1-KO mice with POP. Because parity triggers POP in LOXL1-KO mice, LOXL1-KO mice with POP have variable internal pelvic anatomy, and both parity and POP are associated with a decrease in LPP, we conclude that LOXL1 LUT anatomical and functional phenotype resembles FPFD in humans. The increase in elastin clusters in the urethra of LOXL1-KO mice with POP suggests that elastin disorganization may lead to functional abnormalities. We conclude that LOXL1 warrants further investigation in the pathphysiology of FPFD
