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Departments of Medical Biosciences, Medical Biochemistry (K.L., P.W., T.N.), and Obstetrics and Gynecology (J.O.), Umeå University, S-901 87 Umeå, Sweden
Address all correspondence and requests for reprints to: Professor Tor Ny, Department of Medical Biosciences, Medical Biochemistry, Umeå University, S-901 87 Umeå, Sweden. E-mail: tor.ny{at}medchem.umu.se
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analog, cloprostenol. In
both treatments, collagenase-3 and TIMP-1 were induced only after the
serum level of progesterone had decreased, suggesting that
collagenase-3 and TIMP-1 are induced by physiological signals, which
initiate functional luteolysis to play a role in tissue degradation
during structural luteolysis. In conclusion, our data suggest that
gelatinase A, collagenase-3, and MT1-MMP may have separate functions
during the CL life span: gelatinase A mainly takes part in CL
formation, whereas collagenase-3 mainly takes part in luteal
regression; MT1-MMP is constitutively expressed during the CL life span
and may therefore serve as an in vivo activator of both
gelatinase A and collagenase-3. TIMP-1 is up-regulated both during the
formation and regression of the CL and may therefore regulate MMP
activity during both processes. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The mechanism controlling the activation of MMPs in vivo under physiological conditions is not well understood. Serine proteases, such as plasmin, can cleave the propeptide of some pro-MMPs and thereby initiate their activation (2), whereas other pro-MMPs are resistant to activation by serine proteases. More recent studies have shown that some pro-MMPs, including progelatinase A and procollagenase-3, can be activated through a membrane-associated mechanism by membrane type MMP 1 (MT1-MMP) (2, 3, 6, 7, 8, 9).
The corpus luteum (CL) is formed from an ovulated follicle. During this process, a capillary network invades from the theca tissues into the granulosa layers, through a dynamic angiogenesis process. Formation of the CL is also accompanied by active tissue remodeling and cellular differentiation when theca and granulosa cells transform into luteal cells. Once the CL is formed, it secretes progesterone that prepares the uterine environment for implantation, provided fertilization has occurred (10, 11). If fertilization has not occurred, or if the implantation is unsuccessful, functional luteolysis is initiated whereby the CL gradually loses its progesterone-producing ability, followed by structural luteolysis, which involves degradation of luteal tissue (10, 11, 12). Like many other physiological processes involving angiogenesis, tissue remodeling, and tissue involution, the luteal development and regression might be dependent on the action of controlled and targeted proteolysis. To elucidate the roles of matrix degrading proteases in luteal development and regression, we have examined in this study the regulation of gelatinase A (MMP-2), collagenase-3 (MMP-13), MT1-MMP (MMP-14), and TIMP-1 in the adult pseudopregnant (psp) rat CL.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-32P-labeled UTP (800 Ci/mmol) was from Amersham Pharmacia Biotech (Aylesbury, UK). Restriction enzymes,
Taq polymerase, 4-Nitro blue tetrazolium chloride,
5-Bromo-4-chloro-3-indolyl-phosphate, anti-digoxigenin-AP Fab
fragments, and the Dig RNA Labeling Kit for in situ
hybridization riboprobes were from Roche Molecular Biochemicals (Mannheim, Germany). Tissue-Tec OCT compound was
from Miles (Elkhart, IL), microscope slides (SuperFrost/Plus) were from
MENZEL-GLASER (Braunschweig, Germany), and cloprostenol was from
Sigma Chemical Co. (St. Louis, MO).
Animals
Female Sprague Dawley rats (170–180 g BW) were obtained from
Mollegaard Co. (Ejby, Denmark). The rats were housed under controlled
environmental conditions, with free access to water and food.
Illumination was on between 0600 h and 1800 h. Experimental
protocols were approved by the regional ethical committee of Umeå
University.
Rat model
The adult psp rat model and dissection procedures used were as
previously described, and day 1 of pseudopregnancy was defined as the
day when a vaginal plug was recorded (13, 14). Whole ovaries for
in situ hybridization were frozen in Tissue-Tec OCT compound
at -80 C. For Northern blot analysis, CL were identified according to
previously defined criteria (14); and 10–15 CL from each rat were
pooled and frozen in liquid nitrogen for further extraction of total
RNA.
