Circulating matrix metalloproteinase MMP-9 and MMP-2/TIMP-2 complex are associated with spontaneous early pregnancy fail
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RESEARCH
Open Access
Circulating matrix metalloproteinase MMP-9 and MMP-2/TIMP-2 complex are associated with spontaneous early pregnancy failure Ritva Nissi1*, Anne Talvensaari-Mattila1, Vesa Kotila2, Maarit Niinimäki1, Ilkka Järvelä1 and Taina Turpeenniemi-Hujanen3
Abstract Background: Trophoblast cell (CTB) invasion into the maternal endometrium plays a crucial role during human embryo implantation and placentation. This invasion is facilitated by the activity of matrix metalloproteinases, which are regulated by tissue inhibitors of MMPs (TIMPs). Methods: This study compares the serum levels of MMP-9, MMP-2/TIMP-2 complex, TIMP-1 and TIMP-2 in 129 patients with ongoing pregnancy (n = 40) or spontaneous early pregnancy failure (n = 89). Results: MMP-9 was markedly (p < 0.0001) elevated in missed abortions, as was MMP-2/TIMP-2 complex (p < 0.0005). However, the serum levels of TIMP-1 and TIMP-2 were markedly elevated (p < 0.0001) in ongoing pregnancies. Conclusions: Human placentation is mediated by fetal trophoblastic cells that invade the maternal uterine endometrium. Trophoblast invasion requires a precisely regulated secretion of specific proteolytic enzymes able to degrade the endometrial basement membrane and extracellular matrix. The elevated levels of MMP-9 and MMP-2/ TIMP-2 complex may play a role in spontaneous termination of pregnancy. Keywords: MMP-2, MMP-9, TIMP-1, TIMP-2, Pregnancy, Pregnancy loss, Serum marker, Placentation
Background Matrix metalloproteinases (MMPs) can be produced by numerous cell types. In normal adult tissue they are almost undetectable by immunohistochemistry, but injuries and pregnancy, for example, elevate their protein deposition. MMPs have the ability to break down several proteins of the extracellular matrix (ECM) and they participate actively in remodeling the ECM by degrading important matrix scaffold macromolecules. Together with their tissue inhibitors (TIMPs) they form a balance to maintain normal early pregnancy and placental development. The gelatinases MMP-2 and MMP-9 are especially involved in successful cytotrophoblast invasion in early pregnancy as they are considered key enzymes in * Correspondence: [email protected] 1 Department of Obstetrics and Gynecology, Oulu University Hospital, Kajaanintie 52A, Oulu 90220, Finland Full list of author information is available at the end of the article
degradation of basement membrane, which mainly consists of type IV collagen [1,2]. Tissue inhibitors for MMPs, such as TIMP-1 and TIMP-2, regulate protease activity. MMP-2, MMP-9, TIMP-1 and TIMP-2 have been localized in the placental bed using immunohistochemistry and in situ hybridization. Immunoreactivity for MMP-2 was detected in both decidual cells and extravillous trophoblasts (EVT), but MMP-9 staining was only observed in areas with abundant EVT [1-4]. In early gestation weeks (weeks 6 and 7) the secretion of MMP-9 in placental bed is very low, but the secretion increases gradually after week 8, and in week 11 the cells produce a large amount of MMP-9 [1]. In co
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