Compensatory fetal membrane mechanisms between biglycan and decorin in inflammation

Abstract

Preterm premature rupture of fetal membranes (PPROM) is associated with infection and is one of the most common causes of preterm birth. Abnormalities of biglycan and decorin, two extracellular matrix proteoglycans, lead to preterm birth and abnormal fetal membrane morphology and abnormal signaling in the mouse model as well as being associated with inflammatory cascades. In humans, decorin dysregulation is associated with inflammation in PPROM. We investigated biglycan and decorin’s role in inflammation in fetal membranes using mouse models of intraperitoneal E. coli injections superimposed on biglycan and decorin deficiency. We assessed outcomes in vivo as well as in vitro using quantitative qPCR, Western blotting and ELISA techniques. Our results suggest that biglycan and decorin compensate for each other in the fetal membranes but lose the ability to do so in the setting of inflammation, leading to decreased latency to preterm birth. Furthermore, our findings suggest that biglycan and decorin play discrete roles in fetal membrane signaling pathways in inflammation, leading to changes in expression of MMP-8 and collagen α1VI, two components of the fetal membrane extracellular matrix that play a role in the pathophysiology of PPROM. In summary, these findings underline the importance of biglycan and decorin in fetal membranes as targets for the manipulation of fetal membrane extracellular matrix stability in the setting of inflammation.

Roles of Two Small Leucine-Rich Proteoglycans Decorin and Biglycan in Pregnancy and Pregnancy-Associated Diseases

“…This elevated anticoagulant activity was attributed to a DS proteoglycan [ 131 ], later identified as DCN in the human term placenta [ 132 ]. Both of these interactions may account for proposed roles of DCN in immune signaling [ 133 , 134 ] and blocking thrombosis [ 135 ] involving several abnormal pregnancies.…”

Biglycan in the Skeleton

“…Skeletal manifestations are observed in mouse models in which specific SLRP genes were ablated or altered (leading to altered post-translational modifications), in some cases paralleling clinical phenotypes of human diseases, that is, in spite of compensatory expression of other members of the same sub-class of the ablated SLRP gene. 44,88,89 Many of the clinical phenotypes are associated with abnormal collagen fibril size, shape, and cross-linking. 13,30,[37][38][39][40] Though Decorin is expressed in bone, Decorin-deficient mice did not manifest any changes to bone mass or architecture.…”

Serum Decorin and Biglycan as Potential Biomarkers to Predict PPROM in Early Gestation

“…For the preanalytical and covariate studies, samples were selected from singleton pregnancies in order to assess the effects of gestational age (weeks [15][16][17][18][19][20], freezer storage (0, 6, or 12 months), and maternal race (African American or Non-African American) on biglycan and decorin serum values. Serum samples from nonpregnant women were chosen by a negative human chorionic gonadotrophin result.…”

“…16 We have previously shown that biglycan and decorin transcriptionally compensate for each other during fetal membrane maturation but lose their compensatory activity in the presence of inflammation. 17 Biglycan and decorin have also been shown to be involved in the pathophysiology of preterm birth, with dysregulation of decorin occurring in fetal membranes during the second trimester. 18,19 We have shown that mice deficient in biglycan and decorin, an animal model of EDS, deliver their pups prematurely and display morphologic as well as signaling abnormalities in their fetal membranes.…”