Hysterectomy and cloprostenol treatment
Abdominal hysterectomy was performed as previously described
(15). Briefly, on the 5th day of pseudopregnancy, animals were
anesthetized after premedication with atropine (KabiVitrum Ltd.,
Stockholm, Sweden; 0.05 mg/kg BW sc); and diazepam (Dumex
Ltd., Copenhagen, Denmark; 2.5 mg/kg BW ip); followed 10 min later by
fluanison (0.6 mg/kg BW ip); and fentanyldihydrogencitrate
(Hypnorm Vet, Janssen Pharmaceuticals N.V., Beerse,
Belgium; 0.12 mg/kg BW ip). In one group of rats, hysterectomy was
performed by severing the uterine horns at the tubouterine junctions
and just proximally to the cervix. Sham-operated psp rats were used as
controls.
The cloprostenol treatment was performed as previously described (16).
On the 8th day of pseudopregnancy, animals were given a single sc
injection of 5.0 µg cloprostenol dissolved in 0.25 ml solution
containing 140 mM NaCl, 3 mM KCl, 8
mM Na2HPO4, and 8
mM KH2PO4 (pH 7.4). Cloprostenol is
a stable PGF2 analog, which has been shown to be
luteolytic in most species, including the rat (17). The control group
was only injected with saline.
Synthesis of RNA probes
The subcloning of rat LH receptor complementary DNA (cDNA)
fragment to pGEM-3 vector has been previously described (18). The rat
collagenase-3 cDNA fragment (nucleotides 350–663) was kindly provided
by Dr. Lopez-Otin (19), and the mouse TIMP-1 cDNA fragment (nucleotides
-22 to 663) was kindly provided by Dr. Opdenakker (20). The
subclonings of mouse MT1-MMP (nucleotides 947-1464), gelatinase A cDNA
(nucleotides 916-1414) fragments to pGEM-3 vectors (Promega Corp.), and the subcloning of rat glyceraldehyde-3-phosphate
dehydrogenase (GAPDH) cDNA fragment (nucleotides 255–840) to pT7
vector have been described previously (21, 22). Before in
vitro transcription, plasmids were linearized such that antisense
or sense RNA probes could be synthesized. For Northern blot analysis,
probes were synthesized using an in vitro transcription
system (Promega Corp.) with 32P-labeled UTP
and the appropriate RNA polymerase. The specific activity of the probes
varied between 2–5 x 108 cpm/µg RNA. For in
situ hybridization, plasmids were linearized in the same way, and
riboprobes were synthesized using a Dig RNA Labeling Kit from
Roche Molecular Biochemicals.
RNA preparation and analysis
Total RNA from CL at different stages (n = 3 for each time
point in each experiment) was extracted using the Ultraspec RNA
Isolation System. Northern blot analysis was performed as previously
described (23). The relative abundance of specific messenger RNA
(mRNA)s were analyzed with a PhosphorImager (Molecular Dynamics, Inc.) and normalized to the relative abundance of GAPDH
mRNA in corresponding samples.
In situ hybridization
In situ hybridization was performed using
digoxigenin-labeled riboprobes, as described by Schaeren-Wiemers and
Gerfin-Moser (24). Slides used for comparison were prepared and
hybridized at the same time. To monitor background levels and the
specificity of the hybridization, the sense strands of the probes were
included in each experiment. Photographs were taken with a Carl Zeiss camera attached to a Carl Zeiss Axioplan
microscope (Carl Zeiss, New York, NY) at a magnification
of x10–25.
Data analysis
All experiments for Northern blot analysis and in
situ hybridization with normal adult psp rats were repeated at
least three times. Experiments with hysterectomized rats and
cloprostenol-treated rats were repeated twice. For each experiment,
three rats per time point were used. All quantitative data are given as
the mean ± SEM. Values for mRNA levels in Fig. 1
were normalized against the value for
day 16 by setting it as 1.0. Statistical comparisons were made by
one-way ANOVA followed by Newman-Keuls test. A value of
P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, the adult psp rat model used in this study
provided stable luteal phases, as judged from the serum progesterone
levels (13). After ovulation, the CL is formed from the residual
follicular cells (days 1 and 2) and subsequently starts to secrete
progesterone. The functional luteal phase is characterized by high
levels of progesterone production, such as those at days 7 and 10 in
Fig. 1A. The functional luteolysis is characterized by a decreased
level of serum progesterone (in this model, observed at day 13), after
which luteal regression continues. To determine the expression patterns
of gelatinase A, collagenase-3, MT1-MMP, and TIMP-1 at different
developmental stages of the CL life span, we dissected CL out from
ovaries taken from adult psp rats at different luteal developmental
stages. Total RNA was isolated and analyzed by Northern blot analyses.
