HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: db07-0903v1 db07-0903v2 57/1/150    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hiden, U. Articles by Desoye, G. Search for Related Content PubMed PubMed Citation Articles by Hiden, U. Articles by Desoye, G. Social Bookmarking                What's this?

MT1-MMP Expression in First-Trimester Placental Tissue Is Upregulated in Type 1 Diabetes as a Result of Elevated Insulin and Tumor Necrosis Factor- Levels

¹ Department of Obstetrics and Gynecology, Medical University of Graz, Austria
² Department of Obstetrics and Gynecology, University Hospital, Petrova, Zagreb, Croatia

Address correspondence and reprint requests to Ursula Hiden, MSc, PhD, Department of Obstetrics and Gynecology, Medical University of Graz, Auenbruggerplatz 14, 8036 Graz, Austria. E-mail: ursula.hiden{at}klinikum-graz.at

Key Words: DMEM, Dulbecco's modified Eagle's medium • ECM, extracellular matrix • ERK, extracellular signal–related kinase • GRO, growth-regulated protein • hCG, human chorionic gonadotropin • HIF-1, hypoxia-inducible factor 1 • IL, interleukin • MAPK, mitogen-activated protein kinase • MEK1, MAPK/ERK kinase 1 • MMP, matrix metalloproteinase • PI 3-kinase, phosphatidylinositol 3-kinase • RPL30, ribosomal protein L30 • TNF-, tumor necrosis factor-

OBJECTIVE—In pregestational diabetes, the placenta at term of gestation is characterized by various structural and functional changes. Whether similar alterations occur in the first trimester has remained elusive. Placental development requires proper trophoblast invasion and tissue remodeling, processes involving matrix metalloproteinases (MMPs) of which the membrane-anchored members (MT-MMPs) such as MT1-MMPs are key players. Here, we hypothesize a dysregulation of placental MT1-MMP in the first trimester of type 1 diabetic pregnancies induced by the diabetic environment.

RESEARCH DESIGN AND METHODS—MT1-MMP protein was measured in first-trimester placentas of healthy (n = 13) and type 1 diabetic (n = 13) women. To identify potential regulators, first-trimester trophoblasts were cultured under hyperglycemia and various insulin, IGF-I, IGF-II, and tumor necrosis factor- (TNF-) concentrations in presence or absence of signaling pathway inhibitors.

RESULTS—MT1-MMP was strongly expressed in first-trimester trophoblasts. In type 1 diabetes, placental pro–MT1-MMP was upregulated, whereas active MT1-MMP expression was only increased in late first trimester. In isolated primary trophoblasts, insulin, IGF-I, IGF-II, and TNF- upregulated MT1-MMP expression, whereas glucose had no effect. The insulin effect was dependent on phosphatidylinositol 3-kinase, the IGF-I effect on mitogen-activated protein kinase, and the IGF-II effect on both.

CONCLUSIONS—This is the first study reporting alterations in the first-trimester placenta in type 1 diabetes. The upregulated MT1-MMP expression in type 1 diabetes may be the result of higher maternal insulin and TNF- levels. We speculate that the elevated MT1-MMP will affect placental development and may thus contribute to long-term structural alterations in the placenta in pregestational diabetes.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?