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Molecular Human Reproduction vol.3 no.1 pp. 27–45, 1997
Matrix metalloproteinases as mediators of reproductive function
D.L.Hulboy, L.A.Rudolph and L.M.Matrisian
1
Department of Cell Biology, Vanderbilt University, Nashville, TN 37232, USA
1
To whom correspondence should be addressed
The organs of the adult reproductive system can undergo extensive remodelling, experiencing rapid
changes in tissue mass and function. Much of this matrix remodelling is attributed to the action of matrix
metalloproteinases. Matrix metalloproteinase family members are expressed in a highly-regulated manner in
many reproductive processes, including menstruation, ovulation, implantation, and uterine, breast, and
prostate involution. Metalloproteinase concentrations and activity can be regulated by reproductive hormones,
as well as by growth factors and cytokines that participate in reproductive events. In addition to playing a
role in the loss of connective tissue mass, the metalloproteinases can influence the phenotype of the cellular
components of the tissues, altering basic cellular functions such as proliferation, differentiation, and apoptosis.
This review focuses on the expression of matrix metalloproteinases in reproductive tissues, and discusses the
evidence supporting a role for these enzymes in modulating the structure and function of reproductive organs.
Key words:
collagenase/gelatinase/matrilysin/MMP/stromelysin
Introduction
described. Next is an examination of the regulation of MMP
expression in reproductive organs. Finally, we evaluate how
The reproductive organs are distinctive in their requirement MMPs function in reproductive tissues, discussing their influ-
for dramatic alterations in structural and functional properties ence on cell growth, death, and differentiation. We contend
throughout adult life. These changes, which are orchestrated that the MMPs contribute to the ability of reproductive organs
by hormones and frequently mediated by local growth factors to respond rapidly and dramatically to hormones, local growth
and cytokines, involve extensive remodelling of connective factors, and cytokines.
tissues. Connective tissue constitutes a large portion of the
body, contributing to organ shape and volume. It is separated
from epithelia by basement membrane (BM), and is composed
The matrix metalloproteinase family
of the stromal elements: extracellular matrix (ECM), blood
and lymph vessels, and cellular components, including The MMP family is a group of structurally-related proteins
fibroblasts and macrophages. The structural proteins of the that degrade ECM and BM components in a zinc-dependent
ECM and BM are varied and include fibrillar proteins (e.g. manner at a physiological pH (for review, see Birkedal-Hansen
collagens and elastin), proteoglycans, and multidomain glyco- et al., 1993; Powell and Matrisian, 1996). They are produced
proteins (e.g. fibronectin and laminin). In addition to its role as proenzymes and secreted into the ECM, where they are
in cell shape, the ECM plays a dynamic role in metabolic activated by proteolytic cleavage. All MMPs contain three
processes, influencing cellular proliferation, differentiation, fundamental domains (Table I; for reviews, see Birkedal-
and apoptosis, and serving as a repository for biologically active Hansen et al., 1993; Powell and Matrisian, 1996). At the
growth factors. Remodelling of connective tissue requires amino terminus is the ‘pre’ domain which signals for cellular
both breakdown and resynthesis of ECM components. The export. Following is the ‘pro’ domain; the latent, or proMMPs,
degradation of ECM proteins can be effected by a variety of are activated by cleavage and removal of this domain, in
enzymatic activities, but the matrix metalloproteinases, or turn disengaging the cysteine in the conserved ‘pro’ domain
MMPs, are believed to be primary contributors to this process sequence PRCGVPDV adjacent to the active site which binds
as a result of several key features: they are secreted into zinc. This cleavage is performed by other MMPs, or in some
extracellular space and function under physiological conditions; cases plasmin, and followed by a series of autocatalytic cuts
they are highly regulated and frequently induced in areas of that result in active enzyme. The active site, whose amino
active matrix remodelling; and members of this family are the acid consensus sequence is HEXGHXXGXXHS, is in the
only enzymes capable of denaturing fibrillar collagens. This catalytic domain and holds a zinc ion by co-ordinate bonding
review will focus on the expression and the function of MMP to the three histidines and a water molecule. MMP-7 is known
family members in normal reproductive tissues. Following a as the ‘minimal domain’ MMP (see Table I); its active form
brief summary of the MMP family, the expression patterns of is ~20 kDa and corresponds to the catalytic domain alone.
In addition to the three fundamental MMP domains, MMPMMPs in the uterus, ovary, breast, testes, and prostate are
©European Society for Human Reproduction and Embryology
27
D.L.Hulboy
et al.
Table I. The matrix metalloproteinases (MMP). (Based on Powell and Matrision, 1996)
MMP Structure Substrates*
H5hinge domain; F 5furin consensus site; FN 5fibronectin-like domain; C 5collagen-like domain; TM 5transmembrane-like domain.
*Actual substrates are precursor forms of urokinase-type plasminogen activator (uPA), tumour necrosis factor (TNF)-α, and MMP.
family members have domains that generate diversity in are protein-processing enzymes (Bresnahan et al., 1990). In
MMP-11, this sequence allows for internal cleavage of thesetheir association with substrates and with cellular and matrix
components (Table I). All MMPs, with the exception of MMP- MMPs, resulting in secretion of the enzyme in an activated
form (Pei and Weiss, 1995).7, contain a haemopexin-like domain, which has been shown
to be involved in mediating associations with ECM components Substrate specificity of MMP family members is broad
and diverse. For example, MMP-3, MMP-7, and MMP-10,and inhibitors (for example, see Allan et al., 1991; DeClerck
et al., 1993; Baragi et al., 1994). The haemopexin domain is members of what has been called the stromelysin subclass,
can cleave many ECM components, including proteoglycans,connected to the catalytic domain through a short but variable
hinge region that assists in substrate specificity: its presence fibronectin, collagens, and gelatins. MMP-11, also a stromely-
sin, is a weak protease, thus far shown to cleave laminin andin the collagenases enables them to cleave fibrillar collagen
(Hirose et al., 1993). The gelatinases, MMP-2 and MMP-9, fibronectin (Murphy et al., 1993). The collagenases, MMP-1,
MMP-8, and MMP-13, target primarily fibrillar, but also non-possess fibronectin-like sequences within their catalytic
domains that facilitate gelatin binding by these enzymes. In fibrillar, collagens. In the rodent, the collagenase commonly
referred to as MMP-1 due to its substrate specificity is actuallyaddition, MMP-9 contains a small region that is reminiscent
of α-2(V) collagen; its role in MMP-9 function is unclear. The more homologous to the human MMP-13 (Gack et al., 1995).
To avoid confusion in nomenclature, this review will refer totransmembrane-type (MT)-MMPs contain a transmembrane
domain near their carboxyl termini which localizes the enzymes the rodent homologue as ‘collagenase’. The gelatinases, MMP-
2 and MMP-9, are potent in their ability to cleave denaturedto the plasma membrane (Sato et al., 1994; Takino et al.,
1995; Will and Hinzmann, 1995; Puente et al., 1996). In collagens. A recent report has revealed that MMP-2 can
also cleave native collagen I (Aimes and Quigley, 1995).addition to the transmembrane domains, the MT-MMPs (MMPs
14–17) and MMP-11 contain a short region after their ‘pro’ Metalloelastase (MMP-12) targets elastin in particular, and, to
a lesser extent, fibronectin (Shapiro et al., 1992). Finally, thedomains that fits the consensus cleavage site for furins, which
28
Matrix metalloproteinases in reproductive tissues
four MT-MMPs (MMPs 14–17), are new additions to the We will then move to expression patterns of MMPs during
MMP family, and thus far MMP-2 is the only known substrate implantation, pregnancy and post-partum involution.
for MMP-14 and MMP-16 (Sato et al., 1994; Takino et al.,
Cycling primate endometrium
1995; Will and Hinzmann, 1995; Puente et al., 1996). In The primate endometrium undergoes dramatic tissue sloughing
addition to ECM components, MMPs can cleave precursor and remodelling during the menstrual cycle. Due to their
forms of other MMPs, the serine protease urokinase-type degradative effects on the extracellular matrix, MMPs have
plasminogen activator, protease inhibitor α-1-antitrypsin, and been heavily studied in this model system. Several MMPs are
tumour necrosis factor (TNF)-α(Table I). highly expressed during menstruation, where the vast majority
Natural inhibitors of MMPs can be divided into tissue and of tissue breakdown occurs. In general, MMP concentrations
plasma inhibitors. The tissue inhibitors of metalloproteinases decline to low or undetectable values during the remainder of
(TIMP), are currently represented by four members: TIMP-1, the menstrual cycle, and are particularly low in the endomet-
TIMP-2, TIMP-3, and TIMP-4, have been described (Pavloff rium as it prepares for implantation. Figure 1 provides an
et al., 1992; Birkedal-Hansen et al., 1993 for review; Shi overview, while Table II is a detailed compendium of MMP and
et al., 1996). TIMPs in general are widely expressed; they are TIMP expression patterns in human and monkey endometrium
frequently, but not always, regulated in co-ordination with during the menstrual cycle.
MMPs. TIMP-1 and TIMP-2 bind in a 1:1 ratio to the active Using samples taken directly from the intact endometrium
sites of all MMPs. There is also TIMP interaction with latent during the menstrual cycle, expression of MMP-1, MMP-2,
MMPs, with TIMP-1 preferentially binding proMMP-9, and MMP-3, MMP-7, MMP-9, MMP-10, MMP-11, TIMP-1,
TIMP-2 binding proMMP-2. TIMP-3 and TIMP-4 are not as TIMP-2, and TIMP-3 has been identified at various stages in
well characterized but have been shown to have MMP inhibit- the primate endometrium (see Table II and references therein).
ory activity (Pavloff et al., 1992; Shi et al., 1996). In addition MMP expression is most dramatic during the menstrual phase,
to their MMP inhibitory activity, TIMPs have been implicated with MMPs produced in abundance. Generally, MMP-2 is
in processes involving cell growth. For example, TIMP-1 expressed at relatively constant values thoughout the entire
has long been associated with erythroid-potentiating activity menstrual cycle. During the proliferative phase, MMP-11 and
(Docherty et al., 1985), and has growth-factor-like activities MMP-7 are expressed in moderate abundance, while MMP-1,
in some cell types (Hayakawa et al., 1994). In addition, TIMP- MMP-3, and MMP-9 are expressed at low levels focally. MMP
1 has been reported to be part of a complex that can stimulate expression in general declines in early secretory phase, and
steroidogenesis in the testes and ovary (Boujrad et al., 1995). reappears in the late secretory stage. TIMP-1 and TIMP-2 are
The second group of MMP inhibitors are the plasma α-also found throughout the menstrual cycle. TIMP-3 has only
macroglobulins (Birkedal-Hansen et al., 1993 for review). been detected at the mid-secretory phase of the cycle, although
MMPs rapidly cleave these proteins, changing their conforma- menstrual tissue is yet to be examined.
tion and resulting in covalent binding of inhibitor to MMP. Cellular localization of the MMP family members by
These complexes are then bound to receptors, internalized, in-situ hybridization and immunohistochemistry has also been
and destroyed by cells throughout the body. performed on samples taken from intact cycling endometrium.
While these assays do not determine the activity of the
enzymes, the location of the message or protein may indicate
MMP expression in reproductive organs
a potential function for these genes. MMP-1 is restricted to the
In the following sections, we explore in detail the spatial and stromal components of the endometrium during the menstrual
temporal patterns of MMP expression in reproductive tissues: phase of the cycle with weakly positive cells also found during
the uterus, ovary, breast, testes, and prostate. In general, the the proliferative phase (Table II). MMP-1 mRNA has been
MMPs are synthesized by connective tissue cells residing in found at or around arterioles and small vessels and in stromal
the stroma of reproductive organs. This includes resident cells at the periphery of shedding menstrual fragments in the
fibroblasts, endothelial cells in newly-forming vessels, and functional layer of the endometrium, extending from the
infiltrating cells such as macrophages and neutrophils. An superficial zone and toward the entire functionalis as menstru-
exception is MMP-7, which is secreted primarily by cells of ation proceeds. These results suggest that MMP-1 is ultimately
epithelial origin (Wilson and Matrisian, 1996). This distinction involved in tissue breakdown during menstruation. The cellular
in cell-type expression suggests that stromal and epithelial distribution of the stromelysins is quite similiar. MMP-3,
MMPs may play different functional roles. MMP-10, and MMP-11 mRNA appear to be confined to the
stromal components of the endometrium. Protein expression
Uterus
of MMP-3 has also been associated with areas of stromal
disruption during menstruation. These data support a role for
The production of MMPs in the uterus has been studied using collagenases and stromelysins in the destruction of stromal
observations made from both in-vitro culture systems and ECM during the menstrual phase of the cycle. Indeed, recent
samples taken directly from the intact uterus. Using both organ culture work by Marbaix et al. (1996) reveals that
model systems, expression patterns and enzyme activities have inhibitors specific to MMPs block ECM degradation induced
been clearly mapped throughout the uterine cycle for several by steroid hormone removal.
MMPs. Thus, we will first address MMP expression in the
cycling uterus, followed by studies of cultured uterine cells. The presence of migratory cells in the endometrium has
29
D.L.Hulboy
et al.
Figure 1. Diagrammatic depiction of matrix metalloproteinases (MMP) localization in various reproductive processes. Cycling: MMP
expression patterns during the proliferative, secretory and menstrual phase of the menstrual cycle. MMPs that are expressed focally at low
concentrations are indicated with brackets. Ovulation: MMP and inhibitor expression just prior to ovulation in the ovary. MMP-1 and
MMP-2 are localized at the site of rupture, while the tissue inhibitor of metalloproteinases (TIMP)-1 levels are high in granulosa and thecal
cells. Implantation: the invading trophoblasts produce MMP-2, MMP-9 and MMP-10, with predominately greater amounts of MMP-9.