The RNA probes used for hybridization were obtained by in
vitro transcription of cDNA fragments.
The expression patterns of gelatinase A, collagenase-3, MT1-MMP, and
TIMP-1 mRNA during the luteal development, maintenance, and regression
are shown in Fig. 1, B–E. All four probes studied were found to be
expressed in the rat CL. Gelatinase A was found to be mainly expressed
in the forming/newly formed CL (days 1 and 2) (Fig. 1B). In the
functional CL (days 7 and 10) and regressing (days 13–19) CL, the
expression of gelatinase A was very low (Fig. 1B). As shown in Fig. 1C, no collagenase-3 expression was detected in the forming/newly formed CL
or in the functional CL. However, a dramatic induction of collagenase-3
mRNA was observed in 13-day-old CL, which coincided with the dramatic
decrease in serum progesterone level. The collagenase-3 mRNA expression
remained at relatively high levels in the regressing CL throughout the
later luteal regression (days 16 and 19) (Fig. 1C). MT1-MMP that
in vitro can activate gelatinase A and collagenase-3 from
their proform was found to be constitutively expressed in the CL at all
developmental stages (Fig. 1D). Like gelatinase A and collagenase-3,
TIMP-1 was also temporally expressed in the adult psp rat CL. However,
the mRNA coding for TIMP-1 was expressed at high levels both in the
forming/newly formed CL (day 1) and in the regressing CL (days 13–19).
During the functional period (days 7 and 10), TIMP-1 was down-regulated
and was only detected at very low levels (Fig. 1E).
Regulation of collagenase-3 and TIMP-1 mRNA in rat CL, where the
luteal phase has been prolonged or shortened
The strong induction of collagenase-3 and TIMP-1 mRNAs in the
regressing rat CL suggests that these molecules could be associated
with luteolysis and may therefore be induced by physiological signals
that induce luteal regression. If so, the expression pattern of these
mRNAs would change concomitantly, in relation to the different luteal
length of various CL models. To test this possibility, we performed
hysterectomies to prolong the luteal phase of the adult psp rats (15)
and treated the adult psp rats with a PGF2 analog,
cloprostenol, to induce premature luteal regression and thereby shorten
the luteal phase (17). The expression of collagenase-3 and TIMP-1 mRNA
was determined. As shown in Fig. 2, hysterectomy considerably prolonged the luteal phase, from 13 to 19
days, as judged from the serum progesterone levels (15). In the normal
psp group, both collagenase-3 and TIMP-1 mRNA were expressed in the
regressing CL at days 13, 16, 19, and 21. However, in the
hysterectomized groups, where the serum progesterone levels remained
high at days 13 and 16, collagenase-3 and TIMP-1 mRNA were not induced
until day 19 (Fig. 2).
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). At 0.5 h and
1 h post injection, when the serum progesterone levels were
decreasing, no induction of collagenase-3 mRNA in the CL was detected
(Fig. 3B). However, at 3 h after the cloprostenol treatment, when
the serum progesterone level had reached a low level, expression of
collagenase-3 mRNA was dramatically induced. The cloprostenol induction
of collagenase-3 was transient, and no collagenase-3 mRNA was detected
at time points from 6 h to 48 h after the treatment,
suggesting that the collagenase-3 mRNA has a short half-life. A similar
induction of TIMP-1 mRNA expression by cloprostenol treatment was also
observed (Fig. 3C). Expression of TIMP-1 mRNA was rapidly induced and
could be detected at 1 h after the cloprostenol treatment. In
contrast to the collagenase-3 mRNA, TIMP-1 mRNA remained at relatively
high levels up to 48 h after the treatment. As shown in Fig. 3, no
induction of collagenase-3 or TIMP-1 mRNA was observed in the
saline-treated control groups. The hybridization with GAPDH probe was
performed to monitor an equal loading of RNA samples.
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, 1-day-old CL expressed low levels of LH receptor
mRNA. However, when CL entered the functional phase (day 7), LH
receptor mRNA expression increased dramatically and was evenly
distributed throughout the functional CL (Fig. 4B). At day 16, which
represents the luteal regression phase, the expression of LH receptor
mRNA decreased and almost no LH receptor was detected (Fig. 4C).
