DOI QR코드

DOI QR Code

Vitamin D Proliferates Vaginal Epithelium through RhoA Expression in Postmenopausal Atrophic Vagina tissue

  • Lee, Arum (Department of Interdisciplinary Program in Biomedical Science, Soonchunhyang University Graduate School) ;
  • Lee, Man Ryul (Soonchunhyang Institute of Medi-bio Science (SIMS) and Institute of Tissue Regeneration, College of Medicine, Soon Chun Hyang University) ;
  • Lee, Hae-Hyeog (Department of Obstetrics and Gynecology, Soonchunhyang University College of Medicine) ;
  • Kim, Yeon-Suk (Department of Interdisciplinary Program in Biomedical Science, Soonchunhyang University Graduate School) ;
  • Kim, Jun-Mo (Departments of Urology, Soonchunhyang University College of Medicine) ;
  • Enkhbold, Temuulee (Department of Interdisciplinary Program in Biomedical Science, Soonchunhyang University Graduate School) ;
  • Kim, Tae-Hee (Department of Obstetrics and Gynecology, Soonchunhyang University College of Medicine)
  • 투고 : 2017.02.19
  • 심사 : 2017.07.14
  • 발행 : 2017.09.30

초록

Postmenopausal atrophic vagina (PAV) is the thinning of the walls of the vagina and decreased lugae of the vagina. PAV is caused by decreased estrogen levels in postmenopausal women. However, the harmful effects of hormone replacement therapy (HRT) have resulted in considerable caution in its use. Various estrogen agonist treatment options are available. Vitamin D is influences the regulation of differentiation and proliferation of various cells, especially tissues lining stratified squamous epithelium, such as the vaginal epithelium. In this study, we hypothesized that vitamin D could provide an alternative and a safe treatment option for PAV by promoting the proliferation and differentiation of the vaginal epithelium. Thirty six patients were enrolled in this case-control study. Vitamin D associated proteins in a vitamin D and sex hormone treated vaginal epithelial cell line as well as normal and PAV tissues were measured. To confirm of cell-to-cell junction protein expression, cell line and tissue studies included RT-PCR, immunohistochemistry staining, and immunoblot analyses. The expression of cell-to-cell junction proteins was higher in women with symptoms of atrophic vagina tissue compared to women without the symptoms. Vitamin D stimulated the proliferation of the vaginal epithelium by activating p-RhoA and Erzin through the vitamin D receptor (VDR). The results suggest that vitamin D positively regulates cell-to-cell junction by increasing the VDR/p-RhoA/p-Ezrin pathway. This is the first study to verify the relationship of the expression of RhoA and Ezrin proteins in vaginal tissue of PAV.

