Transcriptional Regulation of Connective Tissue Metabolism Genes in Women With Pelvic Organ Prolapse

Abstract

Objective To compare differences in expressions and relationships between key genes involved in extracellular matrix metabolism and tissue cellularity in women with and without pelvic organ prolapse (POP) Methods A total of 80 biopsies (anterior cuff, posterior cuff, and/or leading edge) were obtained from 30 women: n=10 premenopausal without POP (controls), n=10 premenopausal with POP, and n=10 postmenopausal with POP. Quantitative reverse-transcriptase polymerase chain reaction was used to assess gene expression of BMP1, COL1, COL3, RXFP1, MMP2, TIMP2, and TIMP3. H&E staining was used to assess cellularity of the connective tissue layer. Kruskal-Wallis, Mann-Whitney, Pearson’s correlation, or linear regression analyses were used as appropriate. Results BMP1 expression was significantly upregulated in patients with POP compared to controls. BMP1 expression was correlated with COL1 expression in all groups, but only correlated with TIMP3 expression in controls. Similarly, COL3 expression was correlated with RXFP1 expression in women with POP but not in controls. The degree of dependence (slope of the regression line) between COL1 and COL3 expression was significantly elevated in premenopausal women with POP compared to both other groups. The slopes between COL1-COL3, COL3-MMP2, COL1-RXFP1, and COL3-RXFP1 expression were significantly lower in postmenopausal women compared to premenopausal women with POP. No differences were found in overall tissue cellularity. Conclusions BMP1 expression may play a significant role in the pathophysiology of POP. The finding that BMP1 expression was correlated with COL1 expression in all groups suggests a conserved association between BMP1 and collagen synthesis in the vaginal wall. The elevated slope between COL1-COL3 expressions may be associated with early (premenopausal) development of POP. The expression of RXFP1 in postmenopausal women and its altered inter-gene regulation, suggests a role for RXFP1 in connective tissue metabolism outside of pregnancy.

Evaluation of extracellular matrix protein expression and apoptosis in the uterosacral ligaments of patients with or without pelvic organ prolapse

“…Chtistian et al [6] compared the difference in collagen metabolism between control and POP patients in both USL and vaginal tissue and found a significant increase in pro-MMP-2 expression, but the differences were not statistically significant in USL. Another study [24] obtained a vaginal wall biopsy from three sites (leading edge, anterior and posterior cuffs) at the time of hysterectomy. Interestingly, it was found that COL1, TIMP2 and TIMP3 were all significantly downregulated in the leading edge compared to the posterior cuff in postmenopausal POP women, but no significant differences were found between the posterior cuff and anterior cuff biopsies in any group.…”

Genome‑wide DNA methylation analysis of uterosacral ligaments in women with pelvic organ prolapse

“…In the molecular function category, the terms were ‘cytoskeletal protein binding’, ‘actin binding’, ‘calmodulin binding’, ‘GTPase regulator activity’, ‘calcium channel activity’, ‘calcium-release channel activity’ and ‘protein binding’. Similarly, previous evidence has demonstrated that several families, including collagen (20–22), LOX (15,23–25) and fibulin (25), have important roles in the synthetic metabolism and pathogenesis of POP; however, in the catabolism of the pathogenesis of POP, matrix metalloproteinase (26–30) and tissue inhibitors of metalloproteinase serve vital roles (27,30). In the regulation of anabolic and catabolic processes, the homeobox gene family is key (31,32).…”

Surgical Updates in the Treatment of Pelvic Organ Prolapse

“…Perhaps the future of prolapse management should focus on disease prevention and advancing understanding of pathophysiology of POP, including role of collagen, connective tissue, nerve and muscle injury, and regeneration. Increasingly, investigators are looking for genetic variations that predispose women to early-onset prolapse with the hope that these genes can be selected out in future generations 85. Until these novel pathways of prevention and treatment reach patient application, it is important that a surgeon managing pelvic organ prolapse understands the array of options available for treating prolapse and is able to guide a patient’s decision-making with the available evidence on outcomes and risks.…”