TY - JOUR
T1 - Fetal fibronectin signaling induces matrix metalloproteases and cyclooxygenase-2 (COX-2) in amnion cells and preterm birth in mice
AU - Mogami, Haruta
AU - Kishore, Annavarapu Hari
AU - Shi, Haolin
AU - Keller, Patrick W.
AU - Akgul, Yucel
AU - Word, R. Ann
PY - 2013/1/18
Y1 - 2013/1/18
N2 - Background: The function of fetal fibronectin (fFN) in the pathogenesis of preterm labor is not known. Results: fFN activates MMP-1, MMP-9, and COX-2 in mesenchymal cells and causes preterm labor in mice. Conclusion: fFN is biologically active and plays a significant role in the pathogenesis of preterm labor. Significance: Signaling of fFN in fetal membranes is important in the pathophysiology of premature preterm rupture of the membranes. Fetal fibronectin (fFN) in cervical and vaginal secretions has been used as a predictor of preterm delivery. Here, we clarified the pathological function of fFN on cell type-specific matrix metalloproteinases (MMPs) and prostaglandin synthesis in fetal membranes. Treatment of amnion mesenchymal cells with fFN resulted in dramatic increases in MMP-1 and MMP-9 mRNA and enzymatic activity as well as COX-2 mRNA and prostaglandin E2 synthesis, activating both NFB and ERK1/2 signaling. Fetal FN-induced increases inMMPsand COX-2 were mediated through its extra domainAand Toll-like receptor 4 expressed in mesenchymal cells. Lipopolysaccharide and TNF-increased the release of free FN in medium of amnion epithelial cells in culture. Finally, injection of fFN in pregnant mice resulted in preterm birth. Collectively, these results indicate that fFN is not only a marker of preterm delivery but also plays a significant role in the pathogenesis of preterm labor and premature rupture of fetal membranes.
AB - Background: The function of fetal fibronectin (fFN) in the pathogenesis of preterm labor is not known. Results: fFN activates MMP-1, MMP-9, and COX-2 in mesenchymal cells and causes preterm labor in mice. Conclusion: fFN is biologically active and plays a significant role in the pathogenesis of preterm labor. Significance: Signaling of fFN in fetal membranes is important in the pathophysiology of premature preterm rupture of the membranes. Fetal fibronectin (fFN) in cervical and vaginal secretions has been used as a predictor of preterm delivery. Here, we clarified the pathological function of fFN on cell type-specific matrix metalloproteinases (MMPs) and prostaglandin synthesis in fetal membranes. Treatment of amnion mesenchymal cells with fFN resulted in dramatic increases in MMP-1 and MMP-9 mRNA and enzymatic activity as well as COX-2 mRNA and prostaglandin E2 synthesis, activating both NFB and ERK1/2 signaling. Fetal FN-induced increases inMMPsand COX-2 were mediated through its extra domainAand Toll-like receptor 4 expressed in mesenchymal cells. Lipopolysaccharide and TNF-increased the release of free FN in medium of amnion epithelial cells in culture. Finally, injection of fFN in pregnant mice resulted in preterm birth. Collectively, these results indicate that fFN is not only a marker of preterm delivery but also plays a significant role in the pathogenesis of preterm labor and premature rupture of fetal membranes.
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U2 - 10.1074/jbc.M112.424366
DO - 10.1074/jbc.M112.424366
M3 - Article
C2 - 23184961
AN - SCOPUS:84872721788
SN - 0021-9258
VL - 288
SP - 1953
EP - 1966
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 3
ER -