MMP-1 and MMP-3 have also been detected in the murine blastocyst. The inhibitor TIMP-3 is found mostly in the maternal cells at the site
of implantation.
been well established (Clark, 1992), with endometrial granular and glandular epithelium of the functionalis, and not the
basalis. This suggests that matrilysin does not induce sloughing,
lymphocytes increasing during menstruation (Bulmer et al.,but perhaps degrades luminal debris and subsequently facilit-
1987). A recent immunohistochemistry study localized MMP- ates tissue remodelling during the early and mid-proliferative
9 protein to PMN, monocyte–macrophages, and eosinophils, phases.
suggesting that these cells are the major source of MMP-9 in The ratio of activated MMPs to their inhibitors plays a key
menstrual tissues. In other studies, MMP-9 has also been role in regulating MMP activity. TIMP-1 mRNA has been
immunolocalized to neutrophils in this tissue (Salamonsen and localized to both stromal and epithelial cells throughout the
Woolley, 1996). These results explain the relative paucity of cycle (Table II), and the protein is concentrated around blood
MMP-9 transcripts but abundant enzymatic activity observed vessels in the sheep uterus, suggesting a protective effect on
in primate endometrial tissues (Table II; L.A.Rudolph and the integrity of blood vessel membranes. TIMP-2 is expressed
R.Brenner, unpublished data). during the menstrual cycle, but its cellular localization is
Unlike other MMPs, which are expressed by stromal cells, currently unknown. TIMP-3 mRNA is expressed only during
MMP-7 is an epithelial-specific MMP (Wilson and Matrisian, the middle to late secretory phase, exclusively in the stroma.
1996). MMP-7 mRNA and protein have been localized to
endometrial glandular epithelial cells during most phases of
Uterine in-vitro culture systems
the menstrual cycle. Brenner et al. (1996) reported that The culturing of endometrial tissue, either as full explants or
as isolated stromal or epithelial cells, has assisted in delineatingmatrilysin is detectable only after menses begins, in the luminal
30
Matrix metalloproteinases in reproductive tissues
Table II. Expression of matrix metalloproteinases (MMP) during the menstrual cycle
Phase MMP Cellular
of cycle expressed localization References
Proliferative MMP-1 stroma (low levels) Rodgers et al., 1994
MMP-2 stroma Rodgers et al., 1994; Irwin et al., 1996
MMP-3 stroma (low levels) Rodgers et al., 1994; Jeziorska et al., 1996
MMP-7 glandular epithelium (mid and late phase) Rodgers et al., 1993, 1994
MMP-9 supernuclear regions of GEC; PMN and Jeziorska et al., 1996
monocytes confined to blood vessels (mid
and late)
MMP-11 stroma Rodgers et al., 1994
TIMP-1 stroma, focally positive in epithelium Rodgers et al., 1994; Hampton et al., 1995
TIMP-2 not determined Hampton and Salamonsen, 1994
Secretory MMP-2 stroma Rodgers et al., 1994; Irwin et al., 1996
MMP-3 stroma (low levels) (mid and late phase) Jeziorska et al., 1996
MMP-7 glandular epithelium (late phase) Rodgers et al., 1993, 1994
MMP-9 GEC and lumen of gland (mid phase); Jeziorska et al., 1996
PMN confined to vasculature (late phase)
MMP-10 stroma (low levels; late phase) Rodgers et al., 1994
MMP-11 stroma (late phase) Rodgers et al., 1994
TIMP-1 prominent perivascular and periglandular Rodgers et al., 1994; Hampton et al., 1995
distribution
TIMP-2 not determined Hampton and Salamonsen, 1994
TIMP-3 stroma of functional layer (mid phase) Higuchi et al., 1995
Menstrual MMP-1 stroma cells of functional layer, round Hampton and Salamonsen, 1994; Rodgers
arterioles and small vessels; noted in et al., 1994; Marbaix et al., 1995; Kokrine
epithelium in one case et al., 1996
MMP-2 stroma; noted in epithelium in two cases Rodgers et al., 1994; Irwin et al., 1996
MMP-3 abundant in stromal elements immediately Hampton and Salamonsen, 1994; Rodgers
adjacent to glandular epithelium; associated et al., 1994; Jeziorska et al., 1996
with BM structures of various blood
vessels
MMP-7 glandular epithelium Rodgers et al., 1993, 1994; Brenner et al., 1996
MMP-9 PMN and monocytes/macrophages, stroma Rodgers et al., 1994; Jeziorska et al., 1996
(focal)
MMP-10 stroma Rodgers et al., 1994; Brenner et al., 1996
MMP-11 stroma Rodgers et al., 1994; Brenner et al., 1996
TIMP-1 epithelium and periglandular stroma Rodgers et al., 1994; Hampton et al., 1995
TIMP-2 not determined Hampton and Salamonsen, 1994
PMN 5neutrophils; GEC 5glandular epithelial cells; TIMP 5tissue inhibitor of metalloproteinase; BM 5basement membrane.
the tissue specificity of MMP family members. In addition, it MMPs appearsto be consistent with theirdecreased expression
during the secretory phase of the cycle.has provided a system for examining the mechanisms control-
ling their expression. The expression of MMP-1, MMP-2, MMP-3, MMP-9, and
MMP-11 (Osteen et al., 1994; Rawdanowicz et al., 1994;Cultured explants of endometrial (Marbaix et al., 1992,
1995; Martelli et al., 1993; Osteen et al., 1994; Bruner et al., Schatz et al., 1994a,b) are also detected in human endometrial
stromal cells cultured separately, as revealed by immunoblot,1995) and uterine (Tyree et al., 1980) tissue, which contain a
mixed population of epithelial and stromal cells and are immunoprecipitation, and northern analysis. Ovine endometrial
stromal cells also synthesize and release MMP-1, MMP-2, andgenerally representative of proliferative endometrium, secrete
MMP-1, MMP-2, MMP-3, MMP-7 and MMP-9, consistent MMP-3 in culture (Salamonsen et al., 1994, 1995). MMP-1
and MMP-3 are produced primarily upon stimulation bywith their expression during this phase in vivo (Table II).
Many of these MMPs were identified through their artificial phorbol myristate acetate (PMA), whereas MMP-2 expression
has been shown to be constitutive (Salamonsen et al., 1991,activation by 4-aminophenyl mercuric acetate (APMA), their
activities on collagen or gelatin substrate gels, their dependence 1993). The expression of MMP-3 is reduced by the addition
of various progestins to the media (Osteen et al., 1994; Schatzon zinc, and their inhibition by TIMP. TIMP-1 and TIMP-2
were also detected using this model system (Marbaix et al.,et al., 1994a, 1995b). These results confirm the stromal
localization patterns observed in vivo. The TIMP proteins can1992). The addition of exogenous progesterone to explant
cultures mimics the hormonal status of the endometrium during also be detected in culture medium from endometrial stromal
cells (Salamonsen and Woolley,1996),withTIMP-3 expressionthe secretory phase of the cycle. Physiological concentrations
of progesterone reduce the protein expression and activity of increasing after progesterone addition (Higuchi et al., 1995).
In isolated endometrial epithelial cells, the cell-type specifi-MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, and MMP-11
(Table III, see below); these effects are antagonized by the city of MMP-7 is retained. Interestingly, however, the addition
of progesterone has no repressive effect, in contrast to theprogesterone antagonist mifepristone (RU 38486) (Marbaix
et al., 1992). The reduction in the concentrations of these results obtained with explants and observed in vivo (Osteen
31
D.L.Hulboy
et al.
Table III. Regulation of the matrix metalloproteinases (MMP) by growth factors and hormones
Factor Cell/tissue type Effects Comments References
Progesterone Endometrial cells and ↓MMP-1, MMP-3, MMP-7, MMP- Prevents menstruation Tyree et al., 1980; Marbaix
explants 9, MMP-11, sometimes MMP-2 et al., 1992, 1995; Martelli
et al., 1993; Schatz et al., 1994b;
Osteen et al., 1994; Bruner
et al., 1995
Endometrial cells ↑TIMP-1, TIMP-3 Marbaix et al., 1992; Higuchi
et al., 1995
Ovary ↑TIMP and α-macroglobulin Curry et al., 1988; Mann
et al., 1993; Morgan et al., 1994
Oestrogen Endometrial cells and ↓MMP-1, MMP-3, MMP-7, MMP- Weak ↓unless Jeffrey et al., 1971; Kastner
explants 11, not MMP-2 progesterone present et al., 1990; Schatz et al., 1994b;
Osteen et al., 1994; Marbaix et al.,
1995
Glucocorticoids Mammary glands ↓MMP-3 Inhibits mammary Fanget al., 1995
gland involution
Cytotrophoblasts ↓IL-1β→↓MMP-9 Inhibits invasion Librach et al., 1994
EGF Implantation blastocysts ↑MMP-9 EGF Bass et al., 1994; Harvey
↑cytotrophoblast et al., 1995a,b
invasion
TNF-αEndometrial stromal cells ↑MMP-1, MMP-3, MMP-9, not Rawdanowicz et al., 1994;
MMP-2 Salamonsen and Woolley, 1996
IL-1αEndometrial stromal cells ↑MMP-1, MMP-3, MMP-9, not IL-1 required for Rawdanowicz et al., 1994; Simo
´n
MMP-2 implantation et al., 1994; Salamonsen and
Woolley, 1996
IL-1βCytotrophoblasts ↑MMP-9 Expression correlates Librach et al., 1994
↑Gonadotrophin →↓MMP-9 with invasiveness Masuhiro et al., 1991; Yagel
activity et al., 1993
TGF-βEndometrial explants ↓MMP-3, MMP-7 Progesterone Bruner et al., 1995
→↑TGF-β
Immortalized cervical cell ↑MMP-2, MMP-9 Agarwal et al., 1994
lines
IFN-τEndometrial stromal cells ↓MMP-1, MMP-3, not MMP-2 Salamonsen et al., 1994
Relaxin Cervical cells ↑MMP-1 Dilatation Bryant-Greenwood and
Greenwood, 1988; Mushayandebvu
and Rajabi, 1995
Serotonin Post-partum uterine ↑collagenase Jeffrey et al., 1991; Wilcox
smooth muscle cells et al., 1992
Gonadotrophins Granulosa cells ↑TIMP-1 →↓MMP-9 activity Aston et al., 1996
Cytotrophoblasts No change in TIMP, but ↓MMP-9 Yagel et al., 1993
activity
FSH Sertoli cells ↑TIMP-1, TIMP-2 Ulisse et al., 1994
TIMP 5tissue inhibitor of metalloproteinase; IL 5interleukin; EGF 5epidermal growth factor; TNF 5tumour necrosis factor; TGF 5thyroid growth
factor; IFN 5interferon; FSH 5follicle stimulating hormone.
et al., 1994; Bruner et al., 1995). Bruner et al. (1995) have the highly invasive first-trimester trophoblasts secreting greater
demonstrated that the presence of stromal cells is required to amounts of both gelatinases when compared with third-trimes-
mediate the down-regulation of MMP-7 expression following ter cells (Polette et al., 1994; Shimonovitz et al., 1994). MMP-
progesterone addition. Progesterone treatment of human endo- 2 has been localized to the stromal compartment of floating
metrial explants results in increased transforming growth factor villi cells, with strong labelling in close contact to the tropho-
β(TGF-β) expression by the hormone-responsive stromal blastic basement membrane (Polette et al., 1994), and also in
cells. TGF-βrepresses MMP-7 production by the epithelial syncytiotrophoblasts (Fernandez et al., 1992). In pre-eclampsia,
cells, as demonstrated by reversal of this effect in the presence cytotrophoblast invasion is shallow and uterine arteriole
of TGF-βneutralizing antibodies. invasion is nearly absent. MMP-9 expression is dramatically
reduced in cytotrophoblasts isolated from pre-eclamptic pla-
Implantation
centas, suggesting a necessity for this MMP during the invasion
In order to invade the uterine stroma, trophoblast cells must process (S.Fisher et al., unpublished).
degrade uterine BM and ECM. Therefore, enzymes such as Animal model systems have been used extensively to study
the MMPs that target BM and ECM components have been the process of implantation due to the accessibility of tissue
investigated during the process of implantation (Cross et al.,at all times during trophobast invasion. Investigators have
1994 for review; Figure 1; Harvey et al., 1995b). recently detected strong expression of MMP-9 in the invading
Investigators have determined that human trophoblasts pro- trophoblasts of the mouse, while MMP-2 mRNA was absent
duce both MMP-2 and MMP-9 (Autio-Harmainen et al., 1992; from all cells in the implantation region, including trophoblasts
Fernandez et al., 1992; Polette et al., 1994; Shimonovitz et al.,
1994; Canete-Soler et al., 1995; Reponen et al., 1995), with and stromal cells of the decidual tissue (Canete-Soler et al.,
32
Matrix metalloproteinases in reproductive tissues
1995; Reponen et al., 1995). MMP-11 mRNA was localized 1992). Cultured human fetal membrane explants obtained from
Caesarean sections up-regulate proMMP-1, proMMP-3 and
to trophoblastic cells at the junction of embryonic and maternal proMMP-9, but not proMMP-2, when treated with human
tissues (Lefebvre et al., 1995), while MMP-1 and MMP- relaxin (X. Qin et al., unpublished). Amnion epithelial cells
3 have been detected in the murine blastocyst (Brenner secrete MMP-2 in culture, suggesting that these cells are
et al., 1989). responsible for the MMP-2 detected in second trimester amni-
TIMP-1 and TIMP-2 mRNA and protein are also expressed otic fluid (Lehtovirta and Vartio, 1994). MMP-1 and MMP-2
by human decidual cells during the first and third trimesters are also present in whole fetal membranes, but at relatively
of pregnancy. TIMP-1 is localized to the stromal compartment consistent values before, during, and after labour (Fernandez
of the decidua, and TIMP-2 is expressed in the trophoblast et al., 1992; Bryant-Greenwood and Yamamoto, 1995; Lei
cells of floating villi (Polette et al., 1994). Other investigators et al., 1995; Vadillo-Ortega et al., 1995; X.Qin et al., unpub-
have also identified TIMPs in the murine decidua (Nomura lished). MMP-1 expression has also been localized to cells in
et al., 1989; Werb et al., 1992; Reponen et al., 1995). the amniotic epithelium and the amniotic and chorionic ECM,
TIMP-3 expression has been observed in fetal extravillous with the chorionic cytotrophoblast cells adjacent to the chor-
trophoblasts that have invaded the maternal decidual tissues, ionic ECM staining the strongest (X.Qin et al., unpublished).
as well as in the maternal decidual cells (Higuchi et al., 1995; MMP-3 and MMP-9 expression in human amniochorion, and
Reponen et al., 1995). Observations that TIMP-3 expression MMP-9 in rat amnion, have been shown to increase with the
is up-regulated by progesterone (Higuchi et al., 1995) suggests onset of labour, then decline after delivery (Bryant-Greenwood
that TIMP-3 in particular may play a critical role in the and Yamamoto, 1995; Draper et al., 1995; Lei et al., 1995;
control of trophoblast invasion, potentially by limiting ECM Vadillo-Ortega et al., 1995). MMP-9 mRNA and protein are
degradation. In vitro, the presence of TIMPs has been found localized in human amnion epithelium underlying macrophages
to completely inhibit cytotrophoblast invasion (Graham and and chorion laeve trophoblast and decidual cells after labour
Lala, 1991; Lala and Graham, 1991; Librach et al., 1991; (Vadillo-Ortega etal., 1995). This timing of expression suggests
Behrendtsen et al., 1992). These studies emphasize that a that while many MMPs are expressed in the fetal membrane,
balance between TIMP and MMP expression can strongly only MMP-3 and MMP-9 are associated specifically with the
influence the invasion process. preparation of labour.
