A mouse model of spontaneous preterm birth based on the genetic ablation of biglycan and decorin

Abstract

Preterm premature rupture of membranes is responsible for one third of preterm births. Ehlers-Danlos syndrome (EDS) is associated with preterm premature rupture of membranes in humans. Notably, an EDS variant is caused by a genetic mutation resulting in abnormal secretion of biglycan and decorin, two small leucine-rich proteoglycans highly expressed in reproductive tissues. Because biglycan/decorin null mutant (Bgn−/−Dcn−/−) mice demonstrate phenotypic changes similar to EDS, we utilized this model to test whether either or both biglycan and decorin play a role in the attainment of successful term gestation. Wild-type, biglycan null mutant, decorin null mutant and biglycan/decorin null mutant pregnancies were assessed for length of gestation, pup and placenta weight and litter size. Quantitative real-time polymerase chain reaction was performed to measure biglycan and decorin gene expression and immunohistochemistry was performed to assess protein expression in placenta and fetal membranes at embryonic day E12, E15 and E18. Bgn−/−Dcn−/− dams displayed preterm birth, whereas the possession of at least two biglycan or decorin wild-type alleles was protective of preterm birth. Bgn−/−Dcn−/− pups were decreased at postnatal day P1 but not at E18. Biglycan and decorin were upregulated in the placenta in each other’s absence and were developmentally regulated in fetal membranes, suggesting that these two proteoglycans demonstrate genetic complementation and contribute to gestational success in a dose dependent manner. Thus, the biglycan/decorin null mutant mouse is a model of genetically induced preterm birth and perinatal loss. This model presents novel targets for preventive or therapeutic manipulation of preterm birth.

Dietary Vitamin D Restriction in Pregnant Female Mice Is Associated With Maternal Hypertension and Altered Placental and Fetal Development

“…Finally, data showed that births in Def mice were more likely to occur preterm (ϽE18) compared with Suff mice. The percentage of births less than E18 in vitamin D-deficient mothers was similar to that reported for biglycan and decorin knockout mouse models of spontaneous preterm birth (52). Epidemiological studies have yet to demonstrate a clear association between vitamin D deficiency and spontaneous pre- term birth in humans (28), and at present there are no data for iatrogenic (clinically indicated) preterm births secondary to disorders such as preeclampsia in relation to maternal vitamin D status.…”

Biglycan and decorin differentially regulate signaling in the fetal membranes

“…Examples include skin, bone, muscle, kidney and cornea (Ameye and Young, 2002; Corsi et al, 2002; Zhang et al, 2009) as well as our observations in the placenta (Calmus et al, 2011). Furthermore, fibromodulin and lumican, another pair of SLRPs, compensate for each other in tendon (Svensson et al, 1999).…”

“…Previously, we demonstrated that Bgn −/− ;Dcn −/− mice have an increased incidence of preterm birth (Calmus et al, 2011). MMPs and their inhibitors, TIMPs, as well as their targets, collagens, play a key role in the control of turnover of extracellular matrix in fetal membranes at term rupture as well as at preterm premature rupture of fetal membranes (Parry and Strauss, 1998).…”

“…We have previously shown that mice deficient in both biglycan and decorin, an animal model of EDS, deliver their pups prematurely (Calmus et al, 2011). While these SLRPs are the most abundant proteoglycans expressed in human fetal membranes (Gogiel et al, 2003; Meinert et al, 2001; Valiyaveettil et al, 2004), the mechanism by which biglycan and decorin protect from preterm birth is not known.…”

Maternal Vitamin D Deficiency and Fetal Programming - Lessons Learned from Humans and Mice

“…The observation that low gestational 25OHD also causes prematurity in rodent models is supported by a study from Liu et al which focused on prenatal morphology of offspring from 25OHD deficient mice. They showed that maternal gestational 25OHD deficiency leads to a higher rate of premature births, that is even comparable to established knockout models of prematurity [49,52].…”