Are matrix metalloproteinases and their inhibitors reliable diagnosis biomarkers and attractive therapeutic targets in endometriosis?

Abstract

Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) are expressed in the human endometrium during the menstrual cycle, in particular to induce substantial extracellular matrix breakdown underlying menstruation. Endometriosis (EM) is characterized by the presence of endometrial tissue at ectopic locations. Because EM is thought to often develop from retrograde menstruation followed by implantation of menstrual tissue fragments at ectopic sites, endometrial MMPs and TIMPs were rapidly suspected as contributors to EM development and progression, generating hope for their use as biomarkers to facilitate EM diagnosis and as potential targets for developing new therapies against EM. Here, we not only summarize a substantial literature supporting the presence of MMPs and TIMPs in eutopic and ectopic endometrium of EM patients but also highlight frequent controversies on expression changes and the difficulty in identifying systematic MMP/TIMP differential regulation associated with the disease. Moreover, by reanalyzing publicly available data from a whole genome transcriptomic study, we show that occasional and unexplained endometrial overexpression of selective MMPs regardless of the disease and phase of the menstrual cycle rather discourages the use of eutopic MMPs and TIMPs as diagnosis biomarkers. However, we also review multiple studies using rodent models that collectively provide strong support to the contribution of MMPs in EM development and progression, and therefore to further investigations aiming at targeting MMP activity, especially in light of recent advances in new MMP inhibitors.