title: Lower urogenital tract anatomical and functional phenotype in lysyl oxidase like-1 knockout mice resembles female pelvic floor dysfunction in humans.
abstract: Female pelvic floor dysfunction (FPFD) is a complex group of conditions that 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 wk. Pelvic visceral anatomy in LOXL1-KO was evaluated with a 7-Tesla magnetic resonance imaging (MRI) scanner. LUT function was assessed using conscious cystometry and leak point pressure (LPP) testing. Quantitative histological analysis of elastic fibers was performed on external urethral sphincter (EUS) cross sections. By 25 wk 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.
authors.affiliation: Glickman Urological and Kidney Institute, Department of Obstetrics and Gynecology, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Una J
authors.initials: UJ
authors.lastname: Lee
authors.forename: A Marcus
authors.initials: AM
authors.lastname: Gustilo-Ashby
authors.forename: Firouz
authors.initials: F
authors.lastname: Daneshgari
authors.forename: Mei
authors.initials: M
authors.lastname: Kuang
authors.forename: Drina
authors.initials: D
authors.lastname: Vurbic
authors.forename: Dan Li
authors.initials: DL
authors.lastname: Lin
authors.forename: Chris A
authors.initials: CA
authors.lastname: Flask
authors.forename: Tiansen
authors.initials: T
authors.lastname: Li
authors.forename: Margot S
authors.initials: MS
authors.lastname: Damaser
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D004549:Elastin / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D008279:Magnetic Resonance Imaging; D051379:Mice; D018345:Mice, Knockout; D017773:Pelvic Floor; D010641:Phenotype; D014521:Urethra / Q000473:pathology / Q000503:physiopathology; D001743:Urinary Bladder / Q000473:pathology / Q000503:physiopathology; D014549:Urinary Incontinence / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D014566:Urogenital System / Q000473:pathology / Q000503:physiopathology*; D014596:Uterine Prolapse / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*
chemical_list: D004549:Elastin; D000594:Amino Acid Oxidoreductases; C482019:Loxl1 protein, mouse