Matrix metalloproteinases in pregnancy and parturition

Premature birth is a leading cause of perinatal mortality world-wide. Preterm labor continues to be a major problem with 6–8% of all pregnancies resulting in preterm birth of the infant. Preterm birth is of major concern because 70% of perinatal mortality is associated with this group of infants. A significant portion of premature birth occurs as a result of intrauterine infection. Intrauterine infections are associated with preterm premature rupture of the membranes (PPROM). Recent evidence suggests an important role for matrix metalloproteinases, a family of potent extracellular matrix degrading enzymes in both term and preterm parturition. Cross-sectional studies conducted on human amniotic fluid in our laboratory have shown increased concentrations of MMPs in the context of PROM and microbial invasion of the amniotic cavity. In this study we have (a) investigated the concentrations of MMPs in serially collected amniotic fluid specimens from normal women to identify specific MMPs that are significant during parturition, (b) measured MMPs secreted by gestational tissues in primary cell culture systems, (c) investigated release of MMPs by gestational tissues in response to bacterial lipopolysaccharide, proinflammatory cytokines, activation of protein kinase C and calcium. Our results showed that: (1) amniotic fluid concentrations of MMP-3, MMP-8, and MMP-9 were significantly elevated during early spontaneous labor in women at term gestation, (2) human decidual cells are a major source of MMP secretion, (3) bacterial lipopolysaccharide, interleukin-1β, tumor necrosis factor-α are capable of stimulating increased MMP-3 and MMP-9 by human decidual cells, (4) activation of protein kinase C results in increased release of MMP-3 and MMP-9 by human decidual cells. In conclusion, human amniotic fluid MMP-3, MMP-8 and MMP-9 elevations during spontaneous labor at term may be important in weakening of the fetal membranes leading to rupture of the membranes. Increased release of MMP-3, and MMP-9 by human decidual cells in response to microbial products establishes a clear link between infection and MMPs.