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Coordinated and cell-specific regulation of membrane-type matrix metalloproteinase 1 (MT1-MMP) and its substrate matrix metalloproteinase 2 (MMP-2) by physiological signals during follicular development and ovulation
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
1998 (English)In: Endocrinology, ISSN 0013-7227, E-ISSN 1945-7170, Vol. 139, no 11, 4735-4738 p.Article in journal (Refereed) Published
Abstract [en]

In the ovary, extensive tissue remodeling is required during both follicular development and the break down of the follicular wall at the time of ovulation. Extracellular proteases such as serine proteases and matrix metalloproteinases (MMPs) are thought to play pivotal roles in these processes. In this paper, we have used in situ hybridization to study the regulation and distribution of mRNA coding for MMP-2 (gelatinase A) and its cell surface activator membrane-type MMP1 (MT1-MMP) during gonadotropin induced ovulation in the rat. In ovaries of untreated immature (23 day old) rats, the levels of MT1-MMP and MMP-2 mRNA were low. MMP-2 mRNA was found in theca-interstitial cells while MT1-MMP mRNA was found in both granulosa and theca-interstitial cells and both messages were induced after stimulation with PMSG. After an ovulatory dose of hCG, the expression of MT1-MMP was dramatically down regulated in the granulosa cell layers of large preovulatory follicles but the expression remained and appeared to be up regulated together with MMP-2 in the theca-interstitial cells surrounding the large preovulatory follicles. The expression kinetics and tissue distribution supports the notion that MT1-MMP may have dual functions in the ovary. Initially MT1-MMP may act as a matrix degrading protease inside the follicle during follicular development and later, just prior to ovulation, as an activator of proMMP-2 in theca-interstitial cells surrounding preovulatory follicles.

Place, publisher, year, edition, pages
1998. Vol. 139, no 11, 4735-4738 p.
URN: urn:nbn:se:umu:diva-4005PubMedID: 9794486OAI: diva2:142939
Available from: 2004-05-12 Created: 2004-05-12 Last updated: 2010-09-03Bibliographically approved
In thesis
1. Matrix degrading proteases in the ovary: expression and function
Open this publication in new window or tab >>Matrix degrading proteases in the ovary: expression and function
2004 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Extracellular matrix degrading proteases from the plasminogen (plg) activator (PA) and the matrix metalloproteinase (MMP) systems have been implicated as important mediators of ovulation and corpus luteum (CL) formation and regression. The aim of this thesis was to investigate the expression and regulation of PAs and MMPs in the ovary and to examine their functional roles for CL formation and function.

The expression of membrane-type MMP-1 (MT1-MMP) and its substrate gelatinase A (MMP-2) mRNAs was studied during pregnant mare serum gonadotropin (PMSG)/human chorionic gonadotropin (hCG)-induced ovulation in immature rats. These proteases were coordinately regulated so that both were highly expressed in the theca cells of large preovulatory follicles. This suggests that MT1-MMP activates gelatinase A in preovulatory follicles to degrade the follicular wall during ovulation.

In pseudopregnant (psp) rats, MT1-MMP mRNA was expressed in the CL throughout the luteal phase. Tissue inhibitor of metalloproteases type-1 (TIMP-1) mRNA was expressed during CL formation and regression. MMP-2 and collagenase-3 mRNAs were expressed during CL formation and regression, respectively. When the luteal phase was artificially prolonged or shortened, TIMP-1 and collagenase-3 mRNAs were induced only after the serum progesterone levels had decreased, indicating a close association with luteolysis in the rat.

In psp mice, the expression of mRNAs coding for both PAs, seven MMPs, and five protease inhibitors was studied. Most of the studied molecules were coordinately expressed during formation or regression of the CL. However, uPA, MT1-MMP, and TIMP-3 mRNAs were expressed throughout the luteal phase. The role of uPA was examined in psp uPA deficient mice. These mice displayed no abnormalities in luteal function or vascularity. The role of uPA is thus either not essential or can be compensated by other proteases in the absence of uPA.

In order to control the timing of the CL formation, a mouse model for PMSG/hCG-induced CL formation was developed. Five different protocols were evaluated. One of them provided CL that were stable for six days. In that protocol the mice were treated with prolactin (PRL), twice daily from day 2 of CL life onward. The expression of the steroid acute regulatory protein (StAR) mRNA in the psp CL was also characterized to assess its use as a molecular marker for CL development and regression. It was highly expressed in the forming and functional CL and downregulated at a late stage of CL regression.

The functional role of plg and MMPs for CL formation and function was investigated in plg deficient mice treated with the MMP inhibitor galardin (GM6001). Both psp mice and PMSG/hCG +PRL-induced CL formation were used. Several molecular markers for CL development and regression were used to evaluate the health status of the CL. Our data showed that healthy and vascularized CL formed even in plg deficient mice treated with the inhibitor. However, serum progesterone levels were significantly reduced in these mice, an effect that was mainly attributable to the plg deficiency. In conclusion, neither plg nor MMPs, alone or in combination, seem to be essential for the development of a functional CL.

Place, publisher, year, edition, pages
Umeå: Medicinsk biokemi och biofysik, 2004. 56 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 893
Biochemistry, ovary, ovulation, corpus luteum, plasminogen, PA, MMP, rat, mouse, Biokemi
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Medical Biochemistry
urn:nbn:se:umu:diva-280 (URN)91-7305-659-6 (ISBN)
Public defence
2004-06-03, N350, Naturvetarhuset, Umeå Universitet, Umeå, 13:00
Available from: 2004-05-12 Created: 2004-05-12Bibliographically approved

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