In accordance with the Northern blot analysis (Fig. 1B), in
situ hybridization experiments revealed that gelatinase A was
mainly expressed during the formation of CL. Gelatinase A mRNA was only
found to be expressed in 1-day-old CL (Fig. 4D) but not in the
functional (day 7, Fig. 4E) or in the regressing CL (day 16, Fig. 4F).
During luteal formation, expression of gelatinase A mRNA was observed
in cells localized in the basement membrane area, as well as in cells
localized inside the developing CL (Fig. 4D).
As shown in Fig. 4, G and H, collagenase-3 was not expressed during CL
formation (Fig. 4G) or during the functional phase (Fig. 4H). However,
in the regressing CL (day 16), a considerable induction of dotted
collagenase-3 mRNA expression was detected (Fig. 4I).
Northern blot analysis (Fig. 1D) revealed that MT1-MMP was
constitutively expressed during formation, function, and regression of
the rat CL. As shown in Fig. 4J, MT1-MMP was expressed both in cells
localized in the basement membrane area and in cells in more central
parts of the young CL. Thereby, MT1-MMP exhibits an expression pattern
similar to that of gelatinase A (Fig. 4D). In the functional (Fig. 4K)
and regressing (Fig. 4L) phases, expression of MT1-MMP mRNA was evenly
distributed throughout the CL.
As shown in Fig. 4, M–O, the expression pattern of TIMP-1 mRNA was
different from those of gelatinase A, collagenase-3, and MT1-MMP.
TIMP-1 mRNA was detected in both the forming/newly formed and the
regressing CL but not in the functional phase. In the forming CL (Fig. 4M), TIMP-1 mRNA expression was localized to the luteinized theca
tissue, as well as inside the developing CL. This is similar to the
expression pattern of gelatinase A and MT1-MMP. Like gelatinase A and
collagenase-3, TIMP-1 mRNA expression was undetectable by in
situ hybridization in the functional CL (Fig. 4N). However, during
luteal regression, expression of TIMP-1 mRNA was dramatically
up-regulated and was evenly distributed throughout the entire
regressing CL (Fig. 4O). The even distribution is similar to the
expression pattern of MT1-MMP in the regressing CL (Fig. 4L).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The formation of CL from the cellular remnants of a ruptured follicle, after ovulation, involves extensive connective tissue remodeling and angiogenesis (10, 11, 25). Both the marked vascularization of the CL and the reorganization of the ruptured follicle, to form a CL that takes place during this period, are likely to depend on extracellular proteolysis generated from MMPs. In this report, we show that gelatinase A mRNA was mainly expressed during luteal development, suggesting that this MMP may take part in the angiogenesis and tissue remodeling process during CL formation. Gelatinase A mRNA was expressed in the basement membrane area, as well as inside the developing CL. It is therefore possible that gelatinase A plays a role in the formation of the capillary sprouts when they extend from the theca tissue into the granulosa cell layers. Before gelatinase A can function as a protease, it has to be activated from its proform. MT1-MMP has substrate specificity for the progelatinase A and can activate progelatinase A in vitro through a membrane-associated process (2, 3, 7, 8, 9). Here, we show that MT1-MMP has an expression pattern similar to that of gelatinase A. It is therefore possible that MT1-MMP may activate progelatinase A during luteal development, thereby generating a gelatinolytic activity required for tissue remodeling and angiogenesis processes.
TIMP-1 mRNA was also induced during the formation of CL. Therefore,
TIMP-1 may play a role in the temporal and spatial regulation of MMP
activity during the formation of CL (Fig. 4M). After ovulation, the
basement membrane breaks down, and blood vessels from the theca interna
invade the cavity of the ruptured follicle (25, 26). During this
process, a tight regulation of the proteolytic activity may be
important for defining the orientation and the content of the capillary
invasion and for avoiding excessive lysis of neovascularized tissue.
Formation of CL also involves migration of fibroblasts into the
interior of the follicle, to produce a network of supportive tissue for
the rapidly differentiating cells, which forms the bulk of the
developing CL (26). The expression pattern suggests that TIMP-1 may
play a role in regulating the MMP activity necessary for these
processes.
