title: Transcriptional Regulation of Connective Tissue Metabolism Genes in Women With Pelvic Organ Prolapse.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: 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.
authors.forename: Ali
authors.initials: A
authors.lastname: Borazjani
authors.forename: Nathan
authors.initials: N
authors.lastname: Kow
authors.forename: Samantha
authors.initials: S
authors.lastname: Harris
authors.forename: Beri
authors.initials: B
authors.lastname: Ridgeway
authors.forename: Margot S
authors.initials: MS
authors.lastname: Damaser
mesh_terms: D000328:Adult; D055395:Bone Morphogenetic Protein 1 / Q000378:metabolism; D016022:Case-Control Studies; D024042:Collagen Type I / Q000235:genetics*; D024061:Collagen Type III / Q000235:genetics*; D003238:Connective Tissue / Q000378:metabolism*; D005109:Extracellular Matrix / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D056887:Pelvic Organ Prolapse / Q000145:classification / Q000235:genetics / Q000378:metabolism*; D017698:Postmenopause; D017697:Premenopause; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism; D012044:Regression Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000235:genetics / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D024042:Collagen Type I; D024061:Collagen Type III; C417543:RXFP1 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; C560823:TIMP2 protein, human; D019717:Tissue Inhibitor of Metalloproteinase-3; D019716:Tissue Inhibitor of Metalloproteinase-2; D055395:Bone Morphogenetic Protein 1; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2