Differential gene expression of extracellular-matrix-related proteins in the vaginal apical compartment of women with pelvic organ prolapse

  • Haijiao Wang
  • Yukimi Kira
  • Akihiro Hamuro
  • Aki Takase
  • Daisuke Tachibana
  • Masayasu Koyama
Original Article
  • 27 Downloads

Abstract

Introduction and hypothesis

Pelvic organ prolapse (POP) is a multifactorial disorder that impairs the quality of life (QoL) of older women in particular. The purpose of this study was to elucidate the pathogenesis of POP by focusing on the extracellular matrix (ECM).

Methods

Patients were classified into two groups—with or without cervical elongation—using the POP quantification system. Specimens were obtained from 29 women with POP during hysterectomy. The expression of fibulin-5, elastin, integrin β1 (ITGβ1), lysyl oxidase-like protein-1 (LOXL1) and collagen in the vagina, uterosacral ligament, and uterine cervix was investigated by quantitative real-time polymerase chain reaction (RT-PCR) and correlation between gene levels and severity of POP examined. The location of proteins was analyzed using immunohistochemical staining and expression of fibulin-5 protein analyzed by Western blotting.

Results

Fibulin-5 and elastin were mainly expressed in lamina propria and fibromuscular layers of the vagina and uterosacral ligament. Gene levels of fibulin-5 and ITGβ1 in uterosacral ligaments increased with severity of POP in women with cervical elongation, while no correlation was observed in women with a normal cervix. In women with uterine cervical elongation, each ECM-related gene significantly increased with POP staging. Furthermore, fibulin-5 protein also increased in the uterosacral ligament and uterine cervix.

Conclusions

The severity of POP and gene expression of ECM-related proteins were inversely correlated in vaginal tissue in a normal and elongated cervix. These results suggested that the differing progression of the two types of POP have a relationship with ECM-related protein.

Keywords

Pelvic organ prolapse Cervical elongation Fibulin-5 Integrin β1 Lysyl oxidase-like protein-1 Extracellular matrix 

Notes

Acknowledgments

This work was supported, in part, by Grants-in-Aid for Scientific Research (No.16 K11147) from the Ministry of Education, Culture, Sports, Science and Technology, Japan. The authors would like to acknowledge the doctors in the Department of Obstetrics and Gynecology for their assistance with sample collection, Dr. Ji-Young Hong (BioLead Inc., Korea), Keisuke Inoue and Yoriko Yabunaka (Research support platform of Osaka City University Graduate School of Medicine) for special technical assistance.

Compliance with ethical standards

Conflicts of interest

None.

