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Department of Cell Biology, Vanderbilt University Medical School (L.A.R.-O., D.L.H., C.L.W.. L.M.M.), Nashville, Tennessee 37232; and Merck Research Laboratories (J.M.), Rahway, New Jersey 07065
Address all correspondence and requests for reprints to: Lynn M. Matrisian, Department of Cell Biology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, Tennessee 37232. E-mail: lynn.matrisian{at}mcmail.vanderbilt.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The MMPs are secreted, zinc-containing enzymes that degrade ECM components under physiological conditions and are grouped loosely by substrate specificity (reviewed in Refs. 1–4). The collagenases [interstitial collagenase, neutrophil collagenase, and collagenase-3 (COLL-3)] are capable of denaturing the highly protease-resistant fibrillar collagens, suggesting that these enzymes are particularly important for matrix turnover and remodeling. The stromelysins, including stromelysin-1 (STR-1), STR-2, STR-3, and matrilysin (MAT), can degrade a broad range of substrates, such as proteoglycans, the glycoproteins laminin and fibronectin, elastin, and denatured collagens. The gelatinases, gelatinase A (GEL A) and GEL B, degrade type IV and V collagens, elastin, fibronectin, and denatured collagens. Secreted as proenzymes, the MMPs undergo conversion to a catalytically active form that can be inhibited by specific endogenous tissue inhibitors of metalloproteinases (TIMPs). TIMPs are naturally occurring inhibitors that bind to MMPs in a noncovalent bimolecular complex to inhibit their proteolytic activity (see Refs. 2 and 3 for review). Four members of the TIMP family have been identified to date: TIMP-1 (5), TIMP-2 (6, 7), TIMP-3 (8, 9), and TIMP-4 (10).
The MMPs have been implicated in several normal processes of tissue remodeling, such as wound healing (11, 12), trophoblast invasion (13, 14), organ morphogenesis (15, 16), and uterine (17, 18, 19), mammary (20, 21), and prostate (22, 23) involution. The expression patterns of MMPs have been particularly well studied in the human menstrual cycle (reviewed in Ref.1). In general, MMP expression is most dramatic during the menstrual phase, when the vast majority of tissue breakdown occurs, then declines to low levels as the endometrium prepares for implantation.
Although there is considerable information on the expression patterns, the precise role the MMPs play during the menstrual cycle and other uterine processes is less well understood. A recent study using an in vitro model system has shown that fragmentation of endometrial explants in organ culture can be prevented by MMP inhibitors (24). This study suggests, at least in vitro, that MMPs play an important role in the tissue sloughing that occurs during menstruation. We wished to develop an in vivo model system to define a role for MMPs in the normal tissue remodeling that occurs during various uterine processes. To accomplish this we have examined the expression patterns of the MMPs and their inhibitors in the normal murine uterus during the estrous cycle and postpartum involution. In addition, we have used genetically altered animals to provide insights into roles for specific MMPs in uterine function.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Analysis of estrous cycle
To determine the current day of the estrous cycle, vaginal
smears were performed on each animal before death. Approximately 100
µl 0.9% NaCl were introduced into the vaginal opening with a plastic
pipette, and the resulting liquid and sloughed cells were removed and
spread thinly on a glass slide. Routine hematoxylin and eosin staining
was performed, and the day of the estrous cycle was staged as described
by Snell (26) and Rugh (27). Animals were killed, and uteri were
removed immediately after the stage of the estrous cycle was
determined.
Tissue preparation and RNA extraction
After dissection, uterine tissue to be used for RNA extraction
was quickly frozen on dry ice or in liquid nitrogen and stored at -70
C. Tissue was later homogenized in a guanidinium thiocyanate-acid
phenol solution, and total RNA was extracted as described by
Chomczynski and Sacchi (28). Small portions of the uteri to be used for
in situ hybridization were immediately fixed in 4%
paraformaldehyde in PBS. Tissues were then dehydrated and processed for
embedding in paraffin by standard procedures.
Northern blotting
Ten to 15 µg total cellular RNA was electrophoretically
separated on a 1% agarose-formaldehyde gel, transferred to
nitrocellulose membrane (MSI, Westboro, MA), and cross-linked
(Stratagene, La Jolla, CA). Blots were hybridized at 42 C under high
stringency conditions (50% formamide, 0.1% SDS, and 5 x SSC)
using radiolabeled, random primed complementary DNA (cDNA) probes.
