The bimodal role of matrix metalloproteinases and their inhibitors in etiology and pathogenesis of endometriosis (Review)

Abstract

Aberrant regulation of matrix metalloproteinases (MMPs) may be the primary cause of endometrial lesion formation in a group of predisposed women. Prospect for the genuine origin of endometriosis is ongoing, since retrograde menstruation leads to presence of endometrial debris in peritoneal cavity of many women, which do not experience endometriosis. Tissue remodeling is regulated precisely by a balance of MMPs and their inhibitors. Interplay between factors enhancing and suppressing matrix turnover is crucial for cyclic preparation of endometrium for embryo implantation, and endometrial shedding and renewal in physiology of primates. Disorders of the regulation of matrix remodeling leads to augmentation of implantation and invasive growth of ectopic endometrial tissue. Moreover, endometriosis-induced changes in the matrix balance leads to adhesion formation, ovulatory dysfunction and fertility impairment. The review summarizes the current knowledge regarding the regulation of extracellular matrix turnover in the physiology of the endometrial cycle and in the development of endometriosis, as well as the pathophysiology of ovulatory dysfunction in endometriotic women. Therapeutic modalities utilizing modulation of tissue remodeling were discussed.

Expression of Matrix Metalloproteinases and Their Inhibitors in Endometrium: High Levels in Endometriotic Lesions

“…In light of these information, here we demonstrate that different MMPs are expressed at different levels in healthy and pathological tissues, in accordance with data reported by most of the studies focused on this disease [24,25,27].…”

“…Another interesting finding of the present work is the proven increase in MMP2 expression in OMA, that confirms data reporting higher activity of MMP2 in ectopic lesions in comparison to uterine endometrium [24,30,31]. Altered expression of gelatinases has been correlated to the metastatic state; therefore, these enzymes can influence the ability of cells to invade and metastasize due to their aptitude to degrade the basement membrane [32].…”

“…The main strength of the present study relies on robust inclusion criteria that are crucial for the accurate and conclusive analysis of results and thus allow a deeper understanding of MMPs and TIMPs role in endometriosis etiology. Indeed, the results of this study are normalized for uterine cycle phase, since all tissue biopsies are scheduled in proliferative phase, 2-3 days after the menstrual bleeding, thus overcoming criticisms evident in several published studies, where no attention was paid to the phase of the menstrual cycle during sample collection, which makes the results quite unreliable and difficult to analyze [24]. This criterion enabled us to avoid misinterpretation due to the bimodal distribution of MMPs and TIMPs activity during the physiological menstrual cycle, with MMPs mainly activated in the menstrual and early proliferative phases and TIMPs in the late secretory phase [24].…”

“…Indeed, the results of this study are normalized for uterine cycle phase, since all tissue biopsies are scheduled in proliferative phase, 2-3 days after the menstrual bleeding, thus overcoming criticisms evident in several published studies, where no attention was paid to the phase of the menstrual cycle during sample collection, which makes the results quite unreliable and difficult to analyze [24]. This criterion enabled us to avoid misinterpretation due to the bimodal distribution of MMPs and TIMPs activity during the physiological menstrual cycle, with MMPs mainly activated in the menstrual and early proliferative phases and TIMPs in the late secretory phase [24]. Another important issue comes from the systematic analysis of data through a different setup of a methodological approach including gene expression analysis, proteomic validation of data and protein localization by immunofluorescence.…”

Development of A 3D Tissue Slice Culture Model for the Study of Human Endometrial Repair and Regeneration

“…Although recent studies have demonstrated that endometrial organoid cultures can be used to achieve the complexity of organ structures to a considerable degree through cellular self-assembly and can be used as preclinical models to study the physiology and pathology of human endometrium [17][18][19][20][21][22][23][24], these models do not fully recapitulate the regulatory mechanisms of endometrium in vivo. Herein with the use of full thickness endometrial tissue slice cultures we developed a unique model that dramatically enhances endometrial tissue viability and recapitulates the zone-specific changes seen in normal physiological conditions of endometrium [52][53][54]. It has been reported that the pattern of expression and localization of signaling molecules in cells at various zones of endometrium vary throughout the menstrual cycle but parallel to the cyclical changes in the endometrium; and aberrations in the expression pattern are associated with pathological conditions such as endometriosis [55][56][57].…”