A Single Nucleotide Polymorphism in the Matrix Metalloproteinase-1 (MMP-1) Promoter Influences Amnion Cell MMP-1 Expression and Risk for Preterm Premature Rupture of the Fetal Membranes

Abstract

Interstitial collagen gives fetal membranes tensile strength, and membrane rupture has been attributed to collagen degradation. A polymorphism at ؊1607 in the matrix metalloproteinase-1 (MMP-1) promoter (an insertion of a guanine (G)) creates a core Ets binding site and increases promoter activity. We investigated whether this polymorphism is functionally significant for MMP-1 expression in amnion cells and whether it is associated with preterm premature rupture of the membranes (PPROM). The 2G promoter had >2-fold greater activity than the 1G allele in amnion mesenchymal cells and WISH amnion cells. Phorbol 12-myristate 13-acetate (PMA) increased mesenchymal cell nuclear protein binding with greater affinity to the 2G allele. Induction of MMP-1 mRNA by PMA was significantly greater in cells with a 1G/2G or 2G/2G genotype compared with cells homozygous for the 1G allele. When treated with PMA, the 1G/2G and 2G/2G cells produced greater amounts of MMP-1 protein than 1G/1G cells. A significant association was found between fetal carriage of a 2G allele and PPROM. We conclude that the 2G allele has stronger promoter activity in amnion cells, that it confers increased responsiveness of amnion cells to stimuli that induce MMP-1, and that this polymorphism contributes to the risk of PPROM.Complications resulting from idiopathic preterm birth, defined as delivery before 37 weeks of gestation, account for the majority of perinatal deaths of infants without anomalies in developed nations (1, 2). Preterm premature rupture of the membranes (PPROM) 1 occurs in ϳ1% of all pregnancies and is associated with 30 -40% of preterm deliveries (3). PPROM is thus the leading identifiable cause of preterm birth and its complications, including respiratory distress syndrome, neonatal infection, and intraventricular hemorrhage (3, 4). Consequently, identification of markers that identify patients at risk for PPROM is a subject of considerable interest.Interstitial collagens (type I and type III collagen) of the amnion confer upon the fetal membranes tensile strength (5). Rupture of fetal membranes at term as well as preterm has been attributed, in part, to degradation of the collagens in the extracellular matrix. The breakdown of the interstitial collagens is mediated by matrix metalloproteinases (MMPs). The first step in interstitial collagen catabolism is catalyzed by collagenases including matrix metalloproteinase 1 (MMP-1), the primary collagenase elaborated by fibroblasts (6). It is also produced by monocytic cells (7). MMP-1 is produced as a proenzyme; after proteolytic activation, it cleaves through the fibrillar triple helix at a specific site, producing fragments that can be further degraded by other MMPs, including the gelatinases MMP-2 and MMP-9 (8 -12). Evidence that MMP activity is important for fetal membrane rupture includes the observation that fetal membrane MMP expression increases at the time of parturition (13, 14). Moreover, MMP levels are elevated in human amniotic fluid in association with PPROM (15-18).A single n...

Weakening and Rupture of Human Fetal Membranes – Biochemistry and Biomechanics

“…Several groups have proposed the synergistic effects of MMP activation and apoptosis leading to rupture of the FM (McLaren et al, 2000a;Fortunato et al, 2000;Bowen et al, 2002;Lei et al, 1996). The promoter polymorphisms in some cytokines (TNF and IL-1 ) and MMPs (-1,-8,-9) have been identified to be associated with PPROM (Ferrand et al, 2002;Fujimoto et al, 2002;Hernandez-Guerrero et al, 2003;Roberts et al, 1999). Patients with these polymorphisms may have earlier initiation of the programmed weakening process resulting in premature rupture of FM and earlier deliveries.…”

“…As such, it remains difficult to identify those who will develop PROM before the fact. Recently, several groups have demonstrated that African Americans, a group with a high incidence of PPROM with early delivery, have a higher incidence of certain more active polymorphisms of MMPs and pro-inflammatory cytokines (Ferrand et al, 2002;Fujimoto et al, 2002;Hernandez-Guerrero et al, 2003;Roberts et al, 1999). It is possible that a combination of genes and historical factors could eventually lead to prediction of risk of PPROM with adequate certainty that procedures designed to prevent FM rupture that carry some inherent risk would be justifiable.…”

Genome-Wide Analysis of DNA Methylation in Human Amnion

“…A previous study by Wang et al [15] has shown that matrix metalloproteinase 1 (MMP1), whose genetic variation is associated with susceptibility to PPROM [16], is regulated at the epigenetic level, e Scienti�c World �ournal speci�cally by DNA methylation, and that MMP1 promoter methylation status correlates with its expression in the amnion and association with PPR�M. is �nding suggests that the amnion represents an intriguing source of tissue for studying epigenetic events of potential physiological and pathological relevance.…”

A 12-bp deletion in the 5'-flanking region of theSERPINH1gene affects promoter activity and protects against preterm premature rupture of membranes in African Americans

“…Fetal membranes that rupture prematurely have reduced collagen content, which could be the result of diminished synthesis or increased catabolism (Skinner et al, 1981;Hampson et al, 1997;Vadillo-Ortega et al, 1990;Wang et al, 2004;Fujimoto et al, 2002;Ferrand et al, 2002;Vadillo-Ortega & Estrada-Guiterrez, 2005;Moore et al, 2006). The SERPINH1 gene (*600943, collagen-binding protein 2 (CBP2)), which encodes heat-shock protein 47 (Hsp47), an intracellular chaperone for collagen proteins, plays a key role in governing collagen production in that levels of Hsp47 are directly correlated with collagen synthesis.…”