Thrombin-dependent regulation of matrix metalloproteinase (MMP)-9 levels in human fetal membranes

J Matern Fetal Neonatal Med. 2005 Jul;18(1):17-22. doi: 10.1080/14767050500123632.

Abstract

Objective: Amniochorion matrix metalloproteinase (MMP)-9 levels increase during labor, reaching a maximum in patients with preterm premature rupture of membranes (PPROM). Bleeding is a major risk factor for PPROM. Since such hemorrhage into the tissue factor-enriched decidua induces intense thrombin formation, we determined whether thrombin stimulates MMP levels in amniochorionic membranes.

Study design: Fetal membrane (amniochorion) cultures were maintained in media with and without thrombin, lipopolysaccharide (LPS), thrombin receptor agonist peptide (TRAP)-14, and the anti-inflammatory steroid, dexamethasone (DEX). Concentrations of MMP-9, MMP-1, and tissue inhibitor of metalloproteinase (TIMP)-1 in culture media were measured by ELISA and normalized to total cell protein.

Results: The presence of thrombin induced MMP-9 levels. TRAP-14, a thrombin receptor agonist, also significantly increased MMP-9 levels, suggesting that thrombin-induced changes in MMP-9 expression were mediated through the thrombin receptor. Conversely, levels of MMP-1 and TIMP-1 were not affected by thrombin treatment, indicative of specificity of its action. The presence of LPS increased the concentration of MMP-9 and MMP-1. In contrast, DEX treatment significantly reduced MMP-9 levels.

Conclusion: Our findings clearly demonstrated that thrombin treatment selectively increased the concentration of MMP-9 in culture media of amniochorionic membranes. Our results provide a potential mechanism through which alterations in hemostasis promote PPROM through thrombin-dependent stimulation of MMP-9.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Anti-Inflammatory Agents / pharmacology*
  • Dexamethasone / pharmacology*
  • Extraembryonic Membranes
  • Female
  • Fetal Membranes, Premature Rupture / metabolism
  • Humans
  • Lipopolysaccharides / pharmacology
  • Matrix Metalloproteinase 1 / metabolism
  • Matrix Metalloproteinase 9 / drug effects
  • Matrix Metalloproteinase 9 / metabolism*
  • Organ Culture Techniques
  • Peptide Fragments / pharmacology
  • Pregnancy
  • Thrombin / physiology*
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism

Substances

  • Anti-Inflammatory Agents
  • Lipopolysaccharides
  • Peptide Fragments
  • Tissue Inhibitor of Metalloproteinase-1
  • thrombin receptor peptide (42-55)
  • Dexamethasone
  • Thrombin
  • Matrix Metalloproteinase 9
  • Matrix Metalloproteinase 1