Washes were carried out at 50 C in 0.1 x SSC and 0.1% SDS. Blots
were stripped in boiling 0.01 x SSC, and rehybridized with
another MMP-specific probe or with a cDNA probe specific to the mouse
cytoplasmic 7S RNA (29) or mouse glyceraldehyde 3-phosphate
dehydrogenase (GAPDH) (30). Values for MMP expression were determined
using PhosphorImager (Molecular Dynamics, Sunnyvale, CA) densitometry
and normalized to 7S or GAPDH expression. Student’s paired
t test was used to evaluate statistical
significance.
cDNA probes
The following selected fragments of individual murine MMP cDNAs
have been previously shown to be specific for each murine MMP
transcript (16): the 700-bp MAT cDNA, the 532-bp STR-1 cDNA, the 730-bp
STR-2 cDNA, the 1045-bp STR-3 cDNA, the 965-bp GEL A cDNA, the 815-bp
COLL-3 cDNA, the 350-bp TIMP-1 cDNA, the 360-bp (+308 to 670) TIMP-2
cDNA (31), and the 305-bp (+589 to 894) TIMP-3 cDNA (32). For Northern
blot analysis, isolated cDNA fragments were labeled using the random
primed DNA labeling kit (Boehringer Mannheim, Indianapolis, IN), and
[32P]deoxy-CTP (DuPont-New England Nuclear, Boston,
MA).
For in situ hybridization analyses, these cDNAs were subcloned into pGEM vector series (Promega, Madison, WI), linearized, and used as templates for the generation of sense and antisense 35S-labeled riboprobes using in vitro transcription as previously described (33).
In situ hybridization
Uterine sections from 5–7 µm were treated essentially as
described previously (33), except prehybridization and hybridization
were carried out at 50 C. The slides were dipped in photographic
emulsion (type NTB2, Eastman Kodak, Rochester, NY), developed, and
counterstained with hematoxylin after a 1- to 4-week exposure at 4 C.
Background hybridization was assessed using the sense probe for each
transcript analyzed.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The rodent uterus, unlike the human endometrium, does not undergo a complete menstrual cycle of sloughing and remodeling. Instead, more rapid changes occur throughout a short estrous cycle. The murine estrous cycle consists of five distinct days, estrus, metestrus I (Met I), Met II, diestrus, and proestrus (26). Proestrus and estrus are anabolic stages during which active growth is in progress in various parts of the genital tract. Estrus culminates in ovulation when mating and fertilization occur. Met I and Met II are catabolic stages characterized by degenerative changes in the genital tract. Diestrus, the last phase of the estrus cycle, is a period of quiescence or slow growth (26).
The expression of the messenger RNA (mRNA) for several members of the
MMP family was examined in virgin animals during all stages of the
estrous cycle by Northern blot analysis. Four animals per stage were
examined for MMP expression levels; a representative sample (Fig. 1A
) and the average (Fig. 1B) of these
results are shown in Fig. 1. Of the MMPs examined, MAT, STR-3, and GEL
A were the most abundant, with STR-1 and STR-2 having lower levels of
expression. For MAT, STR-3, and STR-1, the highest mRNA levels were
generally observed during the active phases of estrus and proestrus,
and the lowest levels were seen during the quiescent diestrous phase,
although only in the case of STR-1 was there a statistically
significant decrease in diestrus compared with Met II and proestrus
values (P < 0.05). These data suggest a role for these
MMPs during times of growth or remodeling of the uterus. GEL A and
STR-2 showed a more variable pattern of mRNA expression. COLL-3 and GEL
B transcripts were absent from all cycling uteri examined (data not
shown). MMP expression during the estrous cycle, in general, showed a
great deal of variability, possibly due to the rapid nature of the
estrous cycle and cyclic differences within and between
animals.
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The expression levels of MMPs and TIMPs were determined during the
involution process from 6 h through 5 days after birth. STR-1,
STR-3, GEL A, TIMP-1, TIMP-2, and TIMP-3 transcripts were relatively
constant throughout the entire process of involution, whereas MAT,
STR-2, and COLL-3 were abundant during early involution, then tapered
off to low or undetectable levels by 4.5 days of involution (Fig. 2). There was no detectable mRNA for GEL
B (data not shown).