Much of the work on trophoblast invasion has been done In the maternal tissues, MMP-2 mRNA concentrations in
using in-vivo model systems. However, establishment of the decidua rise throughout gestation, while MMP-10 mRNA
in-vitro culture systems has also been successful. Cultured is detected only at term (Waterhouse et al., 1993). During early
human embryos secrete MMP-2 (Puistola et al., 1989; Graham pregnancy, TIMP expression levels are high, with maximal
et al., 1993), which increases upon addition of fibronectin concentrations of TIMP-1 mRNA at midgestation in the uterus,
(Turpeenniemi-Hujanen etal., 1995). Maximal enzyme concen- decidua, and placenta of the mouse. Similarly, in the placenta,
trations occur at days 4–5 of culture, corresponding with the TIMP-2 shows a seven-fold increase after day 14 in the mouse.
time of implantation in vivo (Turpeenniemi-Hujanen et al.,In contrast, TIMP-2 expression in the uterus, decidua, and
1992). Cultured trophoblasts have also been shown to secrete amnion increases steadily throughout pregnancy (Waterhouse
MMP-2 and MMP-9 (Librach et al., 1991; Shimonovitz et al.,et al., 1993; Hampton et al., 1995). Even though the peak of
1994; Salamonsen et al., 1995; Turpeenniemi-Hujanen et al.,TIMP-1 expression correlates with the most invasive period
1995; Vagnoni et al., 1995). Production of MMP-9 by human of embryo development, mice with a null mutation in the gene
cytotrophoblasts and murine blastocysts has been found to be encoding TIMP-1 have normal fertility (reviewed in Cross
the rate-limiting step of the invasive process in tissue culture et al., 1994). These data suggest that TIMP-1 is not a
models (Librach et al., 1991; Behrendtsen et al., 1992). In critical inhibitor during pregnancy, or that there is sufficient
addition, interleukin (IL)-1-βstimulates production of MMP-9, redundancy in the system to allow pregnancy to proceed
while glucocorticoids decrease the production of this enzyme. It normally.
has been suggested that normal trophoblast invasion may be At parturition, cervical ripening involves remodelling to
regulated by the opposing actions of IL-1-βand glucocorticoids ensure uncomplicated delivery. The uterine cervix is composed
(Librach et al., 1994). primarily of connective tissue, made up of fibrillar collagen
Pregnancy and parturition
and proteoglycans (Kleissl et al., 1978). Several investigators
The human fetus is surrounded by a membrane, the amniocho- have implicated collagenase in cervical ripening (Rajabi et al.,
rion, that isolates it from the external environment. The 1988; Osmers et al., 1990, 1992; Rechberger and Woessner,
amniochorion usually spontaneously ruptures during normal 1993; Mushayandebvu and Rajabi, 1995). In fact, collagenase
labour, but in many pathological conditions it may rupture concentrations are 6–23 times higher in cervices of humans
prematurely. Rupture of the fetal membranes at term was (Rechberger and Woessner, 1993; Rajabi et al., 1988) and
originally thought to be caused by a mechanical force generated guinea pigs (Rajabi et al., 1991b) in labour than at term, and
by the myometrium with the onset of cervical dilatation are associated with a collagenase-mediated degradation of type
(Benirschke and Kaufmann, 1990). However, enzymatic I collagen in the cervical ECM (Rajabi et al., 1991a). In
degradation of the collagenous extracellular matrix of the fetal addition, collagenase is elevated in the blood at the time of
membranes has been proposed as the mechanism that facilitates parturition (Rajabi et al., 1985, 1988). Rajabi et al. (1991a)
reported that collagenase production in primary monolayers ofthis process(Vadillo-Ortega et al., 1990; McGregor and French,
33
D.L.Hulboy
et al.
cervical cells derived from 50 day pregnant guinea pigs key targets for natural selection, it follows that there may be
considerable redundancy in the contributions of MMP family
was controlled by progesterone, oestrogen, and prostaglandin members to reproductive processes. Interestingly, however,
intermediates. These same investigators have separated stromal MMP-3 and MMP-10 mRNAs are strongly upregulated in
and epithelial cervical cells, and have determined that the the stroma of the MMP-7 nullizygous post-partum uterus
origin of collagenase secretion is the stromal cells. Interestingly, (C.L.Wilson and L.M.Matrisian, unpublished). This suggests
cervical epithelial cells secrete factors that stimulate stromal that other MMPs are somehow stimulated to counteract the
cell collagenase production (Rajabi and Singh, 1995). However, absence of MMP-7.
in vivo, the increase in collagenase has been attributed to In addition to MMP-1 and MMP-7, other MMP mRNA
invading leukocytes, rather than cervical fibroblasts (Osmers expression patterns have been investigated during the process
et al., 1991, 1992). of rodent uterine involution (Rudolph and Matrisian, 1994).
Post-partum involution
MMP-1, MMP-2, MMP-3, MMP-11 and TIMP-1 are relatively
The rodent post-partum uterus represents a dramatic example constant throughout involution, while MMP-7 and MMP-10
of rapid and extensive matrix remodelling characterized by are abundant during early involution, then taper off to low or
abundant expression of MMPs. The involuting uterus undetectable levels by 4.5 days of involution (Rudolph and
undergoes a rapid reduction in size as it returns to the pre- Matrisian, 1994; Wilson et al., 1995). Many of these same
pregnancy state which is primarily due to the loss of collagen MMPs are present in the murine uterus during the oestrous
(Harkness and Moralee, 1956). Degradation of the principle cycle, with MMP-7 and MMP-11 elevated periodically through-
collagen of this organ, type I collagen, requires the action of out the cycle (L.A.Rudolph and L.M.Matrisian, unpublished).
collagenases. While collagenase is produced in the rat uterus
during post-partum involution, it is not expressed in the
Ovary
prepartum or non-pregnant uterus (Jeffrey and Gross, 1970; Normal ovarian function, in particular ovulation and luteolysis,
Blair et al., 1986; Rudolph and Matrisian, 1994). During involves considerable tissue remodelling. For oocyte release
uterine involution, however, the perinuclear region of the to occur, the follicle must be ruptured. This requires degradation
smooth muscle cells of the myometrium show collagenase of the membrane propia between the thecal and granulosa
staining by immunohistochemistry. Measurement of colla- cell layers, as well as disruption of the extracellular matrix
genase bound to uterine collagen revealed that it is produced throughout the site of rupture. Following ovulation, the follicle
only as needed and not stored, either intra- or extra-cellularly involutes and forms the corpus luteum. Also during this time,
(Blair et al., 1986). basement membrane disruption allows capillary growth into
The peptide bonds between residues Gly
775
and Ile
776
of the the granulosa layer (Lipner, 1988). Luteolysis, degeneration
α-1(I) chain of native collagen are cleaved by the collagenases, of the corpus luteum and reformation into the corpus albicans,
and mutations in this region make collagen resistant to these is another example of remodelling. These processes would be
enzymes (Liu et al., 1995). Mice carrying this mutation in the expected to involve protease action.
endogenous α-1(I) gene developed normally, although in adult MMP involvement in ovulation has been well demonstrated
mice the skin became thickened. More dramatically, post- (Figure 1), particularly for MMP-1. Throughout ovulation,
partum involution of the uterus was markedly impaired, with MMP-1 protein is found in the theca interna and externa, the
a significant reduction in the number of litters, and the presence interstitial glands, and germinal epithelium (Tadakuma et al.,
of dense, collagenous nodules in post-partum uteri. These 1993). As ovulation approaches, collagenase activity is concen-
results suggest that cleavage of type I collagen at the Gly
775
/trated at the site of future rupture: collagen concentrations
Ile
776
site is required for remodelling of the ECM in the post- drop, while MMP-1 protein and activity increase in the
partum uterus. capillary lumina at the apex of the follicle (Murdoch and
The activity of rat MMP-7 was first identified during early McCormick, 1992; Tadakuma et al., 1993). In addition, specific
involution of the uterus (Sellers and Woessner, 1980), and inhibitors of collagenase block ovulation (Butler et al., 1991).
was later purified and characterized from this same source After follicle rupture, MMP-1 protein is found in granulosa
(Woessner and Taplin, 1988; Abramson et al., 1995). Recently, and thecal cells around the orifice (Tadakuma et al., 1993).
the mouse homologue of MMP-7 was cloned and the mRNA MMP-2 protein and activity increase as ovulation approaches
expression pattern during uterine involution examined (Wilson (Puistola et al., 1986; Curry et al., 1992; Russell et al., 1995).
et al., 1995). Consistent with the previously reported activity Ewes immunized against the α43 subunit of inhibin exhibit
of this enzyme, MMP-7 mRNA is abundant during early poor oocyte release and abnormal follicular involution, which
uterine involution, then tapers off to undetectable amounts by correlates with decreased concentrations of preovulatory MMP-
4.5 days of involution. In addition, murine MMP-7 mRNA 2 (Russell et al., 1994, 1995).
has been detected at low levels in the adult virgin and pregnant During luteolysis, active forms of the gelatinases MMP-2
uterus (Wilson et al., 1995). Although MMP-7 is the only and MMP-9 are induced (Endo et al., 1993). One active form
known epithelial-specific MMP, mice with a null mutation in of MMP-2 that is present in the corpus luteum is the 46 kDa
the gene encoding MMP-7 proceed normally through the size, which is neither bound nor inhibited by TIMP-2 (Fridman
oestrus cycle, pregnancy, and uterine involution (C.L.Wilson et al., 1992; Russell et al., 1995). An interesting possible
et al., unpublished; L.A.Rudolph and L.M.Matrisian, mechanism for MMP activation during this time was proposed
by Endo et al. (1993): collagenases are known to be activatedunpublished). Because agents that affect reproduction are
34
Matrix metalloproteinases in reproductive tissues
by hypochloride (HOCl) and chloramine. These molecules morphology is similar to a normal 9–12 day pregnant gland.
In fact, glands from transgenic virgin mice express mRNA for
can be generated by macrophage and neutrophil peroxidases β-casein, a milk protein, at amounts similar to those of glands
utilizing hydrogen peroxide (H
2
O
2
), whose concentration from normal 9–10 day pregnant mice (Sympson et al., 1994;
increases in the corpus luteum during luteolysis. Witty et al., 1995b). These data suggest that overexpression
Consistent with a balance in expression of MMPs and their of MMP-3 in mammary epithelial cells alters lobular alveolar
inhibitors, TIMP and α-2-macroglobulin proteins are present development.
in human follicular fluid (Curry et al., 1988). Specifically, The major phase of mammary growth and differentiation
during ovulation and luteal development in rats, TIMP-1 occurs during pregnancy and lactation. The mammary gland
concentrations are high in granulosa cells where the basement consists of two types of epithelial cells, luminal epithelial cells
membrane is disrupted, and in thecal cells (Chun et al., 1992; and myoepithelial cells. Luminal mammary epithelial cells
Nothnick et al., 1995). The TIMP-1 gene is active again in make up the inner lining of ducts and alveoli involved in the
late luteolysis (Nothnick et al., 1995). TIMP-2 concentrations synthesis and passage of milk products via the nipple. The
do not change during ovulation in rat, although bovine TIMP- myoepithelial cells are the contractile elements for milk expul-
2 mRNA increases during luteolysis (Juengel et al., 1994; sion, as well as for the production of ECM components.
Nothnick et al., 1995; Smith et al., 1995). TIMP-3 is present Several investigators have suggested that the mammary gland
during early luteolysis (Nothnick et al., 1995). These data BM is synthesized by myoepithelial cells (Warburton et al.,
demonstrate that TIMPs are present during remodelling events 1981, 1987), and that these cells are also responsible for BM
in the ovary, when MMPs are active. degradation (Monteagudo et al., 1990; Dickson and Warburton,
Interestingly, TIMP has also been associated with steroido- 1992). In support of this, MMP-2 and MMP-3 protein have
genesis in granulosa cells, as well as in Leydig cells of the been localized to the basal myoepithelial cells of the murine
testes (Boujrad et al., 1995). TIMP-1 was identified as part of mammary gland (Monteagudo et al., 1990; Dickson and
a complex with cathepsin L that stimulates steroid hormone Warburton, 1992; Andersson et al., 1994; Li et al., 1994).
synthesis in these cells. Whether these effects are related to After lactation, the young are weaned and the mammary
the MMP-inhibitory activity of TIMPs is unknown. gland undergoes involution. Dramatic changes in the structure
of the ECM and BM occur, as well as reduction in cell number
Breast
through apoptosis (Martinez-Hernandez et al., 1976; Warburton
Extensive remodelling of the ECM and structural changes in et al., 1982). Several MMPs have been implicated in the
the mammary gland occur during ductal development, lactation, degradation and remodelling of the ECM during mammary
and involution. Once again, the MMPs have been implicated gland involution. MMP-2 and MMP-3 are detected by day 4
in the dramatic changes that take place in the mammary gland of involution, and maintain their expression until day 10
during these processes. (Dickson and Warburton, 1992; Talhouk et al., 1992; Li et al.,
Temporal expression of several MMP family members 1994). MMP-11 is detected three days after weaning and
correlates with normal ductal branching morphogenesis that persists at low levels for ~2 weeks (Lefebvre et al., 1992).