키워드

참고문헌

  1. Abban, G., Yilidirim, N.B., and Jetten, A.M. (2008). Regulation of the vitamin D receptor and cornifin beta expression in vaginal epithelium of the rats through vitamin D3. Eur. J. Histochem. 52, 107-114.
  2. Chiappetta, C., Leopizzi, M., Censi, F., Puggioni, C., Petrozza, V., Rocca, C.D., and Di Cristofano, C. (2014). Correlation of the Rac1/RhoA pathway with ezrin expression in osteosarcoma. Appl. Immunohistochem. Mol. Morphol. 22, 162-170. https://doi.org/10.1097/PDM.0000000000000033
  3. Choi, S.D. (2012). Ezrin is an essential marker for metastasis of gynecologic cancer. J. Korean Society of Menopause 18, 81-93. https://doi.org/10.6118/jksm.2012.18.2.81
  4. Constantine, G., Graham, S., Koltun, W.D. and Kingsberg, S.A. (2014). Assessment of ospemifene or lubricants on clinical signs of VVA. J. Sex. Med. 11, 1033-1041. https://doi.org/10.1111/jsm.12428
  5. Deeb, K.K., Trump, D.L. and Johnson, C.S. (2007). Vitamin D signalling pathways in cancer: potential for anticancer therapeutics. Nat. Rev. Cancer 7, 684-700. https://doi.org/10.1038/nrc2196
  6. Fadiel, A., Lee, H., Demir, N., Richman, S., Iwasaki, A., Connell, K. and Naftolin, F. (2008). Ezrin is a key element in the human vagina. Maturitas 60, 31-41. https://doi.org/10.1016/j.maturitas.2008.03.007
  7. Farkas, A.E., Capaldo, C.T. and Nusrat, A. (2012). Regulation of epithelial proliferation by tight junction proteins. Ann. N Y Acad. Sci. 1258, 115-124. https://doi.org/10.1111/j.1749-6632.2012.06556.x
  8. Giovannucci, E., Liu, Y., Rimm, E.B., Hollis, B.W., Fuchs, C.S., Stampfer, M.J., and Willett, W.C. (2006). Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J. Natl. Cancer Institute 98, 451-459. https://doi.org/10.1093/jnci/djj101
  9. Kher, S.S., and Worthylake, R.A. (2012). Nuanced junctional RhoA activity. Nat. Cell Biol. 14, 784-786. https://doi.org/10.1038/ncb2553
  10. Kim, T.H., Lee, H.H., and Park, J. (2014). Immunohistochemical detection of the 1, 25-dihydroxy vitamin D receptor in the human vagina. Iran. J. Reprod. Med. 12, 805-810.
  11. Kingsberg, S.A., and Krychman, M.L. (2013). Resistance and barriers to local estrogen therapy in women with atrophic vaginitis. J. Sex. Med. 10, 1567-1574. https://doi.org/10.1111/jsm.12120
  12. Kosova, G., Stephenson, M.D., Lynch, V.J., and Ober, C. (2015). Evolutionary forward genomics reveals novel insights into the genes and pathways dysregulated in recurrent early pregnancy loss. Hum. Reprod. 30, 519-529. https://doi.org/10.1093/humrep/deu355
  13. Minkin, M.J., Maamari, R. and Reiter, S. (2013). Improved compliance and patient satisfaction with estradiol vaginal tablets in postmenopausal women previously treated with another local estrogen therapy. Int. J. Womens Health 5, 133-139.
  14. Mora, J.R., Iwata, M. and Von Andrian, U.H. (2008). Vitamin effects on the immune system: vitamins A and D take centre stage. Nat. Rev. Immunol. 8, 685-698. https://doi.org/10.1038/nri2378
  15. Muhammad, S.I., Maznah, I., Mahmud, R.B., Saeed, M.I., Imam, M.U., and Ishaka, A. (2013a). Estrogen receptor modulatory effects of germinated brown rice bioactives in the uterus of rats through the regulation of estrogen-induced genes. Drug Des. Devel. Ther. 7, 1409-1420.
  16. Notelovitz, M., Funk, S., Nanavati, N., and Mazzeo, M. (2002). Estradiol absorption from vaginal tablets in postmenopausal women. Obstet. Gynecol. 99, 556-562.
  17. Ordonez-Moran, P., Larriba, M.J., Palmer, H.G., Valero, R.A., Barbachano, A., Dunach, M., de Herreros, A.G., Villalobos, C., Berciano, M.T., and Lafarga, M. (2008). RhoA-ROCK and p38MAPKMSK1 mediate vitamin D effects on gene expression, phenotype, and Wnt pathway in colon cancer cells. J. Cell Biol. 183, 697-710. https://doi.org/10.1083/jcb.200803020
  18. Portman, D., Palacios, S., Nappi, R., and Mueck, A. (2014). Ospemifene, a non-oestrogen selective oestrogen receptor modulator for the treatment of vaginal dryness associated with postmenopausal vulvar and vaginal atrophy: a randomised, placebocontrolled, phase III trial. Maturitas 78, 91-98. https://doi.org/10.1016/j.maturitas.2014.02.015
  19. Reiter, S. (2013). Barriers to effective treatment of vaginal atrophy with local estrogen therapy. Int. J. Gen. Med. 6, 153-158.
  20. Schwartz, G.G., and Skinner, H.G. (2007). Vitamin D status and cancer: new insights. Curr. Opin.Clin. Nutr. Metab. Care 10, 6-11.
  21. Suckling, J., Lethaby, A., and Kennedy, R. (2006a). Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane. Database Syst. Rev. 31, Cd001500.
  22. Suckling, J.A., Kennedy, R., Lethaby, A., and Roberts, H. (2006b). Local oestrogen for vaginal atrophy in postmenopausal women. Cochrane. Database Syst. Rev. 18, Cd001500.
  23. Unfer, V., Casini, M.L., Costabile, L., Mignosa, M., Gerli, S., and Di Renzo, G.C. (2004). Endometrial effects of long-term treatment with phytoestrogens: a randomized, double-blind, placebo-controlled study. Fertil. Steril. 82, 145-148. https://doi.org/10.1016/j.fertnstert.2003.11.041
  24. Vasco, V.L., Leopizzi, M., and Della Rocca, C. (2015). Ezrin-related Phosphoinositide pathway modifies RhoA and Rac1 in human osteosarcoma cell lines. J. Cell Commun. Signal. 9, 55-62. https://doi.org/10.1007/s12079-015-0265-y
  25. Wills, S., Ravipati, A., Venuturumilli, P., Kresge, C., Folkerd, E., Dowsett, M., Hayes, D.F., and Decker, D.A. (2012). Effects of vaginal estrogens on serum estradiol levels in postmenopausal breast cancer survivors and women at risk of breast cancer taking an aromatase inhibitor or a selective estrogen receptor modulator. J. Oncol. Practice 8, 144-148. https://doi.org/10.1200/JOP.2011.000352
  26. Woo, S.M., Lim, H.S., Jeong, K.Y., Kim, S.M., Kim, W.J., and Jung, J.Y. (2015). Vitamin D promotes odontogenic differentiation of human dental pulp cells via ERK activation. Mol. Cells 38, 604-609. https://doi.org/10.14348/molcells.2015.2318
  27. Yildirim, B., Abban, G., and Erdogan, B.S. (2004a). Immunohistochemical detection of 1,25-dihydroxyvitamin D receptor in rat vaginal epithelium. Fertil. Steril. 82, 1602-1608. https://doi.org/10.1016/j.fertnstert.2004.07.949
  28. Yildirim, B., Kaleli, B., Düzcan, E., and Topuz, O. (2004b). The effects of postmenopausal Vitamin D treatment on vaginal atrophy. Maturitas 49, 334-337. https://doi.org/10.1016/j.maturitas.2004.02.008
  29. Zhang, Y.G., Wu, S., and Sun, J. (2013). Vitamin D, vitamin D receptor and tissue barriers. Tissue Barriers 1, e23118. https://doi.org/10.4161/tisb.23118

피인용 문헌

  1. A systematic review of the role of vitamin D and calcium in premenstrual syndrome vol.62, pp.2, 2017, https://doi.org/10.5468/ogs.2019.62.2.73
  2. Pharmacotherapy for the treatment of vaginal atrophy vol.20, pp.7, 2019, https://doi.org/10.1080/14656566.2019.1574752
  3. Relationship between vitamin D status and the vaginal microbiome during pregnancy vol.39, pp.6, 2017, https://doi.org/10.1038/s41372-019-0343-8
  4. Intravaginal Administration of Human Type III Collagen-Derived Biomaterial with High Cell-Adhesion Activity to Treat Vaginal Atrophy in Rats vol.6, pp.4, 2017, https://doi.org/10.1021/acsbiomaterials.9b01649