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, panel a). Consistent with the Northern blot results, at 5.5 days of
involution, no hybridization of the MAT probe could be detected (Fig. 3A, panel b). The mRNA for STR-1, STR-2, and STR-3 localized to the
cells in the uterine connective tissue and muscle. The localization
pattern of STR-3 is shown as a representative for these transcripts
(Fig. 3A, panels c and d). Interestingly, at 6 h of involution,
the stromelysin transcripts were found both in the stroma directly
adjacent to the luminal epithelium and in the outer region, which
includes the myometrium (Fig. 3A, panel c). However, at 3.5 days,
transcripts were detected only in the outermost region of the
endometrium and the myometrium (Fig. 3A, panel d). The expression of
GEL A was similar to that of the stromelysins, but did not change as
involution proceeded. As shown in Fig. 3A (panel e), GEL A mRNA was
abundant in all uterine stroma, including the area adjacent to the
luminal epithelium and the myometrium, throughout the entire process of
involution. TIMP-1, -2, and -3 had similar expression patterns. All
TIMP transcripts were expressed at relatively low levels in the
connective tissues, but generally concentrated in the myometrium (Fig. 3A, panel f, shows TIMP-3 transcripts). COLL-3 was only faintly
detected in the outer myometrium layer, whereas transcripts for GEL B
were completely absent during all time points of uterine involution
(data not shown). Hybridization of TIMP-3 (Fig. 3A, panel g) and STR-3
(Fig. 3A, panel h) sense probes are shown for background comparison.
The localization patterns of MMPs and TIMPs in the involuting uterus
are summarized in Fig. 3B.
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We observed no obvious difference in uterine size or morphology between
the MAT null and control animals at various times during uterine
involution (data not shown). As there is significant overlap in the
substrate specificity for members of the stromelysin subfamily of MMPs,
we examined the uteri of MAT null mice for alterations in the levels of
stromelysins during this process. Uteri were removed from animals on
days 1–4 of involution, and MMP mRNA levels were assayed by Northern
blotting (Fig. 4A). The MMP expression
patterns in the null animals during uterine involution was digitally
quantified, normalized to the constitutively expressed GAPDH mRNA, and
compared with RNA expression levels in wild-type control animals of the
same genetic background. These results are depicted in graph form as a
percentage of the values in wild-type control animals (Fig. 4B).
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). The
increase in stromelysin transcripts was most dramatic at the very early
stages of uterine involution when MAT expression is normally the
highest (see Fig. 2) and dropped on day 2 and returned to wild-type
levels by day 4 (Fig. 4). Transcripts for GEL A, COLL-3, TIMP-1,
TIMP-2, and TIMP-3 did not appear to be altered in the MAT null
postpartum uteri compared with those in control uteri (data not shown).
In situ hybridization was used to determine whether there
were any alterations in the localization patterns of STR-1 and
STR-2 transcripts in the MAT-deficient mice. Both STR-1 and STR-2
transcripts were localized in uterine stroma and myometrium, and were
not expressed in the luminal epithelium in the absence of MAT (Fig. 6, a and b). These data indicate that the expression levels of both STR-1
and STR-2 were significantly up-regulated during postpartum uterine
involution in the absence of MAT, although their patterns of
localization were not altered.
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). The up-regulation of these MMPs was
extended through 2.5 days of involution, times during which consistent
expression of STR-1 was seen in wild-type animals (see Fig. 2).
In situ hybridization determined that, although MAT
transcripts and to a lesser extent STR-2 transcripts were up-regulated
in STR-1 postpartum uterus, the localization patterns of MAT and
STR-2 were not modified (Fig. 6, c and d). Transcripts
for GEL A, COLL-3, TIMP-1, TIMP-2, and TIMP-3 did not seem to be
altered in the STR-1 null postpartum uteri compared with those in
control uteri (data not shown). In summary, examination of the
postpartum involution process in MMP null animals revealed that
other stromal- and epithelial-expressed MMPs became
up-regulated.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several members of the MMP family are expressed at different stages of the estrous cycle. The 5-day estrous cycle can be divided into periods of active mitoses (proestrus and estrus), low mitoses and degeneration (Met I and II), and quiescence (diestrus) (26). MMP expression, in general, is relatively high during days of active mitoses or degeneration, but is low or absent when the uterus is quiescent. These expression patterns show similarities to those observed in the human endometrium. Most MMPs are highly expressed during menstruation, when the vast majority of tissue breakdown occurs; a subset of MMPs is expressed during the proliferative phase of the menstrual cycle; and MMP levels are particularly low in the endometrium in its differentiated state as it prepares for implantation (reviewed in Ref.1). In both the human menstrual and murine estrous cycles, mRNA levels for GEL A and GEL B are an exception to this generality. GEL A mRNA levels are high and are not highly regulated by cyclical changes, whereas GEL B mRNA levels are low or undetectable. Evidence for a causal role for MMPs in endometrial tissue degeneration comes from recent work by Marbaix and colleagues in which fragmentation of endometrial explants in organ culture was prevented by MMP inhibitors (24). We examined the uteri of cycling MAT and STR-1 null animals to determine whether either of these MMPs is required for specific events in the estrous cycle. No obvious difference in tissue morphology or the expression levels of other MMPs was observed in the null compared with the wild-type mice (data not shown), although subtle changes may have been obscured by the high degree of variability between animals. Taken together, data from the mouse and human model systems demonstrate that MMP expression, in general, is highest when catabolic or anabolic physical changes occur in the uterus, suggesting a role for the MMPs in the breakdown and remodeling of the uterus during the estrous and menstrual cycles.
