Skip to main content Skip to main navigation menu Skip to site footer

The activity of Matrix Metalloproteinase-2 (MMP-2) and Tissue Inhibitors of Metalloproteinase-2 (TIMP-2) that are associated with the degree of endometrioma tissue invasion transplanted onto the Chorioallantoic Membrane (CAM)

  • Tri Agung Wahyu Cahyono ,
  • Shofwal Widad ,
  • Cahyono Hadi ,
  • Agung Dewanto ,
  • Riris Jenie ,


Abstract

Background. One of the fundamental pathogenesis of endometriosis to grow and develop is to carry out a cellular invasion of the surrounding tissue where it attaches. The invasion process of endometriotic focus is linked with the activity of matrix metalloproteinases-2 (MMP-2) and tissue inhibitors of metalloproteinases-2 (TIMP-2). In this study, we used endometrioma tissue to be implanted in chick chorioallantoic membrane (CAM) as a medium culture model to reconstruct and evaluate the invasion process of endometriosis. Then the MMP-2, TIMP-2 and invasion pattern can be invitro observed.

Methods. Endometrioma tissue fragments were taken from ovarian endometrioma patients, reproductive age, no medication and no malignancy who underwent laparoscopic surgery. Sample research was taken in consecutive and non-probability sampling. The tissue fragments were divided into 4-8 strips, each dimension of 2 x 2 mm2. Two strips were assessed for the activity of MMP-2. Two remaining strips were transplanted onto the CAM. After incubation for five days, the transplanted tissues were harvested for assessment of MMP-2 by gelatin zymography, TIMP-2 by western blot and histological assessment by hematoxylin-eosin staining. The assessment was carried out by two qualified biologists as an observer.

Result. Twenty-four fragments of endometrioma have been collected from 24 endometrioma patients who underwent laparoscopy surgery. The average age was 31±5 years, the BMI was 22±3 kg/m2, the duration of infertility was 58 ± 3 months, and r-ASRM was 67±35. In CAM of transplanted endometriomas tissue, MMP-2 activity was positively correlated with TIMP-2 in a moderate relationship (rô = 0.56, p-value < 0.05), very weak positive correlation with invasion level (rô = 0.08, p-value >0.05). TIMP-2 expression was negatively correlated with invasion level in a strong relationship (rô = -0.35, p-value <0.05). The ratio between MMP-2/TIMP-2 was positively correlated with invasion level in a very strong relationship (rô = 0.72, p-value < 0.05). ICC (intraclass correlation coefficient) value was 0.96, and p-value= 0.01, CI 95%. It shows that there was high reliability between observers.

Conclusion. The invasion level of endometrioma transplanted onto CAM was determined by the balance between MMP-2 and TIMP-2.

