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Expression pattern and functional studies of matrix degrading proteases and their inhibitors in the mouse corpus luteum
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.
Umeå University, Faculty of Medicine, Department of Medical Biochemistry and Biophysics.
2003 (English)In: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 205, no 1-2, 131-140 p.Article in journal (Refereed) Published
Abstract [en]

The formation of the corpus luteum (CL) is accompanied with angiogenesis and tissue remodeling and its regression involves tissue degradation. Matrix degrading proteases such as plasminogen activators (PAs) and matrix metalloproteinases (MMPs) are thought to play important roles in such controlled proteolytic processes. In this study, in situ hybridization has been used to examine the regulation and expression pattern of mRNAs coding for proteases and protease inhibitors belonging to the PA- and MMP-systems during the life cycle of the CL in an adult pseudopregnant mouse model. Of the nine proteases and five protease inhibitors that were studied, the majority were found to be temporally expressed during the formation and/or the regression of the CL. However, the mRNAs coding for urokinase type PA (uPA), membrane-type 1 MMP (MT1-MMP), and tissue inhibitor of metalloproteinases type-3 (TIMP-3) were constantly expressed in the mouse CL throughout its whole life span. To study the functional role of uPA in the CL, we analyzed luteal formation and function in uPA deficient mice. Our results revealed no significant difference in ovarian weight, serum progesterone levels, and blood vessel density in the functional CL between uPA deficient and wild type control mice. The temporal and spatial expression pattern of proteases and protease inhibitors during the CL life span suggests that members of the PA- and MMP-systems may play important roles in the angiogenesis and tissue remodeling processes during CL formation, as well as in the tissue degradation during luteal regression. However, the absence of reproductive phenotypes in mice lacking uPA and several other matrix degrading proteases indicates that there are redundancies among different matrix degrading proteases or that tissue remodeling in the ovary may involve other additional unique elements.

Place, publisher, year, edition, pages
2003. Vol. 205, no 1-2, 131-140 p.
Keyword [en]
Ovary, Corpus luteum, Plasminogen activators, Matrix metalloproteinase
URN: urn:nbn:se:umu:diva-4007DOI: 10.1016/S0303-7207(03)00147-3PubMedID: 12890575OAI: diva2:142941
Available from: 2004-05-12 Created: 2004-05-12 Last updated: 2011-03-30Bibliographically 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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Liu, KuiWahlberg, PatrikHägglund, Anna-CarinNy, Tor
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