Matrix metalloproteinase (MMP)-2 and MMP-9 and their inhibitor, TIMP-1, in human term decidua and fetal membranes: the effect of prostaglandin F2alpha and indomethacin

Abstract

Degradation and breakdown of gestational membranes and the adjacent decidua are essential processes for the advancement of labour. We have assessed the effect of prostaglandin (PG) synthesis on the expression and activity of matrix metalloproteinase (MMP)-2 and MMP-9 and tissue inhibitor of metalloproteinases (TIMP-1) in fetal membranes at the edge of the placenta and decidua, by using ex-vivo organ culture of the tissues in the absence or presence of PGF(2alpha) (0.1, 1.0 and 10 microg/ml) or a PG synthesis inhibitor, indomethacin (10(-4)-10(-6) mol/l). Conditioned media were assessed for MMP by zymography on gelatin containing sodium dodecyl sulphate-polyacrylamide gels and for TIMP-1 by Western blot analysis. Compared to the membranes, decidua produced significantly more MMP-2 and MMP-9 as well as TIMP-1. PGF(2alpha) caused a 2.4- and 1.9-fold increase in the production of MMP-2 and MMP-9 in the decidua, respectively (P < 0.05), and an 11.3-fold increase of the active form of MMP-2 (62 kDa) which could hardly be detected in basal culture conditions (P < 0.01). PGF(2alpha) decreased TIMP-1 production by 70% in the decidua. The production of MMP-2 and MMP-9 and TIMP-1 by the amniotic and chorionic membranes was not affected by PGF(2alpha). Indomethacin decreased the production of MMP-2 and MMP-9 by 78 and 35% in chorion, and by 70 and 58% in amnion, respectively (P < 0.05), but did not affect production in decidual tissue. Indomethacin increased the production of TIMP-1 in chorion and amnion [by 4.1- and 4.5-fold respectively (P < 0.01)], but had no effect on decidua. Cumulatively, PGF(2alpha) increases decidual gelatinolytic activity. Meanwhile the inhibition of PG production by indomethacin reduces total gelatinolytic activity in fetal membranes, possibly accounting for some of its labour-arresting property.

Matrix metalloproteinases-2, -3 and tissue inhibitors of metalloproteinases-1, -2 in placentas from preterm pregnancies and their association with one-carbon metabolites

“…Thus, it could be possible that the increased vitamin B 12 may be related to inflammation which is also one of the underlying causes of preterm birth. Increased inflammatory cytokine levels stimulate prostaglandin production, which in turn are observed to upregulate the expression/activity of MMPs (Locksmith et al 1999, Ulug et al 2001. So, it is likely that increased placental MMP3 levels in women delivering preterm may be due to increased vitamin B 12 levels through the inflammatory pathway.…”

Weakening and Rupture of Human Fetal Membranes – Biochemistry and Biomechanics

“…In contrast, both active and latent forms of Bryant-Greenwood et al, 1995;Osmers et al, 1995;Athayde et al, 1999;Vadillo-Ortega et al, 2002). MMP-9 can also be induced in FM tissue with PGE 2 , PGF 2 , TNF and ROS (Buhimschi et al, 2000;Ulug et al, 2001;Arechavaleta-Velasco et al, 2002;Zaga et al, 2004). TIMP-1, which controls the activity of MMP-9, has been extensively studied in FM and found to decrease with PROM and labor (Ulug et al, 2001;Arechavaleta-Velasco et al, 2002;Buhimschi et al, 2000;Zaga et al, 2004;McLaren et al, 2000b).…”

“…MMP-9 can also be induced in FM tissue with PGE 2 , PGF 2 , TNF and ROS (Buhimschi et al, 2000;Ulug et al, 2001;Arechavaleta-Velasco et al, 2002;Zaga et al, 2004). TIMP-1, which controls the activity of MMP-9, has been extensively studied in FM and found to decrease with PROM and labor (Ulug et al, 2001;Arechavaleta-Velasco et al, 2002;Buhimschi et al, 2000;Zaga et al, 2004;McLaren et al, 2000b). Thus we conclude that MMP-9 plays a major role in FM remodeling, weakening and rupture.…”

OBE022, an Oral and Selective Prostaglandin F2α Receptor Antagonist as an Effective and Safe Modality for the Treatment of Preterm Labor

“…PGF2α has been shown to induce upregulation of matrix metalloproteinase MMP1, an enzyme that breaks down collagen in cervical fibroblasts leading to cervical ripening (Yoshida et al, 2002). PGF2α upregulates MMP2 and MMP9 and downregulates their naturally-occurring tissue inhibitor of metalloproteinases TIMP1 in human term decidua, thus accelerating the breakdown of collagen and the rupture of membranes (Ulug et al, 2001). …”