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 36 h 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 type IV, 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 endlabeling (TUNEL)-positive apoptotic granulosa cells in rats treated with DHEA, that the Fas/FasL/Caspase-8 (death receptordependent) 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)

Advanced Glycation End Products (AGEs) May Be a Striking Link Between Modern Diet and Health

“…Women habituated to high consumption of AGEs had elevated levels of testosterone, AMH, and androgens [92,109]. High levels of testosterone and androstenedione Irregular menstrual cycles [94][95][96] Raised expression of Receptor of AGE (RAGE) in mononuclear cells along with increased glucose, insulin, and testosterone PCOS characterized as both endocrine metabolic disorders [71,95,97] High AGE diet elevates anti-Müllerian hormone, inhibits Follicle-stimulating hormone Provokes anovulation [98,99] High AGEs isocaloric diet elevates testosterone, insulin, and oxidative stress contributing to PCOS and its symptoms Irregular menstrual cycles, high ovarian cysts [92,97,100] Upregulation of RAGE in PCOS, downregulation signal cascade of steroidogenesis in women of reproductive age Disruptive hormone formation [91,101] Vitamin D3 supplementations reduce the effects of AGEs in PCOS Attenuates AGEs and supports ovarian health [102,103] Excess deposition of collagen Cyst formation in ovaries due to enzyme lysyl oxidase [102,104,105] Disruption of renin-angiotensin-aldosterone system Disturbed cardiovascular functioning and hypertension [37,106,107] Another study reported the association of a high AGE isocaloric diet (HA) with PCOS in women. Women consuming a high HA diet had elevated levels of serum AGEs, testosterone, insulin, and oxidative stress, as compared to women on low AGE isocaloric diet.…”

Notch1 signaling enhances collagen expression and fibrosis in mouse uterus

“…Immunostaining of COLI and IV have confirmed the increased expressions of these proteins in IUA horns (Figure 3(D,F)). Matrix metalloproteinases (MMPs) are zinc‐dependent endopeptidases that degrade different components of the ECM and play a role in the remodeling of various tissues during many physiological processes, including decidualization of stromal cells and postpartum uterine repair 29,30 . We found that the expression of Mmp2 and Mmp9 increased 6 and 9 days after the IUA surgery (Figure 3(E)), suggesting rapid ECM remodeling during this period.…”

Apios americana Medikus: A novel and promising food for postpartum uterine involution

“…Matrix metalloproteinases are important for uterine tissue remodeling and collagen degradation in uterus (Endo et al., 2006). To uncover the inner mechanism behind AM‐mediated protection, the expressions of various MMPs and TIMP‐1 were analyzed (Figure 6).…”