Although a role for MMPs and TIMPs in the matrix remodeling process, during angiogenesis, has previously been proposed (27, 28), the mechanism behind MMP activation, as well as the regulation and the functional role of MMP activity in vivo during angiogenic events, is not well understood. Support for an involvement of gelatinase A and TIMP-1 in the formation of new capillaries in vivo comes from in vitro studies that show that these proteins play roles in endothelial cell morphogenesis (29). More recent studies indicate that microvascular endothelial cells coordinately up-regulate the expression of gelatinase A and MT1-MMP when cultured in vitro in the presence of a three-dimensional collagen matrix (30). The appearance of MT1-MMP correlated with the activation of a large proportion of the total gelatinase A protein and with an increased organization of the endothelial cells into multicell chords and sprouting of endothelial tubes. Treatment of endothelial cultures with synthetic MMP inhibitors was found to block the activation of gelatinase A and reduce the formation of endothelial cell networks (1, 28, 30, 31). Results from similar in vitro experiments suggest that TIMP-1 also plays an important role in angiogenesis and that TIMPs can block the angiogenic process at different stages (29, 32). In addition to its well-known function as an MMP inhibitor, TIMP-1 has a growth factor activity, can stimulate gonadal steroidogenesis, and can modulate cell morphology (32). It is therefore possible that TIMP-1 alone, or in complex with other proteins, might have other functions in the CL than that of inhibiting MMPs.
The molecular mechanisms underlining luteal regression are not very
well characterized. However, luteal regression is thought to occur via
proteolytic and apoptotic mechanisms (21, 33, 34) involving an
increased sensitivity toward locally produced PGF2 (15, 35). Using the adult psp rat model, functional luteolysis occurs around
day 13, as indicated by a significant decrement of the serum
progesterone concentration. The functional regression is followed by a
structural regression, which is required to avoid accumulation of
nonfunctional luteal tissue that could otherwise disturb the ovarian
cyclicity (10, 36). In the present study, we show that the protease
collagenase-3 is uniquely induced in connection with functional
luteolysis, suggesting that collagenase-3 may be closely associated
with the tissue degradation that takes place during structural
regression of the CL.
To test the hypothesis that the induction of collagenase-3 was related
to luteal regression, we manipulated the length of the luteal phase, by
hysterectomy, to postpone the CL regression or, by cloprostenol
treatment, to induce a premature CL regression. As shown in Figs. 2 and 3, the induction of collagenase-3 expression was connected with
functional luteolysis not only under normal conditions but also when
the luteal phase was prolonged and shortened. At the moment, we do not
know the molecular mechanisms behind the collagenase-3 induction in
connection with luteolysis. It is possible that the reduction in serum
progesterone levels directly induce expression of collagenase-3. This
suggestion is reinforced by studies in cultured human endometrial cells
and rabbit uterine cervical fibroblasts (37, 38). Furthermore, the
withdrawal of progesterone from the media of cultured human or monkey
endometrial cells increases the production of MMPs (39, 40, 41).
Alternatively, other signals, activated in relation with luteal
regression, may induce collagenase-3 expression by hitherto unknown
pathways.
Collagenase-3 is a powerful collagenolytic and gelatinolytic enzyme that preferentially cleaves type II collagen, implying that this enzyme may play a considerable role in connective-tissue turnover (6, 42). A previous study in the rat revealed that collagenase-3 is expressed in the ovary but not in other organs, including brain, kidney, liver, lung, mammary gland, and uterus (19). Based on these findings, it was hypothesized that collagenase-3 was only induced during specific physiological processes where tissue remodeling or breakdown takes place, such as events occurring in reproductive processes (19). In an attempt to correlate collagenase-3 expression with the ovulatory process, immature female rats were treated with eCG/hCG to induce the follicular development and ovulation. However, no collagenase-3 expression was detected in granulosa or theca cells in follicles from the periovulatory period, including the time point just before ovulation, indicating that this molecule does not play a role in ovulation in the rat (19). This finding is supported by our in situ hybridization analysis with ovaries from adult cycling rats (data not shown), which reveals that collagenase-3 is not expressed in follicles of different developmental stages but only in regressing CL from the previous estrous cycle in the same ovary. Although we do not know the molecular mechanism responsible for the induction of collagenase-3 in regressing CL, the present finding that collagenase-3 is not induced during ovulation or CL formation, but only during luteolysis, suggests that this protease could be used as a marker for luteal regression in the rat.
