desmosine and Uterine-Prolapse

Fibulin-5 is crucial for normal elastic fiber synthesis in the vaginal wall; more than 90% of fibulin-5-knockout mice develop pelvic organ prolapse by 20 weeks of age. In contrast, fibulin-1 and -2 deficiencies do not result in similar pathologies, and fibulin-4-knockout mice die shortly after birth. EFEMP1 encodes fibulin-3, an extracellular matrix protein important in the maintenance of abdominal fascia. Herein, we evaluated the role of fibulin-3 in pelvic organ support. Pelvic organ support was impaired significantly in female Efemp1 knockout mice (Fbln3(-[supi]/-)), and overt vaginal, perineal, and rectal prolapse occurred in 26.9% of animals. Prolapse severity increased with age but not parity. Fibulin-5 was up-regulated in vaginal tissues from Fbln3(-[supi]/-) mice regardless of prolapse. Despite increased expression of fibulin-5 in the vaginal wall, pelvic organ support failure occurred in Fbln3(-[supi]/-) animals, suggesting that factors related to aging led to prolapse. Elastic fiber abnormalities in vaginal tissues from young Fbln3(-[supi]/-) mice progressed to severe elastic fiber disruption with age, and vaginal matrix metalloprotease activity was increased significantly in Fbln3(-[supi]/-) animals with prolapse compared with Fbln3(-[supi]/-) mice without prolapse. Overall, these results indicate that both fibulin-3 and -5 are important in maintaining pelvic organ support in mice. We suggest that increased vaginal protease activity and abnormal elastic fibers in the vaginal wall are important components in the pathogenesis of pelvic organ prolapse.

Topics: Animals; Desmosine; Elastic Tissue; Extracellular Matrix Proteins; Female; Immunoblotting; Immunohistochemistry; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Knockout; Recombinant Proteins; Rectal Prolapse; Reverse Transcriptase Polymerase Chain Reaction; Uterine Prolapse

Genital prolapse is a debilitating manifestation of pelvic floor dysfunction. The cause of this condition has not been elucidated. The purpose of this study was to determine elastin content and RNA expression of related enzymes of elastin synthesis in uterosacral ligament biopsies from women with severe prolapse, and controls with normal pelvic support.. Biopsies were taken from the uterosacral ligament tissue of 31 women with Grade III or greater prolapse and 29 women with normal pelvic support. Elastin content was assessed by measuring desmosine using radioimmunoassay, and quantitative real time PCR was performed to quantify mRNA levels of lysyl oxidase (LOX), lysyl oxidase like-1 (LOXL1), LOXL2 and fibulin-5 (FIB-5).. The mean desmosine concentration found in uterosacral ligaments of women with prolapse (n =26) was 103.3+/-59.3 pmolD/mgP compared to controls (n =29) 120.5+/-47.4 pmolD/mgP (p =0.1943). In the subgroup of subjects with complete procidentia (n =8), mean desmosine concentration was 50.6+/-25.8 and 127.1+/-42.2 pmolD/mgP in age-matched controls (n =12) (p <0.05). In tissue from subjects with more than 2 vaginal deliveries (n =18), the mean desmosine concentration was 99.9+/-60.7 and 133.0+/-44.0 pmolD/mgP in controls (n =17) (p <0.05). Expression of LOX, LOXL1 and LOXL2 decreased 8.2-fold+/-3.4, 5.0-fold+/-1.7 and 15.2-fold+/-5.2, respectively (mean+/-SD) in cases versus controls (p<0.05). Expression of FIB-5 was increased 3.1-fold+/-0.7 compared to controls (p<0.05).. Significantly decreased desmosine content was measured in the uterosacral ligament tissue from women with prolapse versus controls in women with parity >2 and in women with complete procidentia. Suppression of mRNA for LOX and two LOX isoenzymes was correspondingly present. These results suggest that altered elastin metabolism is present in women with uterine prolapse.

Topics: Adult; Aged; Biopsy; Desmosine; Elastin; Extracellular Matrix Proteins; Fascia; Female; Gene Expression; Humans; Isoenzymes; Ligaments; Middle Aged; Pelvic Bones; Protein-Lysine 6-Oxidase; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Uterine Prolapse