The role of the matrix metalloproteinases (MMPs) in the decidua, fetal membranes and amniotic fluid (AF) has been receiving more and more attention. The MMPs are not only important intermediaries in pathological processes leading to preterm labor but it seems that they also play a crucial role in the activation of labor at term. During normal gestation MMP-1, -2, -3, -7 and -9 are found in the amniotic fluid and fetal membranes. MMP-2 and MMP-3 are expressed constitutively while MMP-9 is barely detectable until labor. At labor, while MMP-9 is the major MMP responsible for gelatinolytic activity in the membranes, MMP-2 is dominant in the decidua. MMP-7 (AF) increases with gestation but does not appear to play a major role in labor. The expression of MMPs is attenuated through the expression of relaxins, integrins and extracellular matrix metalloproteinase inducer (EMMPRIN). Spontaneous preterm delivery (PTD) may be a product of preterm labor (PTL), preterm premature rupture of membranes (P-PROM) or placental abruption. Each of these processes may have differing pathways but the presence of an intrinsic inflammatory response with or without infection seems to involve all etiologies. The inflammatory response is mediated with cytokines such as interleukins -1, -6 and -8 and tumor necrosis factor alpha. MMP-3, MMP-7 and MMP-8 appear to be important in these processes. MMP-9, which is the major MMP involved in normal labor, plays an important role in pathological labor as well. Finally, apoptosis seems to play a role in pathological labor, particularly deliveries involving P-PROM. African-American are at greater risk of PTD than white or Hispanic Americans. Environmental differences may not suffice to explain this phenomenon. Genetic polymorphisms of the MMP genes may help explain the greater risk among this population. Finally, manipulating MMPs may have a role in the prevention of PTD. Agents suggested include indomethacin, N-acetylcysteine, progesterone and specific inhibitors of phosphodiesterase 4.

Background: The aim of this study was to examine the invasiveness of first trimester trophoblasts according to the secretion profile of MMP-2 and -9 at different gestational stages, and to test the similarity between primary trophoblast cell-culture and the JAR choriocarcinoma cell-line.

In humans, progesterone levels are sustained before the onset of labour. Therefore, the mechanism for parturition that has been proposed for humans is 'functional' progesterone withdrawal. Immunohistochemical staining for the progesterone receptor (PR) was positive in the decidua with a decline after contractions began. Western blot analysis revealed a number of PR isoforms expressed in the decidua, with the PR-B form being dominant. After contractions began, all PR isoforms decreased sharply. PR-B and PR-A decreased by 85.8% +/- 6.7 and 78.2% +/- 7.1, respectively (P < 0.001). Incubation of decidua with Prostaglandin F2alpha 1.0 microg/ml decreased the expression of all forms of PR isoforms. PR-B was reduced by 64% +/- 6.09 (P < 0.01); PR-A was reduced by 77% +/- 5.9 (P < 0.05), while PR-C was reduced by 80% +/- 7.24 (P < 0.05). Progesterone (80 microg/ml) increased the PR-B, PR-C the 45 and 36 kDa isoforms to 150% +/- 7.89, 210% +/- 12.4, 270% +/- 9.7 and 216% +/- 13.5, respectively (P < 0.05). In immunohistochemical studies, the PR was not identified in the amnion or in the chorion, regardless of the presence or absence of contractions. Western blot analysis demonstrated that PR-C (60 kDa) and the 36 kDa isoforms were dominant in the amnion. After contractions began, PR-A decreased significantly by 61.9% +/- 7.1 (P < 0.001).

The matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) have been postulated to play a critical role in the extracellular matrix (ECM) remodeling associated with follicular development. The gelatinases were localized to the theca of developing follicles and in the stroma of the rodent ovary. Gelatinolytic activity corresponded with the localization of MMP-2 and MMP-9 around the developing follicles and at the apex of preovulatory follicles. The TIMPs-1, -2, and -3 were localized to the stroma and theca of developing follicles and correlation between MMPs and the quality of the developing follicles was found. During the process of ovulation, MMP-1 protein was found in the theca interna and externa, interstitial glands, and germinal epithelium. Synthetic inhibitor of mammalian tissue collagenases was documented to be inhibitory to ovulation in perfused rat ovaries. MMP-19 and TIMP-1 messenger RNA were localized to the granulosa and thecal-interstitial cells of large preovulatory and ovulating follicles. Both were induced and upregulated 5-10 fold by human chorionic gonadotropin (hCG). MMP-2 mRNA found in theca-interstitial cells and membrane-type (MT) 1-MMP mRNA found in granulosa and theca-interstitial cells were both induced after stimulation with pregnant mare's serum gonadotropin (PMSG). Gelatinolytic activity was observed throughout the formation of the corpus luteum. At 12 h after hCG, luteinizing granulosa cells expressed TIMP-1 and TIMP-3 mRNA. In the newly forming corpus luteum at 24 h after hCG administration, the luteal cells expressed TIMP-1, -2, and -3 mRNA with unique pattern of cellular expression for each of the TIMPs. Regression of the corpus luteum is associated with a significant increase in the activity of the metalloproteinases. In luteinized granulosa cells from women with polycystic ovarian syndrome (PCOS) the MMP-TIMP balance is shifted towards greater MMP activity. Cultured luteinized granulosa cells obtained from PCOS patients secrete higher levels of MMP-9 and MMP-2 compared to granulosa cells from normal ovulatory patients whereas the secreted basal level of TIMP-1 was similar in both types of granulosa cells. These results indicate a higher net gelatinolytic activity within the luteinizing granulosa cells of patients with PCOS. It has been shown that in sheep, diversion of normal follicles to atresia by hypophysectomy is followed by a significant increase of intrafollicular levels of MMP-2 and MMP-9 and the disappearance of connexin-43. It is therefore reasonable to speculate that MMP-9 and MMP-2 may be associated with inappropriate atresia in PCOS.

Degradation of the extracellular matrix in fetal membranes has been implicated in the rupture of fetal membranes, the process of parturition and placental detachment from the decidua after parturition. In this study we assessed labour-associated changes in gelatinase activity in cultured human amnion, chorion and decidua, as well as in amniotic fluid. We found that in media conditioned by decidua, following the establishment of uterine contractions, matrix metalloproteinase-2 (MMP-2) activity is increased while the protein tissue inhibitors of matrix metalloproteinase-1 (TIMP-1) level is decreased. The formation of a 130 kDa gelatinase band was also significantly increased after contractions began. In media conditioned by chorion, the initiation of uterine contractions did not change MMP activity or TIMP-1 levels. However, an increase in MMP-9 activity and a decrease in TIMP-1 protein levels were observed following the establishment of uterine contractions in media conditioned by amnion. We suggest that this differential spatial regulation provides a form for modulatory hieratical activity of the MMPs in the onset of labour allowing rupture of the membranes while avoiding premature placental separation.