MMP-3 and MMP-11 have been localized to fibroblasts around
occurs during the development of the murine mammary gland. the degenerating ducts of postlactational mouse mammary
At 5–10 weeks of age, when the mammary ducts are actively glands (Lefebvre et al., 1992; Talhouk et al., 1992; Fang et al.,
growing and branching, MMP-2 and MMP-3 (Talhouk et al.,1995), while MMP-2 and MMP-3 have been immunolocalized
1991; Witty et al., 1995b) are detected at high concentrations, to mammary myoepithelial cells (Dickson and Warburton,
then decrease by 13 weeks of age. MMP-11 and TIMP-1 1992; Li et al., 1994). Degradation of the ECM by MMPs is
mRNAs are also detected during this time period, but at much likely to reduce the volume of connective tissue in the organ.
lower concentrations (Witty et al., 1995b). MMP-3 has been Degradation of the BM, however, may play an even more
localized by in-situ hybridization to the stroma surrounding critical role in mammary gland involution. BM is considered
the growing mammary duct, but not to the region around the a survival factor for mammary epithelial cells, and loss of
terminal end bud (Witty et al., 1995b). This localization pattern contact with the BM results in apoptosis (Boudreau et al.,
of MMP-3 suggests a role in matrix repair after ductal growth 1995; Witty et al., 1995a; Pullan et al., 1996).
has occurred. MMP-7 gene expression has also recently been TIMPs have also been detected during the involution process,
detected in the cycling, lactating and involuting murine mam- with peak expression at 4–6 days of involution (Talhouk et al.,
mary gland (Wilson et al., 1995) and atrophic non-lactating 1992; Li et al., 1994). When slow-release TIMP pellets were
human mammary gland (Saarialho-Kere et al., 1995). surgically implanted into murine mammary glands, involution
Recent studies have indicated a potential role for the MMPs, was delayed. These results, combined with the MMP expression
particularly MMP-3, in the reorganizational events that occur data, support the hypothesis that the balance of ECM-degrading
during mammary development. Transgenic mice with MMP- enzymes and their inhibitors regulates the rate of remodelling
3 under the control of the whey acidic protein (WAP) (Sympson of the basement membrane, and consequently, the tissue-
et al., 1994) or the mouse mammary tumour virus (MMTV) specific function of the mammary gland (Talhouk et al., 1992).
(Witty et al., 1995b) promoters exhibit alterations in normal
Male reproductive system
branching and lactation. At 10–13 weeks of age, the mammary
glands from the transgenic animals appear more mature, with
Testes
additional branches from primary and secondary ducts filling Little is known of MMP expression in the testes, yet there
exists some evidence that points toward a role in maturationthe spaces within the ductal network. This altered mammary
35
D.L.Hulboy
et al.
and progression of sperm through testicular passages. MMP- pipe cleaner’, meaning that it potentially keeps ducts clear by
cleaving other secreted proteins which may cause blockage.
7 has been detected in epithelial cells of the efferent ducts, Indeed, MMP-7 secretion into the lumen of glandular elements
and the initial and caudal segments of the epididymis of the has also been observed by immunohistochemistry (W.C.Powell,
adult mouse (Wilson et al., 1995). MMP-2 is expressed by C.L.Wilson and L.M.Matrisian, unpublished data).
cultured rat Sertoli cells (Sang et al., 1990a,b). TIMP-1 and
TIMP-2 have been detected in rat Sertoli cells of the maturing
testis (Ulisse et al., 1994).
Regulation of MMPs in reproductive tissues
The fertilins, a member of the ADAMs (A Disintegrin And In the reproductive system, hormones, growth factors, and
Metalloproteinase domain) family of proteins, are involved in cytokines play critical roles in regulating organ and cellular
several aspects of male reproductive function (Wolfsberg et al.,functions. It is provocative that these agents also regulate
1995). Besides possessing transmembrane and disintegrin-like MMP and MMP inhibitor expression in ways consistent with
domains, these proteins share motifs with MMPs: they contain a role for metalloproteinase activity as a downstream effector
‘pre’ and ‘pro’ domains, and a putative zinc-dependent metallo- of these biological signals. Table III provides specific examples
proteinase region. They are expressed in spermatogenic cells, of MMP regulation in the reproductive tissues.
with different ADAM family members localized to different MMP regulation by hormones, growth factors, and cytokines
meiotic stages along the seminiferous tubules. It is postulated has largely been associated with changes in the rate of gene
that these ADAMs may aid in migration of spermatids and transcription. A key player in the induction of most MMP
spermatozoa through the tubules (Wolfsberg et al., 1995). promoters is the transcription factor AP-1. Recognition sites
Other ADAMs are believed to be involved in sperm–egg for this factor are found in the promoters of most MMP family
fusion (Wolfsberg et al., 1993). members (Crawford and Matrisian, 1996 for review). AP-1 is
Prostate
composed of members of the Jun and Fos early response
The prostate represents another reproductive tissue that proteins, which are induced rapidly and strongly by signal
undergoes extensive morphological changes throughout life, transduction cascades from tumour promoters, growth factors,
with maturation and involution representing periods of tissue and oncogenes. AP-1 is required for the expression of many
construction and remodelling. In young male rats, the prostate MMPs, since transcription from MMP promoters with mutated
begins to mature shortly after birth, and differentiation is AP-1 sites is greatly reduced (Crawford and Matrisian, 1996).
complete by ~50 days of age. In the maturing prostate and The MMP-2 promoter is set apart from the others; it appears
seminal vesicles, Wilson et al. (1992) found a calcium- to be more of a housekeeping promoter, rather than an inducible
dependent gelatinolytic activity of 64 kDa, most likely active one, since it is GC-rich and lacks AP-1 sites (Huhtala et al.,
MMP-2. Interestingly, the timing of this gelatinase activity 1990). Indeed, MMP-2 does tend to be constitutively expressed,
coincides with the period of differentiation of each structure although it can be enhanced or repressed to some extent
in the prostatic complex. (see below).
Similar to other reproductive organs, the prostate undergoes In addition to control at a transcriptional level, MMPs
involution upon hormone, in this case androgen, withdrawal. can be regulated post-transcriptionally by changes in mRNA
ThisprocessinvolvesextensiveapoptosisandECMdegradation stability, and post-translationally by cleavage and removal of
(Kyprianou and Isaacs, 1988). Apoptosis peaks 2–3 days after the propeptide and interaction with inhibitors (Matrisian, 1990;
castration in the rat; by day 4 there have been considerable Delany and Brinckerhoff, 1992). These mechanisms can play
structural changes; and by 8 days involution is complete. Powell a role in controlling MMP concentrations in response to
et al. (1996) have examined in detail the expression of MMP-7 reproductive hormones and factors, as further detailed below.
anditsrelationshiptorodentprostate involution. MMP-7mRNA
Control of MMPs in the cycling endometrium by
is expressed in the epithelium beginning day 2, is at a maximum
progesterone and oestrogen
at day 5, and has dropped off by day 8. MMP-7 protein is
maximal on day 5, and basal by 8 days following castration. Hormonal regulation of MMP concentrations is perhaps best
TIMP-1 expression closely follows: it peaks on day 5, and studied in the cycling endometrium. In particular, progesterone
decreases to a plateau by days 6–8. Also found in the involuting is a potent repressor of MMP concentrations both in vivo and
prostate is a calcium-dependent gelatinase, probably MMP-2, in vitro. It is tempting to conclude that progesterone is the key
whosemaximumexpression is around day7postcastration (Wil- regulator of MMP expression in the cycling uterus. For
son et al., 1991). Based on their patterns of expression, these example, the MMP genes are expressed during the times in
MMPs may assist in the orchestration of tissue remodelling the cycle when progesterone concentrations are low, i.e. during
involved in involution of the prostate. the proliferative and menstrual stages of the uterus. During
MMPs may also play a role in ensuring that ductal structures the secretory stage when progesterone concentrations are high,
remain open. In adult human, MMP-7 is expressed in ductal the expression levels of most MMP family members decrease
and secretory epithelial cells of exocrine organs, including the (see Table II). Additionally, MMP-1, MMP-2, and MMP-3
prostate (Saarialho-Kere et al., 1995). Because MMP-7 protein have been localized to stromal cells surrounding proliferative
was not detected in the stroma beneath these epithelial cells, glandular epithelium, known to lack progesterone receptors
Saarialho-Kere et al. concluded that it may be secreted into (Kokorine et al., 1996). An exception to this generality is
MMP-2, which is the only MMP expressed at significantthe lumen. Subsequently, they dubbed MMP-7 an ‘enzymatic
36
Matrix metalloproteinases in reproductive tissues
concentrations during the secretory phase of the cycle (Rodgers one is responsible for the increase in MMPs during menstru-
ation. However, recent results from Salamonsen and Woolley
et al., 1994; Brenner et al., 1996). (1996) and Brenner et al. (1996) indicate that progesterone
Progesterone
may not be the principal player in MMP reduction during the
Progesterone regulation of MMP expression has been studied secretory phase. In particular, at the end of the proliferative
extensively in cultured uterine cells and explants. In early stud- stage, MMP concentrations drop before progesterone concen-
ies, Jeffrey et al. (1971) reported that progesterone inhibits trations rise. It is possible that MMP concentrations are initially
collagenase activity in cultured rat uterine cells. They surmised influenced by growth factors, cytokines, or other hormones
that the inhibition is at the level of collagenase expression, since (see below). Further investigation using in-vitro and in-vivo
progesterone does not affect enzyme activity. Since that time, systems should elucidate the mechanisms by which hormones
progesteronehasbeenfoundtorepressMMP-1,MMP-3,MMP- and growth factors co-ordinately regulate MMP concentrations
7, MMP-9, and MMP-11 mRNA and/or protein in cultured to influence endometrial structure and function.
endometrialtissues(TableIII). The mechanism of this inhibition
Oestrogen
is not well understood. Progesterone regulation of gene expres- The effects of oestrogen on MMP expression are not well under-
sion has been shown to be mediated by direct binding of the stood. Certainly, it is an important element of the reproductive
receptor to negative hormone-response elements in the pro- system:targeted deletionof theoestrogenreceptorinmice results
moters of many steroid-responsive genes (Gronemeyer, 1991). ininfertilefemales, and reduced fertility in males (Lubahn et al.,
An attractive hypothesis is that the MMPs are regulated in this 1993). In the rat, removal of all endogenous steroid hormones
manner. While putative hormone-response elements have been by ovariectomy and adrenalectomy resulted in complete loss of
identified in the promoters of MMP-1, MMP-3, and MMP-7 collagenase activity and synthesis in the rat uterus (Anuradha
(Matrisian et al., 1985; Angel et al., 1987; Gaire et al., 1994), and Thampan, 1993). Implantation of ostradiol wax pellets into
there is no direct evidence that these elements respond to these rats brought about a recovery in synthesis of the enzyme
progesterone. At least in the case of MMP-7, there appears to to pre-ovariectomized concentrations, suggesting that uterine
be an indirect effect mediated through the paracrine activity collagenase is indeed under the regulatory influence of oestra-
of TGF-β. When treated with progesterone, human endometrial diol. Oestrogen has little effect on MMP expression in vitro,
stromal cells upregulate their TGF-βproduction (Bruner et al.,although in some cases oestrogen enhanced theinhibitory action
1995). TGF-βthen represses MMP-7 production by co-cultured of progesterone on MMPs, presumably through its ability to up-
epithelial cells, potentially via TGF-βinhibitory elements regulate progesterone receptor production (Table III). In part,
(TIEs)that reside in the MMP-7 promoter. TIEs have previously this lack of effect may be a result of the requirement for an
been demonstrated to be involved in TGF-βrepression of oestrogenic environment for cell viability, thus reducing the
MMP-3 expression in rat fibroblasts (Kerr et al., 1990). effects of exogenous hormone. Oestrogen has been shown to
Progesterone may also modify MMP activity post-transla- stimulate transcription of c-jun,junB, and junD, components of
tionally, at the level of activation, and by altering local AP-1, in the rat uterus (Nephew et al., 1994). Since AP-1 is an
concentrations of specific MMP inhibitors. For example, the important factor in the expression of MMPs (see above), the
serine protease plasmin can activate, by ‘pro’ peptide removal, apparent failure of oestrogen to strongly affect MMP transcrip-
many MMP family members (Powell and Matrisian, 1996 for tion emphasizes the complexity of hormonalregulation of MMP
review). Plasminogen activator inhibitor-1 (PAI-1) inhibits the gene expression.
protease activity of members of the plasmin cascade (Blasi
et al., 1990), and progesterone stimulates production of PAI-
Other factors regulating MMP expression in repro-
1 in cultured endometrial stromal cells (Casslen et al., 1992).
ductive tissues
Consequently, progesterone induction of PAI-1 may ultimately Three other pregnancy-associated hormones have been implic-
lead to a reduction in proMMP activation. In rabbit and human ated in regulation of MMPs (Table III and references therein).
cultured endometrial cells, TIMP-1 mRNA and protein are Relaxins, which are members of the insulin superfamily, are
stimulated by progesterone (Marbaix et al., 1992). Similarly, involved in connective tissue remodelling (Bryant-Greenwood,
progesterone upregulates, in a dose-dependent manner, endo- 1982). In particular, several are expressed by the decidua and
metrial TIMP-3 mRNA concentrations; RU486 blocks this placenta and are implicated in control of collagen degradation
effect (Higuchi et al., 1995). The overall inhibitory effect of that leads to fetal membrane rupture during the process of
progesterone on MMP function in the endometrium may thus parturition (Bryant-Greenwood and Yamamoto, 1995). Consist-
occur by a combination of effects: repressing MMP expression, ent with this function, X.Qin et al. (unpublished) have shown
blocking activation, and tipping the MMP/inhibitor ratio in that the expression of relaxin receptors coincides temporally
favour of the inhibitors. and spatially with that of MMP-1, and that relaxin H2 causes
Additional findings from in-vivo studies of the cycling a dose-dependent increase in production of MMP-1, MMP-3,
uterus remind us that in-vitro experiments are an aid to and MMP-9, but not MMP-2, by human fetal membrane
understanding MMP expression in the uterus, but not the explants. Relaxin is also the putative signal for cervical
whole story. Based on data obtained in cultured endometrial dilatation; it enhances MMP-1 activity in cultured guinea pig
cells, it is logical to speculate that: (i) the rise in progesterone cervical cells. A second hormone, serotonin, may also be
is responsible for the decrease in MMP expression during the involved in MMP induction after parturition. It is required for
expression of collagenase in post-partum rat uterine smoothsecretory phase of the cycle; and (ii) the decrease in progester-
37
D.L.Hulboy
et al.
muscle cells. Wilcox et al. (1992) have determined that leads to activation of proMMP-9, gonadotrophin may indirectly
serotonin exposure for 8–10 h induces maximal concentrations inhibit MMP-9 activity.
of collagenase mRNA in these cells. They speculate that a Cytokines, produced by either local cells or infiltrating
pulse of serotonin around the time of parturition may be inflammatory cells, may also regulate MMP concentrations
sufficient to induce the amounts of collagenase necessary for and influence reproductive processes. TNF-αand IL-1 have
post-partum involution of the uterus. Finally, interferon-tau, been implicated in control of MMP expression in the uterus
the major protein product of preimplantation trophoblasts in (Table III). In endometrial stromal cell culture, either TNF-I
the ewe, inhibits expression of MMP-1 and MMP-3, but not or IL-1-αup-regulates, in a dose-dependent manner, the
MMP-2, by endometrial stromal cells. activities of MMP-1, MMP-3, and MMP-9, but not MMP-2.
