Expression of Extracellular Matrix-Remodeling Proteins Is Altered in Vaginal Tissue of Premenopausal Women With Severe Pelvic Organ Prolapse

Abstract

Aim:

The molecular etiology of pelvic organ prolapse (POP) is complex and not well understood. We compared the expression/activity of extracellular matrix (ECM)-processing (procollagen I N-proteinase/ a disintegrin and metalloproteinase with thrombospondin motifs [ADAMTS]-2,-3,-14) and ECM-degrading (matrix metalloproteinase [MMP]-1, -2, -7, -8, -9, -12) enzymes and their natural tissue inhibitors (tissue inhibitors of metalloproteinase [TIMP]-1,-2,-3,-4) in vaginal tissues from premenopausal women with advanced POP (POP-Q stage ≥ 3) and asymptomatic controls (POP-Q = 0).

Study Design:

We sampled the anterior vaginal wall of 36 premenopausal women (17 patients with POP and 19 controls) undergoing total hysterectomy. Exclusion criteria include steroid therapy, malignancy, previous pelvic surgery, and connective tissue diseases. Total RNAs and proteins were quantified by real-time polymerase chain reaction, immunoblotting, and Luminex assay; MMPs activity was analyzed by zymography and tissue localization by immunohistochemistry.

Results:

The MMP-2 gelatinase activity as well as expression of 58-kDa isoform of ADAMTS-2 was upregulated in patients with POP, irrespective of menstrual phase status, secretory or proliferative, when compared to controls (P < .05). The TIMP-1-4 gene and TIMP-1 protein expression were significantly (P < .05) reduced, whereas protein expression of MMP-12 (pro and active forms) was significantly increased in vaginal biopsies of patients with POP in the proliferative phase of the menstrual cycle compared to corresponding controls. Analyses of MMP-12, TIMP-1, and ADAMTS-2 tissue immunostaining indicate similar localization in the vaginal specimens from control and patients with POP.

Conclusion:

Expression of ECM-remodeling proteins is altered in the vagina of premenopausal patients with severe POP. We speculate that dysregulation of MMP/TIMP complexes and ADAMTS-2 proteins may cause connective tissue defects, which result in weakened vaginal wall support and POP development.

Keywords

POP TIMP MMP PNP/ADAMTS

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