Keywords: CAM Endometrioma Invasion MMP-2 TIMP-2

References

  1. Bulun SE, Yilmaz BD, Sison C, Mizayaki K, Bernardi L, Liu S, et al. Endometriosis. Endocrine Review. 2019;40(1):1048-1079.
  2. Tomassetti C, Jhonson NP, Petrozza J, Abrao M, Einarsson J, Horne AW, et al. An International Terminology for Endometriosis 2021. Human Reproduction. 2021;2021(4):hoab029.
  3. Lin YH, Chen YS, Chang HY. Chronic Niche Inflammation in Endometriosis-Associated Infertility: Current Understanding and Future Therapeutic Strategies. International Journal of Molecular Sciences. 2018;19(8):2385.
  4. Zondervani KT, Becker C, Koga K. Endometriosis. Nat Rev Dis Primers. 2018;4(1):9
  5. Garnica AB. The Role of the Molecular Genetic Approach in the Pathogenesis of Endometriosis, Molecular Bases of Endometriosis - The Integration Between Research and Clinical Practice. Giovana Aparecida Gonçalves: IntechOpen. 2019:1-13.
  6. Gifford V, Itoh Y. MT1-MMP-dependent cell migration: proteolytic and non-proteolytic mechanisms. Biochemical Society Transaction. 2019:47(3):811-826.
  7. Collette T, Bellehumeur C, Kats R, Maheux R, Mailoux M, Villeneuve M, et al. Evidence for an increased release of proteolytic activity by the eutopic endometrial tissue in women with endometriosis and for the involvement of matrix metalloproteinase-9. Hum Reprod. 2004;19(6):1257-1264.
  8. Henriet P, Su Mon K, Marbaix E. Are matrix metalloproteinases and their inhibitors reliable diagnosis biomarkers and attractive therapeutic targets in endometriosis? Metalloproteinases In Medicine, 2016:3:81–92.
  9. Chung HW, Lee JY, Moon HS, Eun HS, Park MH, Wen Y, et al. Matrix metalloproteinase-2, membranous type 1 matrix metalloproteinase, and tissue inhibitor of metalloproteinase-2 expression in ectopic and eutopic endometrium. Fertility and Sterility. 2002;78(4):787-795.
  10. Londero AP, Calcagno A, Grassi T, Marzinotto S, Orsaria M, Beltrami CA, et al. Survivin, MMP-2, MT1-MMP, and TIMP- 2: their impact on survival, implantation, and proliferation of endometriotic tissues. Virchows Arch. 2012;461:589-99.
  11. Nap AW, Dunselman GA, de Goeij AF, Evers JL, Groothuis PG. Inhibiting MMP activity prevents the development of endometriosis in the chicken chorioallantoic membrane model. Human Reproduction. 2004;19(10):2180-2187.
  12. Valdes T, Kreutzer D, Moussy F. The chick chorioallantoic membrane as a novel in vivo model for the testing of biomaterials. J Biomed Mater Res. 2002;62(2):273–282.
  13. Martinez-Madrid B, Donnez J, Van Eyck AS, Veiga-Lopez A, Dolmans MM, Van Langendonckt A, et al. Chick embryo chorioallantoic membrane (CAM) model: a useful tool to study short-term transplantation of cryopreserved human ovarian tissue. Ferti Steril. 2009;91(1):285–292.
  14. Jana S, Banerjee P, Thangaraju S, Chakravarty B, Chaudhury K. Alteration in Endometrial Remodeling: A Cause for Implantation Failure in Endometriosis?. Endometriosis: Basic Concepts and Current Research Trends. 2012:325-342.
  15. Bałkowiec M, Maksym RB, Włodarski PL. The bimodal role of matrix metalloproteinases and their inhibitors in etiology and pathogenesis of endometriosis (review). Molecular Medicine Reports. 2018;18(3):3123-3136.
  16. Zafrakas M, Kotronis K, Papasozoumenou P, Eskitzis P, Grimbiziz G. Extracellular matrix metalloproteinases in the etiopathogenesis of endometriosis: a systematic review and critical appraisal (review). Clin. Exp. Obstet. Gynecol. 2020;1(1):1-12.
  17. Salata N, Stojanovic N, Cadler, Lewandoski K, Lewinski A. Gelatinase A (MMP-2), gelatinase B (MMP-9) and their inhibitors (TIMP 1, TIMP-2) in serum of women with endometriosis: Significant correlation between MMP-2, MMP-9 and their inhibitors without difference in levels of matrix metalloproteinases and tissue inhibitors of metalloproteinases in relation to the severity of endometriosis. Gynecological Endocrinology. 2008;24(6):326–330.
  18. Sotnikova NY, Antsiferova YS, Posiseeva LV, Shishkov DN, Mechanisms regulating invasive- ness and growth of endometriosis lesions in rat experimental model and in humans. Fertil Steril. 2010;93(8):2701-2705.
  19. Jana S, Chatterjee K, Ray K, Regulation of Matrix Metalloproteinase-2 Activity by COX-2-PGE2-pAKT Axis Promotes Angiogenesis in Endometriosis. PloS One. 2016;11(10):e0163540.
  20. Barbe A, Berbet A, Davydenko I, Koval HD, Yuzko VO, Yuzko OM. Expression and Significance of Matrix Metalloproteinase-2 and Matrix Metalloproteinas-9 in Endometriosis. J Med Life. 2020;13(3):314-320.
  21. Szymanowski K, Mikołajczyk M, Wirstlein P, Szymanowska A. Matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of matrix metalloproteinases (TIMP-1) and transforming growth factor-β2 (TGF-β2) expression in eutopic endometrium of women with peritoneal endometriosis. Ann Agric Environ Med. 2016;23(4):649-653.
  22. Prabawa IPY, Bhargah A, Liwang F, Tandio DA, Tandio AL, Lestari AAW, et al. Pretreatment neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) as a predictive value of hematological markers in cervical cancer. Asian Pacific Journal of Cancer Prevention. 2019;20(3):863-868.
  23. Irwanto Y, Mustofa E, Wiyono T, Oktafianto DT, Nurdianto AR, Widodo RR. The effect of kefir polysaccharide extract on the expression of matrix metalloproteinase 9 (MMP-9) and integrin activation of HeLa cervical carcinoma culture cell. Bali Medical Journal. 2022;11(2):803–806.
  24. Kharisma IBA, Semadi IN, Widiana IGR. The effect of hyaluronic acid on the changes in Matrix Metalloproteinase-1 (MMP-1), leukocytes level, and bacteriocide effects among patients with Wagner 3 and 4 diabetic foot ulcer. Indonesia Journal of Biomedical Science. 2019;13(2):57-62.
  25. Henriet P, Emonard H, Matrix metalloproteinase-2: Not (just) a “hero” of the past. Biochimie, biochip. 2019;166(1):223-232.

How to Cite

Tri Agung Wahyu Cahyono, Shofwal Widad, Cahyono Hadi, Agung Dewanto, & Riris Jenie. (2023). The activity of Matrix Metalloproteinase-2 (MMP-2) and Tissue Inhibitors of Metalloproteinase-2 (TIMP-2) that are associated with the degree of endometrioma tissue invasion transplanted onto the Chorioallantoic Membrane (CAM). Bali Medical Journal, 12(2), 2271–2277. https://doi.org/10.15562/bmj.v12i2.3845
ACM ACS APA ABNT Chicago Harvard IEEE MLA Turabian Vancouver
Download Citation
Endnote/Zotero/Mendeley (RIS) BibTeX

HTML
3

Total
2

Share

Search Panel

Tri Agung Wahyu Cahyono
Google Scholar
Pubmed
BMJ Journal

Shofwal Widad
Google Scholar
Pubmed
BMJ Journal

Cahyono Hadi
Google Scholar
Pubmed
BMJ Journal

Agung Dewanto
Google Scholar
Pubmed
BMJ Journal

Riris Jenie
Google Scholar
Pubmed
BMJ Journal