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Mol. Hum. Reprod. Advance Access originally published online on June 29, 2006
Molecular Human Reproduction 2006 12(8):497-503; doi:10.1093/molehr/gal055
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© The Author 2006. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Endometrial TIMP-4 mRNA is expressed in the stroma, while TIMP-4 protein accumulates in the epithelium and is released to the uterine fluid

R. Pilka1,2, V. Noskova1, H. Domanski3, C. Andersson3, S. Hansson1 and B. Casslén1,4

1Department of Obstetrics and Gynecology, University Hospital, Lund, Sweden, 2Department of Obstetrics and Gynecology, Palacky University, Olomouc, Czech Republic and 3Department of Pathology, University Hospital, Lund, Sweden

4 To whom correspondence should be addressed at: BMC C14, SE-221 84 Lund, Sweden. E-mail: bertil.casslen{at}med.lu.se

We have previously reported that endometrial mRNA expression of both tissue inhibitors of metalloproteinase-4 (TIMP-4) and matrix metalloproteinase-26 (MMP-26) peaks in the early secretory phase, which implies a role in implantation. The objective of this study was to compare the distribution of TIMP-4 and MMP-26 in endometrial tissue and uterine fluid over the menstrual cycle. Endometrial tissue was analysed with in situ hybridization and immunohistochemistry to localize mRNA and protein for TIMP-4 and MMP-26 in the same set of samples. TIMP-4 mRNA was quantified in separated stromal and epithelial cells using real-time PCR. Uterine fluid was analysed with western blotting. TIMP-4 mRNA was exclusively localized to the stroma, whereas MMP-26 mRNA was expressed by epithelial cells. TIMP-4 protein was only occasionally found in the stroma but was consistently present in granules of the apical part of luminal and glandular epithelial cells. TIMP-4, but not MMP-26, was demonstrated in uterine fluid. Thus, TIMP-4 is produced in the stroma only, secreted by stromal cells, taken up by epithelial cells, accumulated in apical granules and finally secreted to the uterine fluid. Maximal expression of MMP-26, and its strongest inhibitor TIMP-4, in the early and mid-secretory phase suggests a role during implantation. MMP-26 is stored in epithelial cells in its active form, is not released spontaneously and is controlled by TIMP-4 in both stroma and uterine fluid.

Key words: implantation/MMP-26/mRNA/protein/uptake


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