As shown in Fig. 1E, TIMP-1 mRNA was dramatically induced both during
the formation and regression of CL, whereas TIMP-1 mRNA levels were low
during the functional phase. In the regressing CL, TIMP-1 had an
expression pattern very similar to that of collagenase-3, including a
tight connection between TIMP expression and functional luteolysis when
the luteal phase was prolonged and shortened. Therefore, our data
suggest that TIMP-1, like collagenase-3, is induced by physiological
signals that initiate functional luteolysis, to play a role in the
control of the MMP activity that is required for structural luteolysis
to proceed. The possibility that TIMP-1 is induced by the reduction of
serum progesterone levels, in relation with luteolysis, is supported by
studies with in vitro cultured monkey endometrial cells
(40).
In this study, a physiological adult psp rat model (13) was used to study the regulation and cellular distribution of MMPs and TIMP-1 during the formation and regression of CL. Overall, our results are supported by previous findings obtained using other models to induce formation and regression of CL. Nothnick and colleagues (43, 44) used a model where immature female rats were treated with eCG and hCG to induce luteal development and regression. Using this model, they reported the regulation of TIMP-1, gelatinase A, and a rat collagenase that seems to be collagenase-3. Similar to the present study, not only gelatinase A mRNA, but also the total gelatinase activity, were highest during formation of CL; and the rat collagenase mRNA was dramatically induced in the beginning of luteolysis. In the model used by Nothnick and colleagues (44), the regulation of TIMP-1 was demonstrated to be similar to the present study, with dramatic induction of TIMP-1 both during formation and regression of CL. Support for the finding of gelatinase A and TIMP-1 mRNA in rat CL also comes from a recent immunofluorescence microscopy study in which gelatinase A and TIMP-1 antigens were detected in different phases of the CL life span (45). In the present study, in situ hybridization was used to confirm the Northern blot analysis and to localize the site of cellular expression. In addition, the regulation pattern of MT1-MMP that can activate progelatinase A and procollagenase-3 was also studied. Furthermore, experiments in which the luteal phase was prolonged and shortened indicate that collagenase-3 and TIMP-1 are induced by physiological signals inducing functional luteolysis to play a role in structural luteolysis. Our study therefore completes and extends previous findings regarding the regulation of MMPs and TIMPs in the CL.
In a previous report, we showed that tissue-type plasminogen activator and plasminogen activator inhibitor type 1 mRNA are up-regulated both during the formation and regression of CL (21). Besides PAs, MMPs, and TIMPs, it is likely that other proteases are also involved in generating the broad-spectrum proteolytic activity that is required for the formation and regression of CL. Future studies involving specific synthetic inhibitors directed toward different proteases, as well as studies of gene-deficient animals, will reveal the functional role of individual proteases in the life span of the CL.
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Acknowledgments |
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Footnotes |
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Received April 27, 1999.
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T. A. Towle, P. C.W. Tsang, R. A. Milvae, M. K. Newbury, and J. A. McCracken Dynamic In Vivo Changes in Tissue Inhibitors of Metalloproteinases 1 and 2, and Matrix Metalloproteinases 2 and 9, During Prostaglandin F2{alpha}-Induced Luteolysis in Sheep Biol Reprod, May 1, 2002; 66(5): 1515 - 1521. [Abstract] [Full Text]
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 T. Teesalu, A. E. Hinkkanen, and A. Vaheri Coordinated Induction of Extracellular Proteolysis Systems During Experimental Autoimmune Encephalomyelitis in Mice Am. J. Pathol., December 1, 2001; 159(6): 2227 - 2237. [Abstract] [Full Text] [PDF]
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K. S. Simpson, M. J. Byers, and T. E. Curry Jr. Spatiotemporal Messenger Ribonucleic Acid Expression of Ovarian Tissue Inhibitors of Metalloproteinases throughout the Rat Estrous Cycle Endocrinology, May 1, 2001; 142(5): 2058 - 2069. [Abstract] [Full Text]
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T. E. Curry Jr and K. G. Osteen Cyclic Changes in the Matrix Metalloproteinase System in the Ovary and Uterus Biol Reprod, May 1, 2001; 64(5): 1285 - 1296. [Abstract] [Full Text]
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E. Shalev, S. Goldman, and I. Ben-Shlomo The balance between MMP-9 and MMP-2 and their tissue inhibitor (TIMP)-1 in luteinized granulosa cells: comparison between women with PCOS and normal ovulatory women Mol. Hum. Reprod., April 1, 2001; 7(4): 325 - 331. [Abstract] [Full Text] [PDF]
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