Glucocorticoids have also been shown to depress MMP IL-1-αalso inhibits suppression of MMP-3 by progesterone
values in reproductive tissues, and appear to act through a (E.Sierra-Rivera and K.Osteen, unpublished). IL-1-βexpres-
variety of mechanisms. During involution of the mouse mam- sion in the endometrium is normally weak (Tabibzadeh and Sun,
mary gland, AP-1 and MMP-3 are up-regulated (Marti et al.,1992). During pregnancy, however, human cytotrophoblasts
1994; Fang et al., 1995). Dexamethasone, a synthetic glucocort- express increasing amounts of IL-1-βand its receptors; this
icoid, represses MMP-3 expression and inhibits involution expression correlates with both MMP-9 activity and the invas-
(Fang et al., 1995). The glucocorticoid receptor inhibits MMP-1 iveness of these cells in culture. Interestingly, IL-1-βalso up-
and MMP-3 expression by interfering with AP-1 transactivation regulates trophoblastic expression of human chorionic gonad-
function, without affecting the latter’s DNA binding ability otrophin (HCG), which inhibits MMP-9 activity. This further
(Jonat et al., 1990; Yang-Yen et al., 1990; Konig et al., 1992). highlights the balance of inducers and suppressors inherent in
Additionally, dexamethasone has been found to reduce the control of MMP activity.
stability of MMP mRNA through a pathway that requires de- With regard to MMP inhibitors, TIMPs and α-2-macro-
novo transcription (Delany and Brinckerhoff, 1992). In yet a globulin are induced in the ovary by progesterone (Table
third mechanism, glucocorticoids decrease expression of IL- III). While the anti-oestrogen tamoxifen does not affect this
1-β, and consequently MMP-9, in cultured human cytotropho- induction, the antiprogesterone RU486 represses it (Mann
blasts. In turn, this diminishes in-vitro invasion by these cells et al., 1993; Morgan et al., 1994). In cultured rat granulosa
(Librach et al., 1994). cells, prolactin, which can inhibit proteolytic activity during
Like glucocorticoids, epidermal growth factor (EGF) can ovulation, stimulates expression and activity of TIMP-1 but
regulate both transcription and stability of MMP mRNAs has no effect on TIMP-3 (Murray et al., 1996). In these same
(McDonnell et al., 1990; Delany and Brinckerhoff, 1992; Gaire cells, LH and IL-1-βinduce all three TIMPs, possibly via up-
et al., 1994). EGF stimulates c-fos and c-jun (Muller et al.,regulation of progesterone production (W.B.Nothnick and
1984; Quantin and Breathnach, 1988), both of which are T.E.Curry, Jr, unpublished). Finally, in Sertoli cells from
required for MMP-3 induction by EGF in rat-1 fibroblasts the maturing rat testis, follicle stimulating hormone (FSH)
(McDonnell et al., 1990). EGF induction of MMPs may be stimulates TIMP-1 and TIMP-2 expression through a cAMP-
important for implantation events. Expression of EGF receptors dependent mechanism that results in increased binding of
increases in uterine epithelial cells just prior to implantation AP-1 to the TIMP promoters (Ulisse et al., 1994).
(Harvey et al., 1995b), and EGF has been shown to enhance
invasion by human cytotrophoblasts in vitro (Bass et al., 1994).
Roles of MMPs in cellular processes
In implanting mouse blastocysts, expression of MMP-9, which Throughout this review, we have described the expression of
appears to play a crucial part in this process in humans MMPs and speculated on howtheymayfunctioninreproductive
(Librach et al., 1991; S.Fisher et al., unpublished), increases processes. For example, MMPs appear to be important in the
in the trophoblast giant cells. Addition of EGF to cultures of tissue degradation that occurs during menstration, and the use
these cells at a time equivalent to implantation (day 7) increases of inhibitors or genetic manipulation support a role for MMP
MMP-9 activity; there is no response to EGF by these cells 2 activity in ovulation and uterine and breast involution. Epithelial
days later (Harvey et al., 1995a,b). MMPs may function in glands and ducts as ‘enzymatic pipe
Gonadotrophins appear to affect MMP proteolytic activity cleaners’. It is not always clear whether MMP expression is a
bypost-translational mechanisms (TableIII). Ovariangranulosa direct cause of connective tissue destruction, or more the result
cells cultured on Matrigel in serum-free medium secrete MMP- of anattempttorepair tissue already damaged.Alongtheselines,
9, degrade the Matrigel, and detach. When gonadotrophin is MMPs are expressed during cutaneous wound healing, a form
added to the medium, TIMP-1 release increases. Consequently, of tissue remodelling (Saarialho-Kere et al., 1994). Tissue
gelatinase activity, Matrigel loss, and cell detachment decrease. remodelling in any form can involve a variety of cellular events,
On the other hand, while gonadotrophin does not alter TIMP including proliferation, migration, differentiation, and
production in cultured human trophoblasts, it still inhibits apoptosis. MMPs may participate in these cellular activities in
MMP-9 activity and reduces trophoblast invasion dramatic- a variety of ways. Through their actions, they can alter cell–
ally. This phenomenon may be due to gonadotrophin’s inhibi- matrix and cell–cell interactions, change cell shape, and release
tion of urokinase-type plasminogen activator (uPA), a member or activate growth factors. These are events which in turn can
of the plasmin cascade (Yagel et al., 1993). That is, by
inhibiting a member of the protease cascade that potentially alter cellular processes, as detailed below.
38
Matrix metalloproteinases in reproductive tissues
Proliferation
involution is understandable, their association with apoptosis is
less clear. The prevailing hypothesis is that the BM is asurvival
The relationship between MMPs and cellular proliferation is factor for epithelial cells, and their loss of contact with the BM
enigmatic. As discussed earlier, MMPs are induced by growth results in programmed cell death. In the breast, a BM rich in
factors and oncogenes that also increase the proliferative index laminin is required for normal mammary gland development
of cells in vitro. Indeed, MMPs such as MMP-7 can be found in and gene expression (Li et al., 1987; Lin and Bissell, 1993).
proliferativeendometriumand are expressed in dividing cells, as When mammary epithelial cells are placed in culture without
indicated by co-expression of the nuclear antigen Ki67 (Brenner the critical BM components, they undergo apoptosis (Boudreau
et al., 1996). However, in some cases, serum, a potent inducer of et al., 1995; Pullan et al., 1996). The role of BM as a survival
cell proliferation, can decrease MMP concentrations (Matrisian factorhasbeendemonstrated by disruption of integrin/BMinter-
et al., 1985, for example). Also, while ectopic expression of actions. For example, antibodies against β
1
integrins induce
MMP-3 in the mammary glands of transgenic mice results in mammary epithelial cell apoptosis (Boudreau et al., 1995), and
acceleratedepithelial cell growth, the rates of cellulardifferenti- α
v
β
3
antagonists cause apoptosis in endothelial (Brooks et al.,
ation and death are also increased (Sympson et al., 1994; Witty 1994)andmelanoma (Montgomeryet al.,1994)cells.Invivo, the
et al., 1995a,b). These contradictory results suggest that MMP overexpression of an activated form of MMP-3 in the mammary
involvement in cellular proliferation, differentiation, and death gland of transgenic mice results in loss of BM components
may not be easily separated. (Sympsonetal.,1994), and a marked disruption of BM structure
The potential roles for MMPs in cellular proliferation are (Witty et al., 1995b). Consistent with a role for MMPs in modu-
numerous. It is tempting to speculate that, at least in some cases, lating programmed cell death via alterations in the BM, these
the induction of MMPs in proliferative tissues could facilitate mice show a significant increase in the apoptotic index in
the clearing of basement membrane and/or connective tissue mammary tissue (Boudreau et al., 1995; Witty et al., 1995a).
matrix components to make room for the multiplying cells as Studies by Boudreau et al. (1995) shed some light on the
they expand. In these cases, MMP induction may be part of a molecular pathways connecting cellular ligation to BM and
programme of gene expression designed to prepare the tissue apoptosis. The expression of IL-1-β-converting enzyme (ICE),
for growth. In other cases, changes in the structure or integrity the mammalian homologue of the C.elegans cell death-inducing
of the basement membrane may alter the shape of the cell, ced-3 gene (Vaux et al., 1994), correlates with the loss of ECM
modifying gene expression patterns and stimulating cell growth andtheinductionofapoptosis inmammary epithelialcellsin vivo
(Ingber, 1990). In addition, proteolysis of the ECM could result and in vitro (Boudreau et al., 1995). Inhibitors of ICE activity
in release of matrix-bound growth factors and their receptors, prevent apoptosis in cultured mammary epithelial cells plated in
such as the FGF and heparin-binding epidermal growth factor the absence of basement membrane (Boudreau et al., 1995).
(EGF) (Vlodavsky et al., 1990, Southgate et al., 1992; Lanzrein These results suggest that basement membrane ligation inhibits
et al., 1995; Levi et al., 1996; Whitelock et al., 1996), or growth ICE expression, and the loss of this contact results in elevated
factor-like domains may be released from matrix proteins and ICE and induction of the apoptotic pathway.
havegrowth-stimulatory effects (Panayotouetal., 1989). Athird It is also interesting to consider that MMPs may induce
possibility is that MMPs can directly activate growth factors by apoptosis through alternative mechanisms. Fas interactions with
processing them from precursor molecules. MMP-1, MMP-2, its ligand initiate apoptosis in T lymphocytes (Brunner et al.,
MMP-3, MMP-7, and MMP-9 activate TNF-αin this manner 1995; Ju et al., 1995). Fas is a member of the TNF/nerve growth
(Gearing et al., 1994). Similarly, MMP-7 releases from high- factor receptor family (Suda et al., 1993). MMPs have been
molecular-weight urokinase-type plasminogen activator its implicated in the conversion of TNF-αand Fas ligand to active,
receptor-binding amino-terminal fragment, which has been soluble forms (Gearing et al., 1994; Kayagaki et al., 1995),
shown to be mitogenic and to increase cell motility (Marcotte suggesting that MMPs activate or release factors involved in the
et al., 1992; Odekon et al., 1992; Anichini et al., 1994). MMPs apoptotic process.
may thus affect cellular proliferation by a variety of indirect
mechanisms.
Development and differentiation
The process of embryonic development is characterized by
Apoptosis
dramatic changes in tissue morphology and extensive matrix
Many organs in the reproductive system undergo involution remodelling. MMP expression, however, is surprisingly
in response to hormone withdrawal, including prostate, breast, restricted during this time (Matrisian and Hogan, 1990). MMP-
uterus, and ovary. Involution of reproductive organs employs 1 and MMP-3 transcripts have been detected in preimplantation
drastic reduction of tissue volume through ECM degradation, mouse embryosbyreversetranscription–polymerase chain reac-
and loss of the cellular component by apoptosis (Kerr et al.,tion (RT–PCR) (Brenner et al., 1989). Later in development,
1972; Cunha et al., 1987; Kyprianou and Isaacs, 1988; MMP-1 message and protein have been seen in embryonic bone
Tenniswood et al., 1992; Juengel et al., 1993; Fang et al., 1995). and skin (McGowan et al., 1994; Mattot et al., 1995). MMP-7
MMP expression correlates with this resorption process (see mRNA has been detected in late-stage embryos only by RT–
above), and the MMPs have been causally (albeit indirectly) PCR (Wilson et al., 1995). MMP-9 mRNA has been reported to
implicated in the involution of the breast (Talhouket al., 1992) be restricted to developing bone (Reponen et al., 1994), but
and uterus (Liu et al., 1995). other studies demonstrate more widespread expression patterns
(Canete-Soler et al., 1995). MMP-2 mRNA expression inAlthough theinvolvementof MMPs inthelossof ECMduring
39
D.L.Hulboy
et al.
embryos contrasts with most of the other MMPs in that it is differentiation are likely to be a reflection of the complexity of
the information that resides in BM and ECM and how thatexpressed in many tissues (Reponen et al., 1994), perhaps again
reflecting thedifferences between theMMP-2 promoter andthat information is received and processed by the cell. Disruption of
the matrix by MMPs could either eliminate specific signals,of the other MMP family members (Huhtala et al., 1990). The
relative scarcity of MMPs in developing embryos contrasts reveal cryptic signals, or even act to release or activate factors
stored in the matrix that can in turn alter cellular function. Initialsharply with the abundant expression of MMPs in adult
reproductivetissues undergoing equallyrapidalterationsin mor- studies ablating MMP activities using gene targeting have just
begun to address these issues. The next decade of research holdsphology.
