Skip to main content
SpringerLink
Log in

Altered expression of Fas/Fas ligand/caspase 8 and membrane type 1-matrix metalloproteinase in atretic follicles within dehydroepiandrosterone-induced polycystic ovaries in rats

  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

One of the characteristics of polycystic ovary syndrome (PCOS) is the presence of cystic follicles in various stages of growth and atresia, the latter of which is known to be the result of apoptosis and tissue remodeling. To further investigate the process of follicular atresia, we compared ovarian expression and localization of Fas, Fas ligand (FasL), casapse-8 and membrane-type1 matrix metalloproteinase (MT1-MMP) in rats treated with dehydroepiandrosterone (DHEA) as a model of PCOS, and in control rats. We found that the numbers of TdT-mediated dUTP-biotin nick end-labeling (TUNEL)-positive follicles were significantly higher in ovaries from PCOS rats than in those from control rats (P < 0.05), as were ovarian levels of FasL mRNA and protein, processed caspase-8 protein and MT1-MMP mRNA. Correspondingly, we also observed an increase in the level of MTI-MMP catalytic activity and a decrease in the level of pro-caspase-8 protein. In addition, immunohistochemical analyses showed that MT1-MMP and FasL co-localize with TUNEL-positive apoptotic granulosa cells within atretic follicles of PCOS ovaries. Our results suggest that under the PCOS-like conditions induced by DHEA, the Fas/FasL/Caspase-8 (death receptor dependent) pathway is pivotal for follicular atresia, and that increased levels of MT1-MMP likely play an important role in tissue remodeling during structural luteolysis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Sommers SC, Wadman PJ (1956) Pathogenesis of polycystic ovaries. Am J Obstet Gynecol 72:160–169

    PubMed  CAS  Google Scholar 

  2. Singh KB (2005) Persistent estrus rat models of polycystic ovary disease: an update. Fertil Steril 84 Suppl 2:1228–1234

    Article  Google Scholar 

  3. Ruiz A, Aguilar R, Tebar AM, Gaytan F (1996) RU486-treated rats show endocrine and morphological responses to therapies analogous to responses of women with polycystic ovary syndrome treated with similar therapies. Biol Reprod 55:1284–1291

    Article  PubMed  CAS  Google Scholar 

  4. Jones HM, Vernon MW, Rush ME (1987) Systematic studies invalidate the neonatally androgenized rat as a model for polycystic ovary disease. Biol Reprod 36:1253–1265

    Article  PubMed  CAS  Google Scholar 

  5. Beloosesky R, Gold R, Almog B (2004) Induction of polycystic ovary by testosterone in immature female rats: Modulation of apoptosis and attenuation of glucose/insulin ratio. Int J Mol Med 14:207–215

    PubMed  CAS  Google Scholar 

  6. Mahesh VB (1966) Androgen secretion in the Stein-Leventhal syndrome. Proc R Soc Med 59:1289–1291

    PubMed  CAS  Google Scholar 

  7. Greenblatt RB, Mahesh VB (1974) Some new thoughts on the Stein-Leventhal syndrome. J Reprod Med 13:85–88

    PubMed  CAS  Google Scholar 

  8. Roy S, Mahesh VB, Greenblatt RB (1962) Effect of dehydroepiandrosterone and delta4-androstenedione on the reproductive organs of female rats: production of cystic changes in the ovary. Nature 196:42–43

    Article  PubMed  CAS  Google Scholar 

  9. Mahesh VB, Mills TM, Bagnell CA, Conway BA (1987) Animal models for study of polycystic ovaries and ovarian atresia. Adv Exp Med Biol 219:237–257

    PubMed  CAS  Google Scholar 

  10. Anderson E, Lee MT, Lee GY (1992) Cystogenesis of the ovarian antral follicle of the rat: ultrastructural changes and hormonal profile following the administration of dehydroepiandrosterone. Anat Rec 234:359–382

    Article  PubMed  CAS  Google Scholar 

  11. Anderson E, Lee GY, O'Brien K (1997) Polycystic ovarian condition in the dehydroepiandrosterone-treated rat model: hyperandrogenism and the resumption of meiosis are major initial events associated with cystogenesis of antral follicles. Anat Rec 249:44–53

    Article  PubMed  CAS  Google Scholar 

  12. Anderson E, Lee GY (1997) The polycystic ovarian (PCO) condition: apoptosis and epithelialization of the ovarian antral follicles are aspects of cystogenesis in the dehydroepiandrosterone (DHEA)-treated rat model. Tissue Cell 29:171–189

    Article  PubMed  CAS  Google Scholar 

  13. Anderson E, Lee GY (1996) The effects of dehydroepiandrosterone (DHEA) and its metabolites on the polycystic ovarian condition (PCO): cystogenic changes of rat granulosa cells in vitro. Tissue Cell 28:673–685

