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

Abstract

Endometriosis is a condition defined as presence of endometrium outside of the uterine cavity. These endometrial cells are able to attach and invade the peritoneum or ovary, thus forming respectively the deep infiltrating endometriosis (DIE) and the ovarian endometrioma (OMA), the ectopic lesions feature of this pathology. Endometriotic cells display high invasiveness and share some features of malignancy with cancer cells. Indeed, the tissue remodeling underlining lesion formation is achieved by matrix metalloproteinases (MMPs) and their inhibitors. Therefore, these molecules are believed to play a key role in development and pathogenesis of endometriosis. This study investigated the molecular profile of metalloproteinases and their inhibitors in healthy (n = 15) and eutopic endometrium (n = 19) in OMA (n = 10) and DIE (n = 9); moreover, we firstly validated the most reliable housekeeping genes allowing accurate gene expression analysis in these tissues. Gene expression, Western blot, and immunofluorescence analysis of MMP2, MMP3, and MMP10 and their tissue inhibitors TIMP1 and TIMP2 demonstrated that these enzymes are finely tuned in these tissues. In OMA lesions, all the investigated MMPs and their inhibitors were significantly increased, while DIE expressed high levels of MMP3. Finally, in vitro TNFα treatment induced a significant upregulation of MMP3, MMP10, and TIMP2 in both healthy and eutopic endometrial stromal cells. This study, shedding light on MMP and TIMP expression in endometriosis, confirms that these molecules are altered both in eutopic endometrium and endometriotic lesions. Although further studies are needed, these data may help in understanding the molecular mechanisms involved in the extracellular matrix remodeling, a crucial process for the endometrial physiology.

Proteomic analysis of peritoneal fluid identified COMP and TGFBI as new candidate biomarkers for endometriosis

“…Protein–protein interaction analyses of the identified proteins have also confirmed the central position of MMP2 and TIMP1 in protein–protein interaction networks. Furthermore, TIMP1 has already been described as a protein that is secreted by endometriotic lesions 53 , and the present study supports its great value as a potential biomarker.…”

Homing Peptide-Based Targeting of Tenascin-C and Fibronectin in Endometriosis

“…Microscopic imaging of the central core and peripheral rim of the spheroids showed that at 2 and 4 h of incubation, the PL1-AgNPs were internalized in the spheroid cells at the periphery of the spheroids To bind MMAE to AgNPs we used a valine-citrulline linker that is cathepsin B sensitive. Some ECM proteases, such as matrix metalloproteinases, are overexpressed in ectopic endometrial tissue [61,62]. It is possible that application of alternative enzyme-cleavable linkers might result in increased release of the drug in endometriotic lesions as we have shown previously in tumor mouse models [63,64].…”

Dienogest exerts its anti-endometriotic effect throughthe direct suppression of matrix metallopeptidases

“…Some studies indicated that progesterone inhibited MMP-2 or MMP-9 expression in endometriotic cells, whereas other studies indicated that progesterone did not change the MMP-2 or MMP-9 expression [23,24]. It was also reported that the MMP-10 expression in the endometriotic tissues of ovarian endometriosis was significantly increased compared to the expression in eutopic endometrial tissues without endometriosis [25], and our present results demonstrated that dienogest directly inhibited the MMP-10 expression in the endometriotic stromal cells. Taken together, the previous and present findings indicate that the suppression of MMP-10 expression (as well as those of MMP-1 and MMP-3) by dienogest might be one of dienogest's direct anti-endometriotic effects.…”