Complex mechanisms of matrix metalloproteinases involvement in endometrial physiology and pathology-an update

Abstract

Matrix metalloproteinases (MMPs) belong to a multigenic family of proteolytic enzymes with great structural variability which provide a complex intervention in pathophysiological conditions. Our review is focused on both MMPs key role in physiological reproductive events, such as embryo implantation, uterine involution, normal endometrial cycle, and on their role in the main endometrial pathologies. MMPs activity is closely regulated by tissue inhibitors of MMPs (TIMPs). MMP: TIMP imbalance has been incriminated in various pathological conditions, including endometrial cancer and endometriosis. Accumulated data support the involvement of a large spectrum of MMPs and TIMPs in endometrial carcinogenesis. Strong MMP-2 and weak TIMP-2 tissue immunoexpressions have a powerful prognosis value, while MMP-9 high expression suggests its important involvement in endometrial tumor invasiveness. Endometriosis development implies an accumulation of events showing partial overlap with endometrial carcinogenesis and invasion, requiring MMPs involvement. Therefore, increased levels of several MMPs have been detected in peritoneal fluid and/or endometrial tissue of patients diagnosed with endometriosis. Endometriotic mesenchymal stem cells (MSCs) may be involved in the pathogenesis of endometriosis due to their upregulated expression for markers of migration and angiogenesis, such as MMP-2, MMP-3, MMP-9, and VEGF. The hypothesis of therapeutic benefits of synthetic MMPs inhibitors, added to the progesterone or progestins action, has been based on the complex MMPs involvement in endometrial pathology. Future research is necessary to elucidate the complex interactions between molecules involved in proliferation, angiogenesis and apoptosis, opening new perspectives in the early diagnosis and treatment of endometrial neoplasia and endometriosis.