    Article  PubMed  CAS  Google Scholar 

  14. Henmi H, Endo T, Nagasawa K et al (2001) Lysyl oxidase and MMP-2 expression in dehydroepiandrosterone-induced polycystic ovary in rats. Biol Reprod 64:157–162

    Article  PubMed  CAS  Google Scholar 

  15. Lee MT, Anderson E, Lee GY (1991) Change in ovarian morphology and serum hormones in the rat after treatment with dehydroepiandrosterone. Anat Rec 231:185–192

    Article  PubMed  CAS  Google Scholar 

  16. Parker CR, Mahesh VB (1976) Interrelationship between excessive levels of circulating androgens in blood and ovulatory failure. J Reprod Med 17:75–90

    PubMed  CAS  Google Scholar 

  17. Hsueh AJ, Billig H, Tsafriri A (1994) Ovarian follicle atresia: a hormonally controlled apoptotic process. Endocr Rev 15:707–724

    Article  PubMed  CAS  Google Scholar 

  18. Ju ST, Panka DJ, Cui H (1995) Fas(CD95)/FasL interactions required for programmed cell death after T-cell activation. Nature 373:444–448

    Article  PubMed  CAS  Google Scholar 

  19. Kim JM, Boone DL, Auyeung A, Tsang BK (1998) Granulosa cell apoptosis induced at the penultimate stage of follicular development is associated with increased levels of Fas and Fas ligand in the rat ovary. Biol Reprod 58:1170–1176

    Article  PubMed  CAS  Google Scholar 

  20. Roughton SA, Lareu RR, Bittles AH, Dharmarajan AM (1999) Fas and Fas ligand messenger ribonucleic acid and protein expression in the rat corpus luteum during apoptosis-mediated luteolysis. Biol Reprod 60:797–804

    Article  PubMed  CAS  Google Scholar 

  21. Hakuno N, Koji T, Yano T et al (1996) Fas/APO-1/CD95 system as a mediator of granulosa cell apoptosis in ovarian follicle atresia. Endocrinology 137:1938–1948

    Article  PubMed  CAS  Google Scholar 

  22. Sakamaki K, Yoshida H, Nishimura Y, Nishikawa S, Manabe N, Yonehara S (1997) Involvement of Fas antigen in ovarian follicular atresia and luteolysis. Mol Reprod Dev 47:11–18

    Article  PubMed  CAS  Google Scholar 

  23. Manabe N, Goto Y, Matusda-Minehata F et al (2004) Regulation mechanism of selective atresia in porcine follicles: regulation of granulosa cell apoptosis during atresia. J Reprod Dev 50:493–514

    Article  PubMed  Google Scholar 

  24. Cataldo NA, Dumesic DA, Goldsmith PC, Jaffe RB (2000) Immunolocalization of Fas and Fas ligand in the ovaries of women with polycystic ovary syndrome: relationship to apoptosis. Hum Reprod 15:1889–1897

    Article  PubMed  CAS  Google Scholar 

  25. Tsafriri A (1995) Ovulation as a tissue remodelling process. Proteolysis and cumulus expansion. Adv Exp Med Biol 377:121–140

    PubMed  CAS  Google Scholar 

  26. Ny T, Wahlberg P, Brandstrom IJ (2002) Matrix remodeling in the ovary: regulation and functional role of the plasminogen activator and matrix metalloproteinase systems. Mol Cell Endocrinol 187:29–38

    Article  PubMed  CAS  Google Scholar 

  27. Endo T, Aten RF, Wang F, Behrman HR (1993) Coordinate induction and activation of metalloproteinase and ascorbate depletion in structural luteolysis. Endocrinology 133:690–698

    Article  PubMed  CAS  Google Scholar 

  28. Liu K, Olofsson JI, Wahlberg P, Ny T (1999) Distinct expression of gelatinase A [matrix metalloproteinase (MMP)-2], collagenase-3 (MMP-13), membrane type MMP 1 (MMP-14), and tissue inhibitor of MMPs type 1 mediated by physiological signals during formation and regression of the rat corpus luteum. Endocrinology 140:5330–5338

    Article  PubMed  CAS  Google Scholar 

  29. Goto T, Endo T, Henmi H et al (1999) Gonadotropin-releasing hormone agonist has the ability to induce increased matrix metalloproteinase (MMP)-2 and membrane type 1-MMP expression in corpora lutea, and structural luteolysis in rats. J Endocrinol 161:393–402

    Article  PubMed  CAS  Google Scholar 

  30. Manase K, Endo T, Henmi H et al (2002) The significance of membrane type 1 metalloproteinase in structural involution of human corpora lutea. Mol Hum Reprod 8:742–749

