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

Borazjani, Ali PhD; Kow, Nathan MD; Harris, Samantha BS; Ridgeway, Beri MD; Damaser, Margot S. PhD

Female Pelvic Medicine & Reconstructive Surgery: January/February 2017 - Volume 23 - Issue 1 - p 44–52
doi: 10.1097/SPV.0000000000000337
Original Articles

Objective: The aim of this study was 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 bone morphogenetic protein 1 (BMP1), collagen types I (COL1) and III (COL3), relaxin family peptide receptor 1 (RXFP1), matrix metallopeptidase 2, and TIMP metallopeptidase inhibitors 2 and 3. Hematoxylin and eosin staining was used to assess cellularity of the connective tissue layer. Kruskal-Wallis test, Mann-Whitney U test, Pearson correlation, or linear regression analyses were used, as appropriate.

Results: Bone morphogenetic protein 1 expression was significantly up-regulated in patients with POP compared with controls. Bone morphogenetic protein 1 expression was correlated with COL1 expression in all groups but only correlated with TIMP metallopeptidase inhibitor 3 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 expressions was significantly elevated in premenopausal women with POP compared with the other 2 groups. The slopes between COL1-COL3, COL3–matrix metallopeptidase 2, COL1-RXFP1, and COL3-RXFP1 expressions were significantly lower in postmenopausal women compared with premenopausal women with POP. No differences were found in overall tissue cellularity.

Conclusions: Bone morphogenetic protein 1 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 and COL3 expressions may be associated with early (premenopausal) development of POP. The expression of RXFP1 in postmenopausal women and its altered intergene regulation suggests a role for RXFP1 in connective tissue metabolism outside pregnancy.

Early and late development of POP have different expression profiles of connective tissue metabolism genes.

From the *Department of Biomedical Engineering, Cleveland Clinic; †Department of Chemical & Biomedical Engineering, Cleveland State University; ‡Department of Obstetrics & Gynecology and §Glickman Urological and Kidney Institute, Cleveland Clinic; and ∥Advanced Platform Technology Center, Louis Stokes Cleveland VA Medical Center, Cleveland, OH.

Reprints: Margot S. Damaser, PhD, Department of Biomedical Engineering, Cleveland Clinic, 9500 Euclid Ave, ND20, Cleveland, OH 44195. E-mail: damasem@ccf.org.

Presented as a podium presentation at the American Urological Association Annual Meeting in New Orleans, LA, May 15-19, 2015.

Supported in part by NIH R01 HD059859 (to M.S.D.), the Cleveland Clinic Research Projects Committee (to N.K.), National Science Foundation Graduate Research Fellowship Grant #1000139839 (to A.B.), the Rehabilitation R&D Service of the Department of Veterans Affairs (M.S.D.), and the Cleveland Clinic (M.S.D. and B.R.).

The authors have declared they have no conflicts of interest.

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