Extracellular matrix remodeling effects of serum amyloid A1 in the human amnion: Implications for fetal membrane rupture.

ABSTRACT

PROBLEM: Rupture of fetal membranes is a crucial event at parturition, which is preceded by extensive extracellular matrix (ECM) remodeling. Our recent studies have demonstrated that the human fetal membranes are capable of de novo synthesis of serum amyloid A1 (SAA1), an acute phase protein, and the abundance of SAA1 in the amnion was increased at parturition. However, the exact role of SAA1 in human parturition remains to be established. METHOD OF STUDY The effects of SAA1 on the abundance of collagenases and lysyl oxidase, the enzyme that cross-links collagens, were investigated in culture primary human amnion fibroblasts and tissue explants with an aim to examine the involvement of SAA1 in the ECM remodeling in the amnion. RESULTS: Serum amyloid A1 (SAA1) time- and dose-dependently increased the abundance of collagenases MMP-1, MMP-8, and MMP-13, while decreased the abundance of lysyl oxidase-like 1 (LOXL1). These effects of SAA1 were attenuated by siRNA-mediated knockdown of the Toll-like receptor (TLR) 4 and its antagonist CLI-095, but not by siRNA-mediated knockdown of TLR2. Furthermore, the inhibitors for NF-κB (JSH-23) and mitogen-activated protein kinases (MAPKs) p38 (SB203580) and JNK (SP600125) could also attenuate the effects of SAA1, while the inhibitor for MAPK ERK1/2 (PD 98059) could block the effects of SAA1 only on MMP-1, MMP-8, and LOXL1 but not on MMP-13. CONCLUSION: These data highlight a possible role for SAA1 in ECM remodeling preceding membrane rupture by regulating the expression of collagenases MMP-1, MMP-8, MMP-13, and LOXL1 through TLR4-mediated activation of the NF-κB and MAPK pathways in amnion fibroblasts.