The rodent postpartum uterus represents a dramatic example of extensive
matrix remodeling. The involuting uterus undergoes a rapid reduction in
size as it returns to the prepregnancy state, which is primarily due to
the loss of collagen (36). Degradation of type I collagen requires the
action of collagenases. Collagenase has been shown to be produced in
the rodent uterus during postpartum involution and was localized to the
perinuclear region of the smooth muscle cells of the myometrium by
immunohistochemistry (19, 39). Our in situ hybridization
studies with a COLL-3 probe confirmed the myometrial localization of
collagenase. Measurement of collagenase bound to uterine collagen
revealed that it is produced only as needed and is not stored, either
intra or extracellularly (39). The peptide bonds between residues
Gly775 and Ile776 of the 
-1(I) chain of
native collagen are cleaved by the collagenases, and mutations in this
region make collagen resistant to these enzymes. Overexpression of a
collagen gene carrying such mutations caused transgenic mice to die
during gestation (40). Surprisingly, mice with the
mutation in the endogenous gene developed normally, although during
times of intense collagen resorption, phenotypic alterations were
observed. In particular, postpartum involution of the uterus was
markedly impaired, with the development of collagenous nodules in the
uterine wall (40). These results suggest that the efficient cleavage of
collagen is required for normal remodeling of the ECM in the postpartum
uterus, where type I collagen is particularly abundant.
Another member of the MMP family, MAT, has also been previously associated with involution of the rodent uterus (18). MAT activity was initially identified in homogenates of involuting rat uteri after activation with trypsin or organomercurials and was inhibited by 1,10-phenanthroline, a metalloproteinase inhibitor, but not by inhibitors of thiol or serine proteinases (18). Rat MAT was later purified and cloned from this same source and identified as a distinct member of the MMP family of enzymes (17, 41). Recently, the mouse homolog of MAT was cloned from postpartum uterus using rapid amplification of cDNA ends PCR (36). The mRNA expression pattern during murine uterine involution was also examined, and the transcript was localized to the glandular epithelium of the uterus (36).
We have extended these observations and shown that transcripts for several other MMP family members as well as their inhibitors, TIMPs, were expressed during uterine involution. Consistent with previous reports, MAT mRNA was abundant during early involution, tapering off to undetectable levels by 4.5 days postpartum (17, 36, 37). STR-2 and COLL-3 were also expressed at their highest level early during involution, then decreased to undetectable levels, whereas STR-1, STR-3, GEL A, and TIMP transcripts were consistently expressed throughout the involution process. The greatest diversity in the expression of MMP family members, therefore, occurs at the earliest time of involution, when tissue loss is most rapid. It is interesting that the only time COLL-3 transcripts were detected was during the earliest phases of involution. As rodents lack the equivalent of human interstitial collagenase (MMP-1), it is presumed that COLL-3 is responsible for the degradation of type I collagen in this tissue. The extensive loss of type I collagen that occurs therefore appears to be confined to a narrow window in time and to be mediated by an enzyme whose mRNA is expressed at relatively low levels compared with that of other MMPs. These results have several potential implications; low levels of COLL-3 may be very effective in collagen degradation, mRNA levels do not accurately reflect ultimate enzymatic activity due to the multiple points at which MMPs are regulated, other enzymes contribute to type I collagen degradation (potentially GEL A) (42), or any combination of the above. In general, we can conclude that the abundant and diverse expression of MMPs during uterine involution suggests that MMP family members may work in concert to effect the dramatic tissue loss and extensive restructuring that occur during uterine involution.
We have also determined the localization for each MMP and TIMP during
the process of uterine involution (summarized in Fig. 3B). The
stromelysin family of MMPs showed an interesting pattern of expression.
