Developmental Regulation of the Human Relaxin Genes in the Decidua and Placenta: Overexpression in the Preterm Premature Rupture of the Fetal Membranes1

Abstract

The decidua and placenta synthesize the human relaxins, termed H1 and H2, believed to be involved in collagen remodeling in the amnion and chorion in an autocrine/paracrine manner. The developmental regulation of the relaxin genes was quantitated in normal pregnancy by in situ hybridization histochemistry with six 48-mer oligonucleotide probes that detect both relaxin genes. A significant increase in relaxin expression occurred in both decidua (p < 0.01) and placenta (p < 0.05) at 12.5-14.4 wk gestation, with the mean peak value in the placenta more than double that of the decidua, suggesting a coordinate regulation of the relaxin genes. At term after spontaneous labor and delivery, a marginal increase in both decidual and placental relaxin gene expression occurred. Given these normal data, three abnormal preterm situations were investigated: 1) premature uterine contractions without prior rupture of the membranes, 2) premature rupture of the fetal membranes (PPROM), 3) cesarean section for medical reasons with intact membranes and no uterine contractions. Tissues showing intrauterine infection were eliminated. Significantly more relaxin was expressed in the preterm decidua from patients with PPROM when compared to patients in group 1 (p < 0.02) or group 3 (p < 0.008). These data were confirmed by Northern analysis with a relaxin cRNA probe. The placental tissues after PPROM also had a significantly higher and a uniform overexpression of relaxin in the placental syncytiotrophoblast. Tissues collected at term, in comparison, showed no such increases in decidua or placenta.

Analysis of the 5'-upstream regions of the human relaxin H1 and H2 genes and their chromosomal localization on chromosome 9p24.1 by radiation hybrid and breakpoint mapping

“…In many of the tissues producing relaxins, the mRNA level is constantly low and they therefore appear to be constitutively expressed. However, in certain pathological conditions, such as in the preterm premature rupture of membranes, an increased level of total relaxin gene expression was observed in both the decidua and placenta (Bogic et al 1997), implying an inducible control mechanism. The presence of cis elements such as the MREs, ZREs, and the enhancer core element in both genes suggests that the expression of these genes may be influenced by other metabolites or hormones.…”

“…An overexpression of the relaxins in the decidua and placenta has been shown to be associated with the preterm premature rupture of the membranes (Bogic et al 1997), but it is not yet known whether one or both relaxins are upregulated in this condition. Relaxin overproduction in turn upregulates the expression of the matrix metalloproteinases (MMPs), which then increase the degradation of the extracellular matrix in this tissue, leading to tissue weakening, and premature rupture and preterm birth (Qin et al 1997a,b).…”

Relaxin, Its Receptor (RXFP1), and Insulin-Like Peptide 4 Expression Through Gestation and in Placenta Accreta

“…The primary antibodies used for RLN and RXFP1 were commercially available and immunolocalized to these proteins in the tissues in an identical way to the previously published work. 15,16,19 The specificity of the monoclonal antibody to INSL4 was evaluated and confirmed by Dr Bellet.…”

Serum relaxin levels are reduced in pregnant women with a history of recurrent miscarriage, and correlate with maternal uterine artery Doppler indices in first trimester

“…(11,12) Relaxin genes are over-expressed in preterm rupture of fetal membranes (13) and change with the remodelling of the extracellular matrix prior to parturition. (14) However RLX expression during pregnancy to women with a history of RPL has not been studied.…”