MMP activity has been implicated in branching ductal mor- exceptional promise for understanding the roles these enzymes
play in reproductive function, and lead the way for the use ofphogenesis in the salivary gland, the lung, and the mammary
gland (Nakanishi et al., 1986; Ganser et al., 1991; Sympson MMP-related therapies in the treatment of reproductive dys-
function.et al., 1994; Witty et al., 1995b). Genetic ablation of the MMP-
3 (J.S.Mudgett et al., unpublished), MMP-7 (C.L.Wilson et al.,
unpublished), and MMP-12 (Shipley et al., 1996) genes, how-
Acknowledgments
ever, have revealed no apparent defects in embryonic develop-
The authors wish to thank G.D.Bryant-Greenwood, T.E.Curry, Jr.,
ment or adult organ remodelling. Mutation of the endogenous
S.J.Fisher, E.Marbaix, J.S.Mudgett, K.Osteen, and L.A.Salamonsen
α-1(I) chain of collagen, resulting in resistance to collagenase
for sharing manuscripts in preparation, submitted, and in press.
digestion, also has no effect on embryonic development,
Work in the authors’ laboratory is supported by grants from the
although it hinders post-partum involution of the uterus (Liu
NIH (CA46843, CA60867) and the U.S. Department of Defense
(DAMD17-94-J-4448). D.L.H. Is supported by a postdoctoral fellow-
et al., 1995). Generation of mice deficient in more than one
ship from the NIH (5-T32-CA09592) and L.A.R. is supported by a
MMP will be required to clarify the role of these enzymes
predoctoral fellowship from the D.O.D. (DAMD17-94-J-4226).
in embryonic development, as well as in reproductive organ
structure and function.
Evidence for MMP involvement in differentiation comes
References
primarily from studies with mammary epithelial cells. As eleg-
Abramson, S.R., Conner, G.E., Nagase, H. et al. (1995) Characterization of
antlydemonstrated by Lietal. (1987)andLinand Bissell(1993),
rat uterine matrilysin and its cDNA. Relationship to human pump-1 and
activation of procollagenases. J. Biol. Chem.,270, 16016–16022.
BM and ECM components possess information critical to the
Agarwal, C., Hembree, J.R., Rorke, E.A. and Eckert, R.L. (1994) Transforming
differentiatedfunction ofthesecells. Asmentionedearlier,trans-
growth factor β-1 regulation of metalloproteinase production in cultured
genicmicethatoverexpressMMP-3 in the mammary gland have
human cervical epithelial cells. Cancer Res.,54, 943–949.
Aimes, R.T. and Quigley, J.P. (1995) Matrix metalloproteinase-2 is an
altered BM structure, and the mammary ducts of virgin females
interstitial collagenase. Inhibitor-free enzyme catalyzes the cleavage of
show increased proliferation and differentiation into alveoli
collagen fibrils and soluble native type I collagen generating the specific
which express β-casein, a milk protein usually expressed during
3
4
- and
1
4
-length fragments. J. Biol. Chem.,270, 5872–5876.
pregnancy (Sympson et al., 1994; Witty et al., 1995b). MMP
Allan, J.A., Hembry, R.M., Angal, S. et al. (1991) Binding of latent and high
M
r
active forms of stromelysin to collagen is mediated by the C-terminal
expression may therefore contribute indirectly to changes in the
domain. J. Cell Sci., 99, 789–795.
differentiation state of reproductive and other tissues by its
Andersson, L.M., Dundas, S.R., O’Hare, M.J. et al. (1994) Synthesis of
ability to alter BM and ECM composition.
gelatinases by rat mammary epithelial and myoepithelial cell lines. Exp.
Cell Res.,212, 389–392.
Conclusions and future directions
Angel, P., Baumann, I., Stein, B. et al. (1987) 12-O-tetradecanoyl-phorbol-
13-acetate induction of the human collagenase gene is mediated by an
Reproductive organs respond to complex hormonal signals in
inducible enhancer element located in the 59-flanking region. Mol. Cell.
the adult animal, resulting in alterations in shape, size, and
Biol.,7, 2256–2266.
Anichini, E., Fibbi, G., Pucci, M. et al. (1994) Production of second messengers
function. This review focused on the MMPs as potential medi-
following chemotactic and mitogenic urokinase-receptor interaction in
atorsof thesephysiological changes.MMPsare highlyexpressed
human fibroblasts and mouse fibroblasts transfected with human urokinase
in many reproductive organs and their expression pattern
receptor. Exp. Cell Res.,213, 438–448.
Anuradha, P. and Thampan, R.V. (1993) Hormonal regulation of rat uterine
changes with variations in hormonal and functional status. This
collagenase. Arch. Biochem. Biophys.,303, 81–89.
is particularly evident in the cycling endometrium and post-
Aston, K.E., Stamouli, A., Thomas, E.J. et al. (1996) Effect of gonadotrophin
partum uterus, where the production of many MMP family
on cell and matrix retention and expression of metalloproteinases and their
members rises with a decrease in circulating progesterone con-
inhibitor in cultured human granulosa cells modelling corpus luteum
function. Mol. Hum. Reprod.,2, 26–30.
centrations.The effect of hormones on MMP expressionis often
Autio-Harmainen, H., Hurskainen, T., Niskasaari, K. et al. (1992) Simultaneous
indirect, acting through modifications in local concentrations of
expression of 70 kilodalton type IV collagenase and type IV collagen α-
growth factors or cytokines, or perhaps through a more general
1(IV) chain genes by cells of early human placenta and gestational
endometrium. Lab. Invest.,67, 191–200.
modulation of the differentiation state of the tissue. The MMPs
Baragi, V.M., Fliszar, C.J., Conroy, M.C. et al. (1994) Contribution of the
may then alter the structure and function of the reproductive
C-terminal domain of metalloproteinases to binding by tissue inhibitor of
organ. This can be manifest by extensive tissue loss or destruc-
metalloproteinases. C-terminal truncated stromelysin and matrilysin exhibit
tion, such as that seen in menstruation or involution. In other
equally compromised binding affinities as compared to full-length
stromelysin. J. Biol. Chem.,269, 12692–12697.
cases,MMPproductionisassociated with cell growth, such as in
Bass, K.E., Morrish, D., Roth, I. et al. (1994) Human cytotrophoblast invasion
theproliferative endometrium, andduringductalmorphogenesis
is up-regulated by epidermal growth factor: evidence that paracrine factors
and lobuloalveolar development of the mammary gland. The
modify this process. Dev. Biol.,164, 550–561.
Behrendtsen, O., Alexander, C.M. and Werb, Z. (1992) Metalloproteinases
diverse effects of MMPs on cellular growth, apoptosis, and
40
Matrix metalloproteinases in reproductive tissues
mediate extracellular matrix degradation by cells from mouse blastocyst Curry, T.E., Jr., Mann, J.S., Huang, M.H. and Keeble, S.C. (1992) Gelatinase
and proteoglycanase activity during the periovulatory period in the rat.outgrowth. Development,114, 447–456. Biol. Reprod.,46, 256–264.
Benirschke, K. and Kaufmann, P. (1990) Pathology of the human placenta. In
Benirschke, K. and Kaufmann, P. (eds), Placental Membranes. Springer Curry, T.E. Jr., Sanders, S.L., Pedigo, N.G. et al. (1988) Identification and
Verlag, New York, pp. 130–179. characterization of metalloproteinase inhibitor activity in human ovarian
follicular fluid. Endocrinology,123, 1611–1618.
Birkedal-Hansen, H., Moore, W.G.I., Bodden, M.K. et al. (1993) Matrix
metalloproteinases: a review. Crit. Rev. Oral Biol. Med.,4, 197–250. DeClerck, Y.A., Yean, T.-D., Lee, Y. et al. (1993) Characterization of the
functional domain of tissue inhibitor of metalloproteinases-2 (TIMP-2).
Blair, H.C., Teitelbaum, S.L., Ehlich, L.S. and Jeffrey, J.J. (1986) Collagenase Biochem. J.,289, 65–69.
production by smooth muscle: correlation of immunoreactive with functional
enzyme in the myometrium. Cell. Phys.,129, 111–123. Delany, A.M. and Brinckerhoff, C.E. (1992) Post-transcriptional regulation of
collagenase and stromelysin gene expression by epidermal growth factor
Blasi, F., Behrendt, N., Cubellis, M.V. et al. (1990) The urokinase receptor and dexamethasone in cultured human fibroblasts. J. Cell. Biochem.,50,
and regulation of cell surface plasminogen activation. Cell Differ. Dev.,32, 400–410.
247–254. Dickson, S.R. and Warburton, M.J. (1992) Enhanced synthesis of gelatinase
Boudreau, N., Sympson, C.J., Werb, Z. and Bissell, M.J. (1995) Suppression and stromelysin by myoepithelial cells during involution of the rat mammary
of ICE and apoptosis in mammary epithelial cells by extracellular matrix. gland. J. Histochem. Cytochem.,40, 697–703.
Science,267, 891–893. Docherty, A.J., Lyons, A., Smith, B.J. et al. (1985) Sequence of human tissue
Boujrad, N., Ogwuegbu, S.O., Garnier, M. et al. (1995) Identification of a inhibitor of metalloproteinases and its identity to erythroid-potentiating
stimulator of steroid hormone synthesis isolated from testis. Science,268, activity. Nature,318, 66–69.
1609–1612. Draper, D., McGregor, J., Hall, J. et al. (1995) Elevated protease activities in
Brenner, C., Adler, R., Rappolee, D. et al. (1989) Genes for extracellular- human amnion and chorion correlate with preterm premature rupture of
matrix-degrading metalloproteinases and their inhibitors, TIMPs, are membranes. Am. J. Obst. Gyn.,173, 1506–1512.
expressed during early mammalian development. Genes Dev.,6, 848–859. Endo, T., Aten, R.F., Wang, F. and Behrman, H.R. (1993) Coordinate induction
Brenner, R.M., Rudolph, L.A., Matrisian, L.M. and Slayden, O.D. (1996) and activation of metalloproteinase and ascorbate depletion in structural
Nonhuman primate models: Artificial menstrual cycles, endometrial matrix luteolysis. Endocrinology,133, 690–698.
metalloproteinases and subcutaneous endometrial grafts. Hum. Reprod.,11,
in press. Fang, Z., Marti, A., Jehn, B. et al. (1995) Glucocorticoid of progesterone
inhibit involution and programmed cell death in the mouse mammary
Bresnahan, P.A., Leduc, R., Thomas, L. et al. (1990) Human fur gene encodes gland. J. Cell. Biol.,131, 1095–1103.
a yeast KEX2-like endoprotease that cleaves pro-beta-NGF in vivo.J. Cell.
Biol.,111, 2851–2859. Fernandez, P., Merino, M., Nogales, F. et al. (1992) Immunohistochemical
and profile of basement membrane proteins and 72 kilodalton type IV
Brooks, P.C., Montgomery, A.M.P., Rosenfeld, M. et al. (1994) Integrin I
v
J
3
collagenase in the implantation placental site. Lab. Invest.,66, 572–579.
antagonists promote tumor regression by inducing apoptosis of angiogenic
blood vessels. Cell,79, 1157–1164. Fridman, R., Fuerst, T.R., Bird, R.E. et al. (1992) Domain structure of human
72-kDa gelatinase/type IV collagenase. Characterization of proteolytic
Bruner, K.L., Rodgers, W.H., Gold, L.I. et al. (1995) Transforming growth activity and identification of the tissue inhibitor of metalloproteinase-2
factor beta mediates the progesterone suppression of an epithelial (TIMP-2) binding regions. J. Biol. Chem.,267, 15398–15405.
metalloproteinase by adjacent stroma in the human endometrium. Proc.
Natl. Acad. Sci. USA,92, 7362–7366. Gack, S., Vallon, R., Schmidt, J. et al. (1995) Expression of interstitial
collagenase during skeletal development of the mouse is restricted to
Brunner, T., Mogil, R.J., LaFace, D. et al. (1995) Cell-autonomous Fas osteoblast-like cells and hypertrophic chondrocytes. Cell Grow. Diff.,6,
(CD95)/Fas-ligand interaction mediates activation-induced apoptosis in T- 759–767.
cell hybridomas. Nature,373, 441–444. Gaire, M., Magbanua, Z., McDonnell, S. et al. (1994) Structure and expression
Bryant-Greenwood, G.D. (1982) Relaxin as a new hormone. Endo. Rev.,3, of the human gene for the matrix metalloproteinase matrilysin. J. Biol.
62–90. Chem.,269, 2032–2040.
Bryant-Greenwood G.D. and Greenwood F.C. (1988) The human fetal Ganser, G.L., Stricklin, G.P. and Matrisian, L.M. (1991) EGF and TGFalpha
membranes and decidua as a model for paracrine interactions. In McNellis, influence in vitro lung development by the induction of matrix-degrading
D., Challis, J.R.G., MacDonald, P.C. et al. (eds), The Onset of Labor: metalloproteinases. Int. J. Dev. Biol,,35, 1–8.
Cellular and Integrative Mechanisms. Perinatology Press, New York, pp.
253–273. Gearing, A.J.H., Beckett, P., Christodoulou, M. et al. (1994) Processing of
tumour necrosis factor-αprecursor by metalloproteinases. Nature,370,
Bryant-Greenwood, G.D. and Yamamoto, S.Y. (1995) Control of peripartal 555–557.
collagenolysis in the human chorion-decidua. Am. J. Obst. Gyn.,172,63–70. Graham, C.H., Hawley, T.S., Hawley, R.G. et al. (1993) Establishment and
Bulmer, J.N., Hollings, D. and Ritson, A. (1987) Immunocytochemical characterization of first trimester human trophoblast cells with extended
evidence that endometrial stromal granulocytes are granulated lymphocytes. lifespan. Exp. Cell Res.,206, 204–211.
J. Pathol.,153, 281–288. Graham, C.H. and Lala, P.K. (1991) Mechanism of control of trophoblast
Butler, T.A., Zhu, C., Mueller, R.A. et al. (1991) Inhibition of ovulation in invasion in situ. J. Cell. Physiol.,148, 228–234.
the perfused rat ovary by the synthetic collagenase inhibitor SC 44463.
Biol. Reprod.,44, 1183–1188. Gronemeyer, H. (1991) Transcription activation by estrogen and progesterone
receptors. Ann. Rev. Genet.,25, 89–123.
Canete-Soler, R., Gui, Y.H., Linask, K.K. and Muschel, R.J. (1995)
Developmental expression of MMP-9 (gelatinase B) mRNA in mouse Hampton, A.L., Butt, A.R., Riley, S.C. and Salamonsen, L.A. (1995) Tissue
embryos. Dev. Dynamics,204, 30–40. inhibitors of metalloproteinases in endometrium of ovariectomized steroid-
treated ewes and during the estrous cycle and early pregnancy. Biol.