At early stages of involution, STR-1, -2, and -3 were highly expressed
in the stroma directly adjacent to the luminal epithelial layer, and
these same transcripts were abundant in the outer muscle or myometrial
layer. As involution progressed, the expression of mRNA for the
stromelysin family decreased close to the luminal epithelial layer and
was only evident in the outer stroma and muscle layer. These results
suggest that remodeling of the uterus proceeds from the luminal to the
external surfaces and may be more extensive in the muscle layers,
thereby requiring the expression of MMPs for an extended length of
time.
Although MAT is the only known epithelial-specific MMP, mice with a null mutation in the gene encoding MAT proceed normally through the estrous cycle, pregnancy, and uterine involution (25). STR-1 null animals also have no obvious reproductive defects, although alterations in wound healing have recently been detected in these animals (Mudgett, J., unpublished results). Because reproductive events are key targets for natural selection, it follows that important mediators of these processes may have evolved highly regulated and redundant pathways. MAT, STR-1, and STR-2 have very similar substrate specificities and may perform a similar function during involution despite differences in their cellular origin. Interestingly, we showed that STR-1 and STR-2 mRNAs are strongly up-regulated in the stroma of the MAT null postpartum uterus, and that MAT, and to a lesser extent STR-2 and STR-3, are up-regulated in the involuting uterus in the absence of STR-1. There was no difference in the cellular localization of these up-regulated genes. It is possible that this apparent compensation for the loss of one family member by overexpression of other family members is an artifact of the mechanism used for targeted gene deletion. The MAT and STR-1 genes map to the same region on the proximal end of murine chromosome 9, and disruption of sequences in one gene or the insertion of strong promoters driving the selectable neomycin resistance genes may alter the expression of nearby promoters. This seems an unlikely explanation, at least in the MAT null animals, as up-regulation of STR-1 and STR-2 expression is only observed in the involuting uterus and not in the small intestine or male reproductive tract, where MAT is also endogenously expressed (data not shown). In addition, although the STR-2 gene maps to the same chromosomal location as MAT and STR-1 in humans (43, 44), the STR-3 gene is located on a distinct chromosome (45). These observations suggest that there may be a more physiological explanation for this apparent compensation in the expression of MMPs during uterine involution.
We speculate that active MMPs may trigger a pathway that represses the expression of other MMPs with similar substrates to control the extent of matrix degradation, and that this negative feedback loop is disrupted in the MMP-targeted mice. A potential mediator of this pathway is transforming growth factor-ß (TGFß). TGFß is bound to ECM components (for review, see Ref.46) and is known to inhibit the expression of STR-1 (47, 48, 49) and MAT (50). MAT and STR-1 expression during uterine involution may normally release active TGFß from matrix stores and maintain the expression of the MAT and STR-1 genes at a tightly controlled level. In situations of reduced matrix degradation, as might occur in the null animals, MAT and STR-1 mRNA levels may be elevated as a result of a decrease in the exposure to this negative regulator. Alternatively, the expression of MMP genes may be sensitive to mechanical pressures that result from unbalanced matrix degradation. For example, if MAT degrades the basement membrane during uterine involution, a decrease in the rate of basement membrane loss relative to stromal matrix loss in MAT null mice may slightly deform the tissue. As a result, the expression of stromal-derived MMPs may increase. STR-1 mRNA, in fact, has been previously shown to be induced by alterations in cell shape in fibroblasts (51, 52). Although we can only speculate on the mechanism, our results provide experimental support for the assumption that overlapping substrate specificites of MAT, STR-1, and STR-2 allow for potential functional compensation by these MMP family members.
Previous studies indicated that type I collagen degradation is critical for normal uterine involution (35, 40). Our results support the expression of COLL-3 during early uterine involution and demonstrate that many MMP family members are coexpressed in distinct spatial and temporal patterns throughout the involution process. Although mice deficient in MAT and STR-1 demonstrate that these specific MMPs are not required for uterine involution, the apparent compensatory increase in MMP family members with similar substrate specificities suggests that the lack of an effect is a result of redundant and compensatory mechanisms that have evolved to maintain reproductive capacity. Experiments examining the effects of genetic ablation of multiple MMPs or the in vivo administration of broad spectrum MMP inhibitors may further clarify the specific roles that MMPs play in reproductive processes.
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Acknowledgments |
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Footnotes |
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2 Supported by a predoctoral fellowship from the NIH
(T32-HD07043).
3 Present address: Dermatology Division, Washington University
School of Medicine, 216 South Kingshighway Boulevard, St. Louis,
Missouri 63110.
Received March 19, 1997.
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), STR-2 (
), and STR-3 (
) mRNA for two samples over the value
for mRNA isolated from wild-type controls and analyzed in the same
experiment is plotted in B. The average value for each time point is
connected with a line.
), and STR-3 (