References

  1. 1.
    Weber AM, Richter HE. Pelvic organ prolapse. Obstet Gynecol. 2005;106(3):615–34.  https://doi.org/10.1097/01.Aog.0000175832.13266.Bb.CrossRefPubMedGoogle Scholar
  2. 2.
    DeLancey JO. Functional anatomy of the female lower urinary tract and pelvic floor. CIBA Found Symp. 1990;151:57–69.PubMedGoogle Scholar
  3. 3.
    Drewes PG, Yanagisawa H, Starcher B, Hornstra I, Csiszar K, Marinis SI, et al. Pelvic organ prolapse in fibulin-5 knockout mice - pregnancy-induced changes in elastic fiber homeostasis in mouse vagina. Am J Pathol. 2007;170(2):578–89.  https://doi.org/10.2353/ajpath.2007.060662.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Chin K, Wieslander C, Shi H, Balgobin S, Montoya TI, Yanagisawa H, et al. Pelvic organ support in animals with partial loss of fibulin-5 in the vaginal wall. Plos One. 2016;11(4).  https://doi.org/10.1371/journal.pone.0152793.
  5. 5.
    Bump RC, Mattiasson A, Bo K, Brubaker LP, DeLancey JO, Klarskov P, et al. The standardization of terminology of female pelvic organ prolapse and pelvic floor dysfunction. Am J Obstet Gynecol. 1996;175(1):10–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Ibeanu OA, Chesson RR, Sandquist D, Perez J, Santiago K, Nolan TE. Hypertrophic cervical elongation: clinical and histological correlations. Int Urogynecol J. 2010;21(8):995–1000.  https://doi.org/10.1007/s00192-010-1131-3.CrossRefPubMedGoogle Scholar
  7. 7.
    Bortolini MA, Rizk DE. Genetics of pelvic organ prolapse: crossing the bridge between bench and bedside in urogynecologic research. Int Urogynecol J. 2011;22(10):1211–9.  https://doi.org/10.1007/s00192-011-1502-4.CrossRefPubMedGoogle Scholar
  8. 8.
    Budatha M, Roshanravan S, Zheng Q, Weislander C, Chapman SL, Davis EC, et al. Extracellular matrix proteases contribute to progression of pelvic organ prolapse in mice and humans. J Clin Invest. 2011;121(5):2048–59.  https://doi.org/10.1172/JCI45636.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    De Landsheere L, Munaut C, Nusgens B, Maillard C, Rubod C, Nisolle M, et al. Histology of the vaginal wall in women with pelvic organ prolapse: a literature review. Int Urogynecol J. 2013;24(12):2011–20.  https://doi.org/10.1007/s00192-013-2111-1.CrossRefPubMedGoogle Scholar
  10. 10.
    Zhao BH, Zhou JH. Decreased expression of elastin, fibulin-5 and lysyl oxidase-like 1 in the uterosacral ligaments of postmenopausal women with pelvic organ prolapse. J Obstet Gynaecol Res. 2012;38(6):925–31.  https://doi.org/10.1111/j.1447-0756.2011.01814.x.CrossRefPubMedGoogle Scholar
  11. 11.
    Hamuro A, Tachibana D, Wang H, Hayashi M, Yanai S, Kurihara Y, et al. Combined reconstructive surgery involving uterosacral colpopexy and anterior vaginal mesh implantation for pelvic organ prolapse. J Obstet Gynaecol Res. 2016;42(6):707–15.  https://doi.org/10.1111/jog.12952.CrossRefPubMedGoogle Scholar
  12. 12.
    Zheng Q, Davis EC, Richardson JA, Starcher BC, Li T, Gerard RD, et al. Molecular analysis of fibulin-5 function during de novo synthesis of elastic fibers. Mol Cell Biol. 2007;27(3):1083–95.  https://doi.org/10.1128/MCB.01330-06.CrossRefPubMedGoogle Scholar
  13. 13.
    Yanagisawa H, Davis EC, Starcher BC, Ouchi T, Yanagisawa M, Richardson JA, et al. Fibulin-5 is an elastin-binding protein essential for elastic fibre development in vivo. Nature. 2002;415(6868):168–71.  https://doi.org/10.1038/415168a.CrossRefPubMedGoogle Scholar
  14. 14.
    Yanagisawa H, Schluterman MK, Brekken RA. Fibulin-5, an integrin-binding matricellular protein: its function in development and disease. Journal Cell Commun Signal. 2009;3(3–4):337–47.  https://doi.org/10.1007/s12079-009-0065-3.CrossRefGoogle Scholar
  15. 15.
    Alarab M, Bortolini MA, Drutz H, Lye S, Shynlova O. LOX family enzymes expression in vaginal tissue of premenopausal women with severe pelvic organ prolapse. Int Urogynecol J. 2010;21(11):1397–404.  https://doi.org/10.1007/s00192-010-1199-9.CrossRefPubMedGoogle Scholar
  16. 16.
    Zhou Y, Ling O, Bo L. Expression and significance of lysyl oxidase-like 1 and fibulin-5 in the cardinal ligament tissue of patients with pelvic floor dysfunction. Journal Biomed Res. 2013;27(1):23–8.  https://doi.org/10.7555/JBR.27.20110142.Google Scholar
  17. 17.
    Kerkhof MH, Hendriks L, Brolmann HA. Changes in connective tissue in patients with pelvic organ prolapse--a review of the current literature. Int Urogynecol J Pelvic Floor Dysfunct. 2009;20(4):461–74.  https://doi.org/10.1007/s00192-008-0737-1.CrossRefPubMedGoogle Scholar
  18. 18.
    Antovska SV. A new modification of the POPQ system - its effectiveness in the diagnosis of supravaginal elongation of the uterine cervix in cases with genital prolapse. Bratisl Med J. 2008;109(7):307–12.Google Scholar
  19. 19.
    Berger MB, Ramanah R, Guire KE, DeLancey JO. Is cervical elongation associated with pelvic organ prolapse? Int Urogynecol J. 2012;23(8):1095–103.  https://doi.org/10.1007/s00192-012-1747-6.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Hirai M, Ohbayashi T, Horiguchi M, Okawa K, Hagiwara A, Chien KR, et al. Fibulin-5/DANCE has an elastogenic organizer activity that is abrogated by proteolytic cleavage in vivo. J Cell Biol. 2007;176(7):1061–71.  https://doi.org/10.1083/jcb.200611026.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Choi J, Bergdahl A, Zheng Q, Starcher B, Yanagisawa H, Davis EC. Analysis of dermal elastic fibers in the absence of fibulin-5 reveals potential roles for fibulin-5 in elastic fiber assembly. Matrix Biol. 2009;28(4):211–20.  https://doi.org/10.1016/j.matbio.2009.03.004.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Nosti PA, Gutman RE, Iglesia CB, Park AJ, Tefera E, Sokol AI. Defining cervical elongation: a prospective observational study. J Obstet Gynaecol Can. 2017;39(4):223–8.  https://doi.org/10.1016/j.jogc.2016.10.012.CrossRefPubMedGoogle Scholar

Copyright information

© The International Urogynecological Association 2018

Authors and Affiliations

  • Haijiao Wang
    • 1
  • Yukimi Kira
    • 2
  • Akihiro Hamuro
    • 1
  • Aki Takase
    • 1
  • Daisuke Tachibana
    • 1
  • Masayasu Koyama
    • 1
  1. 1.Department of Obstetrics and GynecologyOsaka City University Graduate School of MedicineOsakaJapan
  2. 2.Department of Research Support PlatformOsaka City University Graduate School of MedicineOsakaJapan

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