Casslen, B., Urano, S. and Ny, T. (1992) Progesterone regulation of Reprod.,53, 302–311.
plasminogen activator inhibitor 1 (PAI-1) antigen and mRNA levels in
human endometrial stromal cells. Thromb. Res.,66, 75–87. Hampton, A.L. and Salamonsen, L.A. (1994) Expression of messenger
ribonucleic acid encoding matrix metalloproteinases and their tissue
Chun, S.-Y., Popliker, M., Reich, R. and Tsafriri, A. (1992) Localization of inhibitors is related to menstruation. J. Endocrinol.,141, R1–R3.
preovulatory expression of plasminogen activator inhibitor type-1 and tissue
inhibitor of metalloproteinase type-1 mRNAs in the rat ovary. Biol. Reprod.,Harkness, R.D. and Moralee, B.E. (1956) The time course and route of loss
47, 245–253. of collagen from the rat’s uterus during post-partum involution. J. Physiol.,
132, 502–508.
Clark D.A. (1992) Cytokines in uterine bleeding. In Alexander, N.J. and
d’Arcangues, C. (eds), Steroid hormones and uterine bleeding. American Harvey, M.B., Leco, K.J., Arcellana-Panlilio, M.Y. et al. (1995a) Proteinase
Association for the Advancement of Science, Washington, pp. 263–275. expression in early mouse embryos is regulated by leukaemia inhibitory
factor and epidermal growth factor. Development,12, 1005–1014.
Crawford, H.C. and Matrisian, L.M. (1996) Mechanisms controlling the
transcription of matrix metalloproteinase genes in normal and neoplastic Harvey, M.B., Leco, K.J., Arcellana-Panlilio, M.Y. et al. (1995b) Roles of
cells. Enz. Prot.,49, 20–37. growth factors during peri-implantation development. Hum. Reprod.,10,
712–718.
Cross, J.C., Werb, Z., and Fisher, S.J. (1994) Implantation and the Placenta:
Key Pieces of the Development Puzzle. Science,266, 1508–1518. Hayakawa, T., Yamashita, K., Ohuchi, E. and Shinagawa, A. (1994) Cell
growth-promotingactivity of tissue inhibitorof metalloproteinases-2 (TIMP-Cunha, G.R., Donjacour, A.A., Cooke, P.S. et al. (1987) The endocrinology
and developmental biology of the prostate. Endo. Rev.,8, 338–362. 2). J. Cell Sci.,107, 2373–2379.
41
D.L.Hulboy
et al.
Higuchi, T., Kanzaki, H., Nakayama, H. et al. (1995) Induction of tissue Lefebvre, O., Regnier, C., Chenard, M. et al. (1995) Developmental expression
of mouse stromelysin-3 mRNA. Development,12, 947–955.inhibitor of metalloproteinase-3 gene expression during in vitro
decidualization of human endometrial stromal cells. Endocrinology,136, Lehtovirta, J. and Vartio, T. (1994) Type IV collagenases in human amniotic
4973–4981. fluids and amnion epithelial cells. Biochim. Biophys. Acta (Protein Struct.
Mol. Enzymol.),1206, 83–89.
Hirose, T., Patterson, C., Pourmotabbed, T. et al. (1993) Structure–function
relationship of human neutrophil collagenase: Identification of regions Lei, H., Vadillo-Ortega, F., Paavola, L.G. and Strauss, J.F., III (1995) 92-kDa
responsible for substrate specificity and general proteinase activity. Proc. gelatinase (matrix metalloproteinase-9) is induced in rat amnion immediately
Natl. Acad. Sci. USA,90, 2569–2573. prior to parturition. Biol. Reprod.,53, 339–344.
Huhtala, P., Chow, L.T. and Tryggvason, K. (1990) Structure of the human Levi, E., Fridman, R., Miao, H.-Q. et al. (1996) Matrix metalloproteinase 2
type IV collagenase gene. J. Biol. Chem.,265, 11077–11082. releases active soluble ectodomain of fibroblast growth factor receptor 1.
Proc. Natl. Acad. Sci. USA,93, 7069–7074.
Ingber, D.E. (1990) Fibronectin controls capillary endothelial cell growth by
modulating cell shape. Proc. Natl. Acad. Sci. USA,87, 3579–3583. Li, M.L., Aggeler, J., Farson, D.A. et al. (1987) Influence of a reconstituted
basement membrane and its components on casein gene expression and
Irwin, J.C., Kirk, D., Gwatkin, R.B.L. et al. (1996) Human endometrial matrix secretion in mouse mammary epithelial cells. Proc. Natl. Acad. Sci. USA,
metalloproteinase-2, a putative menstrual proteinase. J. Clin. Invest.,97, 84, 136–140.
438–447. Li, F., Strange, R., Friis, R.R. et al. (1994) Expression of stromelysin-1 and
Jeffrey, J.J. and Gross, J. (1970) Collagenase from rat uterus. Isolation and TIMP-1 in the involuting mammary gland and in early invasive tumors of
partial characterization. Biochemistry,9, 268–273. the mouse. Int. J. Cancer,59, 560–568.
Jeffrey, J.J., Coffey, R.J. and Eisen, A.Z. (1971) Studies on uterine collagenase Librach, C.L., Werb, Z., Fitzgerald, M.L. et al. (1991) 92-kD Type IV
in tissue culture. II. Effect of steroid hormones on enzyme production. collagenase mediates invasion of human cytotrophoblasts. J. Cell Biol.,
Biochim. Biophys. Acta,252, 143–149. 113, 437–449.
Jeffrey, J.J., Ehlich, L.S. and Roswit, W.T. (1991) Serotonin: an inducer of Librach, C.L., Feigenbaum, S.L., Bass, K.E. et al. (1994) Interleukin-1β
collagenase in myometrial smooth muscle cells. J. Cell. Physiol.,146, regulates human cytotrophoblast metalloproteinase activity and invasion
399–406. in vitro.J. Biol. Chem.,269, 17125–17131.
Jeziorska, M., Nagase, H., Salamonsen, L.A. and Woolley, D.E. (1996) Lin, C.Q. and Bissell, M.J. (1993) Multi-faceted regulation of cell
Immunolocalisation of the matrix metalloproteinases genatinase B and differentiation by extracellular matrix. FASEB J.,7, 737–743.
stromelysin-1 in human endometrium throughout the menstrual cycle.
J. Reprod. Fertil.,107, 43–51. Lipner H. (1988) Mechanism of mammalian ovulation. In Knobil, E. and
Neill, J.D. (eds), The Physiology of Reproduction. Raven Press, New York,
Jonat, C., Rahmsdorf, H.J., Park, K.-K. et al. (1990) Anti-tumor promotion pp. 447–488.
and anti-inflammation: down-modulation of AP-1 (Fos/Jun) activity by
glucocorticoid hormone. Cell,62, 1189–1204. Liu, X., Wu, H., Byrne, M. et al. (1995) A targeted mutation at the known
collagenase cleavage site in mouse type I collagen impairs tissue remodeling.
Ju, S., Panka, D.J., Cui, H. et al. (1995) Fas (CD95)/FasL interactions required J. Cell. Biol.,130, 227–237.
for programmed cell death after T-cell activation. Nature,373, 444–448. Lubahn, D.B., Moyer, J.S., Golding, T.S. et al. (1993)Alteration of reproductive
Juengel, J.L., Garverick, H.A., Johnson, A.L. et al. (1993) Apoptosis during function but not prenatal sexual development after insertional disruption of
luteal regression in cattle. Endocrinology,132, 249–254. the mouse estrogen receptor gene. Proc. Natl. Acad. Sci. USA,90,
Juengel, J.L., Smith, G.W., Smith, M.F. et al. (1994) Pattern of protein 11162–11166.
production by bovine corpora lutea during luteolysis and characterization Mann, J.S., Kindy, M.S., Hyde, J.F. et al. (1993) Role of protein synthesis,
of expression of two major secretory products of regressing corpora lutea. prostaglandins and estrogen in rat ovarian metalloproteinase inhibitor
J. Reprod. Fertil.,100, 515–520. production. Biol. Reprod.,48, 1006–1013.
Kastner, P., Krust, A., Turcotte, B. et al. (1990) Two distinct estrogen- Marbaix, E., Donnez, J., Courtoy, P.J. and Eeckhout, Y. (1992) Progesterone
regulated promoters generate transcripts encoding the two functionally regulates the activity of collagenase and related gelatinases A and B in
different human progesterone receptor forms A and B. EMBO J.,9, human endometrial explants. Proc. Natl. Acad. Sci. USA,89, 11789–11793.
1603–1614. Marbaix, E., Kokorine, I., Henriet, P. et al. (1995) The expression of interstitial
Kayagaki, N., Kawasaki, A., Ebata, T. et al. (1995) Metalloproteinase- collagenase in human endometrium is controlled by progesterone and by
mediated release of human Fas ligand. J. Exp. Med.,182, 1777–1783. oestradiol and is related to menstruation. Biochem. J., 1027–1030.
Kerr, J.F., Wyllic, A.H. and Curric, A.R. (1972) Apoptosis: a basic biological Marbaix, E., Kokorine, I., Moulin, P. et al. (1996) Menstrual breakdown of
phenomenon with wide-ranging implications in tissue kinetics. Br. human endometrium can be mimicked in vitro and is selectively and
J. Cancer,26, 239–244. reversibly blocked by inhibitors of matrix metalloproteinases. Proc. Natl.
Kerr, L.D., Miller, D.B. and Matrisian, L.M. (1990) TGF-beta-1 inhibition of Acad. Sci. USA,93, 9120–9125.
transin-stromelysin gene expression is mediated through a fos binding Marcotte, P.A., Kozan, I.M., Dorwin, S.A. and Ryan, J.M. (1992) The matrix
sequence. Cell,61, 267–278. metalloproteinase pump-1 catalyzes formation of low molecular weight
Kleissl, H.P., Van der Rest, M., Naftolin, F. et al. (1978) Collagen changes in (pro)urokinase in cultures of normal human kidney cells. J. Biol. Chem.,
the human uterine cervix at parturition. Am. J. Obstet. Gynecol.,130, 267, 13803–13806.
748–753. Martelli, M., Campana, A. and Bischof, P. (1993) Secretion of matrix
Kokorine, I., Marbaix, E., Henriet, P. et al. (1996) Focal cellular origin and metalloproteinases by human endometrial cells in vitro.J. Reprod. Fertil.,
regulation of interstitial collagenase (matrix metalloproteinase-1) are related 98, 67–76.
to menstrual breakdown in the human endometrium. J. Cell Sci.,109, Marti, A., Jehn, B., Costello, E. et al. (1994) Protein kinase A and AP-1 (c-
2151–2160. Fos/JunD) are induced during apoptosis of mouse mammary epithelial
Konig, H., Ponta, H., Rahmsdorf, H.J. and Herrlich, P. (1992) Interference cells. Oncogene,9, 1213–1223.
between pathway-specific transcription factors: glucocorticoids antagonize Martinez-Hernandez, A., Fink, L.M. and Pierce, G.B. (1976) Removal of
phorbol ester-induced AP-1 activity without altering AP-1 site occupation basement membrane in the involuting breast. Lab. Invest.,31, 455–462.
in vivo.EMBO J.,11, 2241–2246. Masuhiro, K., Matsuzaki, N., Nishino, E. et al. (1991) Trophoblast-derived
Kyprianou, N. and Isaacs, J.T. (1988) Activation of programmed cell death interleukin-1 (IL-1) stimulates the release of human chorionic gonadotropin
in the rat ventral prostate after castration. Endocrinology,122, 552–562. by activating IL-6 and IL-6-receptor system in first trimester human
Lala, P.K. and Graham, C.H. (1991) Mechanisms of trophoblast invasiveness trophoblasts. J. Clin. Endocrinol. Metab.,72, 594–601.
and their control: the role of proteases and protease inhibitors. Cancer Matrisian, L.M. (1990) Metalloproteinases and their inhibitors in matrix
Metastasis Rev.,148, 228–234. remodeling. TIG,6, 121–125.
Lanzrein, M., Garred, O., Olsnes, S. and Sandvig, K. (1995) Diphtheria toxin Matrisian, L.M. and Hogan, B.L.M. (1990) Growth factor-regulated proteases
endocytosis and membrane translocation are dependent on the intact and extracellular matrix remodeling during mammalian development. Curr.
membrane-anchored receptor (HB-EGF precursor): studies on the cell- Top. Dev. Biol.,24, 219–259.
associated receptor cleaved by a metalloprotease in phorbol-ester-treated
cells. Biochem J.,310, 285–289. Matrisian, L.M., Glaichenhaus, N., Gesnel, M.C. and Breathnach, R. (1985)
Epidermal growth factor and oncogenes induce transcription of the same
Lefebvre, O., Wolf, C., Limacher, J.-M. et al. (1992) The breast cancer- cellular mRNA in rat fibroblasts. EMBO J.,4, 1435–1440.
associated stromelysin-3 gene is expressed during mouse mammary gland
apoptosis. J. Cell Biol.,119, 997–1002. Mattot, V., Raes, M.B., Henriet, P. et al. (1995) Expression of interstitial
42
Matrix metalloproteinases in reproductive tissues
collagenase is restricted to skeletal tissue during mouse embryogenesis. A and B and their tissue inhibitors by cells of early and term human
placenta and gestational endometrium. Lab. Invest.,71, 838–846.J. Cell Sci.,108, 529–535. Powell W.C. and Matrisian L.M. (1996) Complex roles of matrix
McDonnell, S.E., Kerr, L.D. and Matrisian, L.M. (1990) Epidermal growth metalloproteinases in tumor progression. In Gunthert, U. and Birchmeier,
factor stimulation of stromelysin mRNA in rat fibroblasts requires induction W. (eds), Attempts to Understand Metastasis Formation I: Metastasis-
of proto-oncogenes c-fos and c-jun and activation of protein kinase C. Mol. Related Molecules. Springer-Verlag, Berlin, pp. 1–21.
Cell. Biol.,10, 4284–4293. Powell, W.C., Dormann, F.E., Jr., Michen, J.M. et al. (1996) Matrilysin
McGowan, K.A., Bauer, E.A. and Smith, L.T. (1994) Localization of type I expression in the involuting rat ventral prostate. Prostate,29, 159–168.
human skin collagenase in developing embryonic and fetal skin. J. Invest.
