Significance of matrix metalloproteinases in the pathophysiology of the ovary and uterus.

Abstract

Matrix metalloproteinases (MMP) are capable of degrading a variety of extracellular matrix (ECM) proteins and are also involved in the processing of a number of bioactive molecules. Our findings indicate that the functions of MMP in the ovary and uterus are organ-specific and time-dependently vary during the reproductive cycle. Prolactin induces structural luteolysis indicated by loss of luteal weight, protein and DNA within 36h after pretreatment with ergot alkaloid. MMP activation appears crucial for the selective depletion of protein during luteal involution, which entails loss of ECM accompanied by apoptosis. During GnRHagonist-induced luteolysis, this response was also associated with marked increases in MMP-2, which degraded collagen typeIV, and MT1-MMP, which in addition to activating MMP-2 also degrades collagen type I, III and V. We also found that the level of MT1-MMP and MMP-2 expression in the human CL is greater during the late luteal phase than during either the early mid luteal phases or during gestation, respectively. That dehydroepiandrosterone (DHEA) treatment caused the formation of cysts from antral follicles in the ovaries of immature rats while depressing MMP-2 collagenolytic activity and enhancing lysyl oxidase expression highlights the importance of collagen degradation in the process of ovulation and suggests that changes in the activities of these enzymes play a key role in ovarian cystogenesis in polycystic ovary syndrome patients. Furthermore, immunohistochemical analyses showed that MT1-MMP and FasL co-localize with TdT-mediated dUTP-biotin nick end-labeling (TUNEL)-positive apoptotic granulosa cells in rats treated with DHEA, that the Fas/FasL/Caspase-8 (death receptor-dependent) pathway is pivotal for follicular atresia and that increased levels of MT1-MMP likely play an important role in tissue remodeling during follicular atresia. After parturition, the uterus undergoes involution, a conspicuous feature characterized by a rapid reduction in the collagen content mediated by degradation of extracellular collagen bundles. Our findings strongly suggest that MT1-MMP, MMP-2 and MMP-9 are each time-dependently regulated and play important roles in tissue remodeling during postpartum uterine involution. (Reprod Med Biol 2006; 5: 235-243).