Imbalance between matrix metalloproteinases and their tissue inhibitors in preeclampsia and gestational trophoblastic diseases

Abstract

The invasion cascade exhibited by placental trophoblasts and cancerous cells bears many similarities, and it is attributed to extracellular matrix degradation mediated by matrix metalloproteinases (MMPs). Although proper and controlled invasion by trophoblasts into the maternal uterus is an essential requirement for maintenance of normal pregnancy, any abnormality in this phenomenon results in the development of invasion-related disorders such as gestational trophoblastic diseases (GTDs) and preeclampsia. We studied the epigenetic basis of differential expression of two placental MMPs (MMP2 and MMP9) and tissue inhibitors of metalloproteinases (TIMP2 and TIMP1) during normal gestation and invasion-related disorders, i.e., preeclampsia and GTDs. Our study suggests the association of H3K9/27me3 with differential expression of these MMPs and their inhibitors, which regulate the placental invasion during normal pregnancy, whereas no role of CpG methylation was observed in the differential expression of MMPs/TIMPs. Further, development of GTDs was associated with abnormally higher expression of these MMPs and lower levels of their inhibitors, whereas the reverse trends were observed for MMPs and their TIMPs in case of preeclampsia, in association with abnormal changes in H3K9/27me3. These results suggest the involvement of higher levels of MMPs in an aggressive invasive behavior depicted by GTDs, whereas lower levels of these MMPs in shallow and poor invasive phenotype associated with preeclampsia. Thus, our study shows the significance of a proper balance regulated by histone trimethylation between differential expression of MMPs and their TIMPs for maintaining normal pregnancy and its deregulation as a contributing factor for pathogenesis of invasive disorders during pregnancy.

Could perturbed fetal development of the ovary contribute to the development of polycystic ovary syndrome in later life?

“…Bovine fetal fibroblasts from the second trimester were treated with growth factors and hormones and the expression of PCOS candidate genes measured. Previous examination of these cells in culture found that FBN3 expression declined whilst FBN1 increased [66] with time in culture, suggesting that the fibroblasts were undergoing maturation similar to changes in fibrillin gene expression during fetal ovarian development [40]. Most genes were unresponsive to treatments except HMGA2 which increased in response to fibroblast growth factor 9 (FGF-9), and INSR, AR, C8H9orf3 and RAD50 all decreased while TGFB1I1 increased in response to TGFβ-1.…”

Chronic Hypoxia-Induced Microvessel Proliferation and Basal Membrane Degradation in the Bone Marrow of Rats Regulated through the IL-6/JAK2/STAT3/MMP-9 Pathway

“…To further verify the involvement of the IL-6-JAK2-STAT3-MMP-9 pathway, we inhibited STAT3 using an inhibitor [45]. Treatment with the STAT3 inhibitor decreased STAT3 phosphorylation in the CH rat bone marrow and resulted in a decrease in tissue MMP-9 concentration [52][53][54][55]. With the STAT3 inhibitor, many factors should be analyzed.…”

MMP-2, MMP-9, and TIMP-4 and Response to Aspirin in Diabetic and Nondiabetic Patients with Stable Coronary Artery Disease: A Pilot Study

“…They are expressed at low level in normal adult tissue turnovers such as reproduction [5, 6], development [7], tissue repair [8], or immune response [9, 10] and are upregulated during pathological processes including inflammation [11], autoimmune diseases [12], neurogenerative disorders [13], tumor invasion and metastasis [14, 15], and heart injury [16]. Broad substrate specificities and strict regulation of their expression, activation, and inhibition levels contribute to maintenance of tissue homeostasis.…”