Dermatol.,102, 951–957. Puente, X.S., Pendas, A.M., Llano, E. et al. (1996) Molcular cloning of
a novel membrane-type matrix metalloproteinase from a human breast
McGregor, J. and French, J. (1992) Use of antibiotics for preterm premature carcinoma. Cancer Res.,56, 944–949.
rupture of membranes. Rationales and results. Obstet. Gynecol. Clin. North
Am.,19, 327–338. Puistola, U., Salo, T., Martikainen, H. and Ronnberg, L. (1986) Type IV
collagenolytic activity in human preovulatory follicular fluid. Fertil. Steril.,
Monteagudo, C., Merino, M., San-Juan, J. et al. (1990) Immunohistochemical 45, 578–580.
distribution of type IV collagenase in normal, benign and malignant breast Puistola, U., Ronnberg, L., Martikainen, H. and Turpeenniemi-Hujanen, T.
tissue. Am. J. Pathol.,136, 585–592. (1989) The human embryo produces basement membrane collagen (type
Montgomery, A.M.P., Reisfeld, R.A. and Cheresh, D.A. (1994) Integrin I
v
J
3
IV collagen)-degrading protease activity. Hum. Reprod.,4, 309–311.
rescues melanoma cells from apoptosis in a three-dimensional dermal Pullan, S., Wilson, J., Metcalfe, A. et al. (1996) Requirement of basement
collagen. Proc. Natl. Acad. Sci. USA,91, 8856–8860. membrane for the suppression of programmed cell death in mammary
Morgan, A., Keeble, S.C., London, S.N. et al. (1994) Antiprogesterone epithelium. J. Cell Science, 109, 631–642.
(RU486) effects on metalloproteinase inhibitor activity in human and rat Quantin, B. and Breathnach, R. (1988) Epidermal growth factor stimulates
granulosa cells. Fertil. Steril.,61, 949–955. transcription of the c-jun proto-oncogene in rat fibroblasts. Nature, 334,
Muller, R., Bravo, R., Burckhardt, J. and Curran, T. (1984) Induction of c- 538–539.
fos gene and protein by growth factor procedes activation of c-myc. Nature,Rajabi, M.R. and Singh, A. (1995) Cell origin and paracrine control of
312, 716–720. interstitial collagenase in the guinea pig uterine cervix. Evidence for a
Murdoch, W.J. and McCormick, R.J. (1992) Enhanced degradation of collagen low molecular weight epithelial cell-derived collagenase stimulator. Biol.
within apical vs. basal wall of ovulatory ovine follicle. Am. J. Physiol.,Reprod.,52, 516–523.
263, 221–225. Rajabi, M., Dean, D.D. and Woessner, J.F. Jr. (1985) Serum collagenase
Murphy, G., Segain, J.-P., O’Shea, M. et al. (1993) The 28-kDa N-terminal activity in pregnant, parturient and post-partum women. Ann. N.Y. Acad.
domain of mouse stromelysin-3 has the general properties of a weak Sci.,460, 492–493.
metalloproteinase. J. Biol. Chem.,268, 15435–15441. Rajabi, M.R., Dean, D.D., Beydoun, S.N. and Woessner, J.F. Jr. (1988)
Murray, S.C., Keeble, S.C., Muse, K.N. and Curry, T.E. Jr. (1996) Prolactin Elevated tissue levels of collagenase during dilation of uterine cervix in
regulation of granulosa cell-derived ovarian metalloproteinase inhibitor(s). human parturition. Am. J. Obstet. Gynecol.,159, 971–976.
J. Reprod. Fertil., in press. Rajabi, M.R., Dodge, G.R., Solomon, S. and Robin, A. (1991a)
Mushayandebvu, T.I. and Rajabi, M.R. (1995) Relaxin stimulates interstitial Immunochemical and immunohistochemical evidence of estrogen-mediated
collagenase activity in cultured uterine cervical cells from nonpregnant and collagenolysis as a mechanism of cervical dilatation in the guinea pig at
pregnant but not immature guinea pigs; Estradiol-17Beta restores relaxin’s parturition. Endocrinology,128, 371–378.
effect in immature cervical cell. Biol. Reprod.,53, 1030–1037. Rajabi, M.R., Solomon, S. and Poole, A.R. (1991b) Biochemical evidence of
Nakanishi, Y., Sugiura, F., Kishi, J.-I. and Hayakawa, T. (1986) Collagenase collagenase–mediated collagenolysis as a mechanism of cervical dilatation
inhibitor stimulates cleft formation during early morphogenesis of mouse at parturition in the guinea pig. Biol. Reprod.,45, 764–772.
salivary gland. Dev. Biol.,113, 201–206. Rawdanowicz, T.J., Hampton, A.L., Nagase, H. et al. (1994) Matrix
Nephew, K.P., Tang, M. and Khan, S.A. (1994) Estrogen differentially affects metalloproteinase production by cultured human endometrial stromal cells:
c-jun expression in uterine tissue compartments. Endocrinology,134, Identification of interstitial collagenase, gelatinase-A, gelatinase-B and
1827–1834. stromelysin-1 and their differential regulation by interleukin-1αand tumor
Nomura, S., Hogan, B.L.M., Wills, A.J. et al. (1989) Developmental expression necrosis factor-α.J. Clin. Endocrinol. Metab.,79, 530–536.
of tissue inhibitor of metalloproteinase (TIMP) RNA. Development,105, Rechberger, T. and Woessner, J.F. Jr. (1993) Collagenase, its inhibitors and
575–583. decorin in the lower uterine segment in pregnant women. Am. J. Obstet.
Nothnick, W.B.,Edwards, D.R., Leco, K.J. and Curry, T.E. (1995) Expression Gynecol.,168, 1598–1603.
and activity of ovarian tissue inhibitors of metalloproteinases during Reponen, P., Sahlberg, C., Munaut, C. et al. (1994) High expression of 92-
pseudopregnancy in the rat. Biol. Reprod.,53, 684–691. kD type IV collagenase (gelatinase B) in the osteoclast lineage during
Odekon, L.E., Sato, Y. and Rifkin, D.B. (1992) Urokinase-type plasminogen mouse development. J. Cell. Biol.,124, 1091–1102.
activator mediates basic fibroblast growth factor-induced bovine endothelial Reponen, P., Leivo, I., Sahlberg, C. et al. (1995) 92-kDa type IV collagenase
cell migration independent of its proteolytic activity. J. Cell. Physiol.,150, and TIMP-3, but not 72-kDa type IV collagenase or TIMP-1 or TIMP-2,
258–263. are highly expressed during mouse embryo implantation. Dev. Dyn.,202,
Osmers, R., Rath, W., Adelmann-Grill, B.C. et al. (1990) Collagenase activity 388–396.
in the cervix of non-pregnant and pregnant women. Arch. Gynecol. Obstet,,Rodgers, W.H., Osteen, K.G., Matrisian, L.M. et al. (1993) Expression
248, 75–80. and localization of matrilysin, a matrix metalloproteinase, in human
Osmers R., Rath W., Adelmann-Grill B.C. et al. (1991) Collagenase activity endometrium during the reproductive cycle. Am. J. Obstet. Gynecol.,168,
in the human cervix during parturition: the role of polymorphonuclear 253–260.
leukocytes. In Leppert, P.C. and Woessner, J.F., Jr. (eds), The Extracellular Rodgers, W.H., Matrisian, L.M., Giudice, L.C. et al. (1994) Patterns of matrix
Matrix of the Uterus,Cervix and Fetal Membranes: Synthesis,Degradation metalloproteinase expression in cycling endometrium imply differential
and Homonal Regulation. Perinatology Press, New York, pp. 113–118. functions and regulation by steroid hormones. J. Clin. Invest.,94, 946–953.
Osmers, R., Rath, W., Adelmann-Grill, B.C. et al. (1992) Origin of cervical Rudolph L.A. and Matrisian L.M. (1994) Matrix metalloproteinase expression
collagenase during parturition. Am. J. Obst. Gyn.,166, 1455–1460. in murine uterine tissue suggests regulation by steroid hormones. [Abstract.]
Osteen, K.G., Rodgers, W.H., Gaire, M. et al. (1994) Stromal–epithelial in Mammary Gland Gordon Conference, Wolfsboro, N.H., July, 1994.
interaction mediates steroidal regulation of metalloproteinase expression in Russell, D.L., Salamonsen, L.A. and Findlay, J.K. (1995) Immunization
human endometrium. Proc. Natl. Acad. Sci. USA,91, 10129–10133. against the N-terminal peptide of the inhibin Alpha43-subunit (AlphaN)
Panayotou, G., End, P., Aumailley, M., Timpl, R. and Engel, J. (1989) Domains disrupts tissue remodeling and the increase in matrix metalloproteinase-2
of laminin with growth-factor activity. Cell,56, 93–101. during ovulation. Endocrinology,136, 3657–3664.
Pavloff, N., Staskus, P.W., Kishnani, N.S. and Hawkes, S.P. (1992) A new Saarialho-Kere, U.K., Pentland, A.P., Birkedal-Hansen, H. et al. (1994)
inhibitor of metalloproteinases from chicken: ChIMP-3. A third member Distinct populations of basal keratinocytes express stromelysin-1 and
of the TIMP family. J. Biol. Chem.,267, 17321–17326. stromelysin-2 in chronic wounds. J. Clin. Invest.,94, 79–88.
Pei, D. and Weiss, S.J. (1995) Furin-dependent intracellular activation of the Saarialho-Kere, U.K., Crouch, E.C. and Parks, W.C. (1995) The matrix
human stromelysin-3 zymogen. Nature,375, 244–247. metalloproteinase matrilysin is constitutively expressed in adult human
exocrine epithelium. J. Invest. Dermatol.,105, 190–196.Polette, M., Nawrocki, B., Pintiaux, A. et al. (1994) Expression of gelatinases
43
D.L.Hulboy
et al.
Salamonsen, L.A. (1996) Matrix metalloproteinases and their tissue inhibitors Talhouk, R.S., Chin, J.R., Unemori, E.N. et al. (1991) Proteinases of the
mammary gland: developmental regulation in vivo and vectorial secretionin endocrinology. Trends Endocrinol. Metab.,7, 28–34. in culture. Development,112, 439–449.
Salamonsen, L.A. and Woolley, D.E. (1996) Matrix metalloproteinases in
normal menstruation. Hum. Reprod., in press. Talhouk, R.S., Bissell, M.J. and Werb, Z. (1992) Coordinated expression of
extracellular matrix-degrading proteinases and their inhibitors regulates
Salamonsen, L.A., Nagase, H. and Woolley, D.E. (1991) Production of matrix mammary epithelial function during involution. J. Cell Biol.,118, 1271–
metalloproteinase-3 (stromelysin) by cultured ovine endometrial cells. 1282.
J. Cell Sci.,100, 381–385. Tenniswood, M.P., Guenette, R.S., Lakins, J. et al.. (1992) Active cell death
Salamonsen, L.A., Nagase, H., Suzuki, R. and Woolley, D.E. (1993) Production in hormone-dependent tissues. Cancer Metastasis Rev.,11, 197–220.
of matrix metalloproteinase-1 (interstitial collagenase) and matrix
metalloproteinase-2 (gelatinase A: 72 kDa gelatinase) by ovine endometrial Turpeenniemi-Hujanen, T., Ro
¨nnberg, L., Kauppila, A. and Puistola, U. (1992)
Laminin in the human embryo implantation: analogy to the invasion bycells in vitro: Different regulation and preferential expression by stromal
fibroblasts. J. Reprod. Fertil.,98, 583–589. malignant cells. Fertil. Steril.,58, 105–113.
Turpeenniemi-Hujanen, T., Feinberg, R.F., Kauppila, A. and Puistola, U. (1995)Salamonsen, L.A., Hampton, A.L., Suzuki, R. and Nagase, H. (1994)
Modulation of production of matrix metalloproteinases from ovine Extracellular matrix interactions in early human embryos: implications for
normal implantation events. Fertil. Steril.,64, 132–138.endometrial cells by ovine trophoblast interferon. J. Reprod. Fertil.,102,
155–162. Tyree, B., Halme, J. and Jeffrey, J.J. (1980) Latent and active forms of
collagenase in rat uterine explant cultures: regulation of conversion ofSalamonsen, L.A., Nagase, H. and Woolley, D.E. (1995) Matrix
metalloproteinases and their tissue inhibitors at the ovine trophoblast– progestational steroids. Arch. Biochem. Biophys.,202, 314–317.
uterine interface. J. Reprod. Fertil.,103, 29–37. Ulisse, S., Farina, A.R., Piersanti, D. et al. (1994) Follicle-stimulating hormone
increases the expression of tissue inhibitors of metalloproteinases TIMP-1Sang, Q.-X., Dym, M. and Byers, S.W. (1990a) Secreted metalloproteinases
in testicular cell culture. Biol. Reprod.,43, 946–955. and TIMP-2 and induces TIMP-1 AP-1 site binding complex(es) in
prepubertal rat Sertoli cells. Endocrinology, 2479–2487.
Sang, Q.-X., Stetler-Stevenson, W.G., Liotta, L.A. and Byers, S.W. (1990b)
Identification of type IV collagenase in rat testicular cell culture: Influence Vadillo-Ortega, F., Gonzalez-Avila, G., Karchmer, S. et al. (1990) Collagen
metabolism in premature rupture of amniotic membranes. Obstet. Gynecol.,of peritubular-Sertoli cell interactions. Biol. Reprod.,43, 956–964. 75, 84–88.
Sato, H., Takino, T., Okada, Y. et al. (1994) A matrix metalloproteinase
expressed on the surface of invasive tumour cells. Nature,370, 61–64. Vadillo-Ortega, F., Gonzalez-Avila, G., Furth, E.E. et al. (1995) 92-kd type
IV collagenase (matrix metalloproteinase-9) activity in human amniochorion
Schatz, F., Papp, C., Toth-Pal, E. et al. (1994a) In vitro regulation of increases with labor. Am. J. Pathol.,146, 148–156.
stromelysin-1 in human endometrial stromal cells. Ann. N.Y. Acad. Sci.,
732, 479–481. Vagnoni, K.E., Ginther, O.J. and Lunn, D.P. (1995) Metalloproteinase activity
has a role in equine chorionic girdle cell invasion. Biol. Reprod.,53,
Schatz, F., Papp, C., Toth-Pal, E. and Lockwood, C.J. (1994b) Ovarian steroid- 800–805.
modulated stromelysin-1 expression in human endometrial stromal and
decidual cells. J. Clin. Endocrinol. Metab.,78, 1467–1472. Vaux, D.L., