Membrane-type matrix metalloproteinases: membrane-type 1 matrix metalloproteinase, membrane-type 2 matrix metalloproteinase and membrane-type 3 matrix metalloproteinase in endometriosis and adenomyosis

Abstract

Endometriosis is a benign gynecological disease characterized by the presence of endometrial tissue; endometrial glands and stroma outside the uterus. Even though endometriosis affects about 0.7-8.6% women of the reproductive age, the pathogenesis is not well understood and there is no reliable non-invasive biomarker for diagnosis. Matrix metalloproteinases are significantly expressed in the endometrium and also in endometriosis. The aim of this study was to investigate the role of membrane-type MMPs in the pathogenesis of endometriosis. To achieve this, we analysed tissue samples from patients with and without endometriosis, adenomyotic lesions and the three endometriotic entities; ovarian, peritoneal and deep infiltrating endometriosis and evaluated their HSCORE and percentage of stained glands. Also, we studied the levels of MT1-MMP in serum and endocervical mucus samples of patients with and without endometriosis. In addition, we also investigated MT1-, MT2- and MT3-MMP protein expression in endometrial and endometriotic cells and the role of MT1-MMP and MT3-MMP in betaglycan shedding in endometriotic epithelial cells. Our results showed that all studied MT-MMPs are expressed in the human endometrium with high similarities between women with and without endometriosis except for MT1- MMP which we only evaluated in few samples. Variations in protein expression were found with a reduced MT1-MMP expression in ovarian endometriosis, MT2-MMP in ovarian, peritoneal and deep infiltrating endometriosis as well as MT3-MMP in peritoneal and deep infiltrating endometriosis. Similarly, in adenomyosis, MT1-MMP was increased while MT2-MMP and MT3-MMP abundance was highly identical to eutopic endometrium. Consequently, we suggest that variations most likely occur after implantation of the endometriotic tissue in the ectopic sites and endometrial glands could be the sole source of adenomyotic glands. This could also suggest that endometriosis and adenomyosis do not share a common pathogenesis but are distinguishable by, invasion versus invagination, respectively. In addition, we demonstrated that MT1-MMP levels in endocervical mucus of patients with and without endometriosis were highly similar. Furthermore, we revealed that MT1- MMP concentration in endocervical mucus samples of patients with endometriosis was decreased by hormonal contraceptives, but further investigations are needed to ascertain the specific contraceptions involved. Our results further revealed that MT1-MMP, MT2-MMP and MT3-MMP proteins are expressed in endometrial and endometriotic cells and downregulation of MT1-MMP and MT3-MMP had no effect on betaglycan shedding. Taken together, these findings provide new evidence on the function of MT1-, MT2- and MT3-MMP in the pathophysiology of endometriosis and adenomyosis. However, more experiments are needed to understand the role of these proteins in adenomyosis and endometriosis using primary endometrial and endometriotic cells as well as animal models.