    Article  PubMed  CAS  Google Scholar 

  31. Gavrieli Y, Sherman Y, Ben-Sasson SA (1992) Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol 119:493–501

    Article  PubMed  CAS  Google Scholar 

  32. Sato H, Kida Y, Mai M et al (1992) Expression of genes encoding type IV collagen-degrading metalloproteinases and tissue inhibitors of metalloproteinases in various human tumor cells. Oncogene 7:77–83

    PubMed  CAS  Google Scholar 

  33. Yamazaki K, Endo T, Kitajima Y et al (2006) Elevation of both Cyclooxygenase-2 and Prostaglandin E(2) Receptor EP3 expressions in rat placenta after uterine artery ischemia-reperfusion. Placenta 27:395–401

    Article  PubMed  CAS  Google Scholar 

  34. KitajimaY, Endo T, Nagasawa K et al (2006) Hyperstimulation and a gonadotropin-releasing hormone agonist modulate ovarian vascular permeability by altering expression of the tight junction protein claudin-5. Endocrinology 47:694–699

  35. Hamm ML, Bhat GK, Thompson WE, Mann DR (2004) Folliculogenesis is impaired and granulosa cell apoptosis is increased in leptin-deficient mice. Biol Reprod 71:66–72

    Article  PubMed  CAS  Google Scholar 

  36. Nagata S (1997) Apoptosis by death factor. Cell 88:355–365

    Article  PubMed  CAS  Google Scholar 

  37. Kuranaga E, Kanuka H, Bannai M, Suzuki M, Nishihara M, Takahashi M (1999) Fas/Fas ligand system in prolactin-induced apoptosis in rat corpus luteum: possible role of luteal immune cells. Biochem Biophys Res Commun 260:167–173

    Article  PubMed  CAS  Google Scholar 

  38. Syed V, Ho SM (2003) Progesterone-induced apoptosis in immortalized normal and malignant human ovarian surface epithelial cells involves enhanced expression of FasL. Oncogene 22:6883–6890

    Article  PubMed  CAS  Google Scholar 

  39. Muzio M, Chinnaiyan AM, Kischkel FC et al (1996) FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death–inducing signaling complex. Cell 85:817–827

    Article  PubMed  CAS  Google Scholar 

  40. Medema JP, Scaffidi C, Kischkel FC et al (1997) FLICE is activated by association with the CD95 death-inducing signaling complex (DISC). Embo J 16:2794–2804

    Article  PubMed  CAS  Google Scholar 

  41. Navarro A, Torrejon R, Bandez MJ, Lopez-Cepero JM, Boveris A (2005) Mitochondrial function and mitochondria-induced apoptosis in an overstimulated rat ovarian cycle. Am J Physiol Endocrinol Metab 289:E1101–E1109

    Article  PubMed  CAS  Google Scholar 

  42. Harayama T, Ohuchi E, Aoki T, Sato H, Seiki M, Okada Y (1999) Shedding of membrane type 1 matrix metalloproteinase in a human breast carcinoma cell line. Jpn J Cancer Res 90:942–950

    PubMed  CAS  Google Scholar 

  43. Holmbeck K, Bianco P, Chrysovergis K, Yamada S, Birkedal-Hansen H (2003) MT1-MMP-dependent, apoptotic remodeling of unmineralized cartilage: a critical process in skeletal growth. J Cell Biol 163:661–671

    Article  PubMed  CAS  Google Scholar 

  44. d'Ortho MP, Will H, Atkinson S et al (1997) Membrane-type matrix metalloproteinases 1 and 2 exhibit broad-spectrum proteolytic capacities comparable to many matrix metalloproteinases. Eur J Biochem 250:751–757

    Article  PubMed  Google Scholar 

  45. Polette M, Birembaut P (1998) Membrane-type metalloproteinases in tumor invasion. Int J Biochem Cell Biol 30:1195–1202

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Sapporo Medical University School of Medicine, South 1 West 16, Chuo-ku, Sapporo, 060-8543, Japan

    Hiroyuki Honnma, Toshiaki Endo, Hirofumi Henmi, Kunihiko Nagasawa, Tsuyoshi Baba, Kiyohiro Yamazaki, Yoshimitsu Kitajima, Takuhiro Hayashi, Kengo Manase & Tsuyoshi Saito

Authors
  1. Hiroyuki Honnma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Toshiaki Endo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hirofumi Henmi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kunihiko Nagasawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tsuyoshi Baba
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kiyohiro Yamazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yoshimitsu Kitajima
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Takuhiro Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kengo Manase
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Tsuyoshi Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Toshiaki Endo.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Honnma, H., Endo, T., Henmi, H. et al. Altered expression of Fas/Fas ligand/caspase 8 and membrane type 1-matrix metalloproteinase in atretic follicles within dehydroepiandrosterone-induced polycystic ovaries in rats. Apoptosis 11, 1525–1533 (2006). https://doi.org/10.1007/s10495-006-9148-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-006-9148-2

Keywords

Search

Navigation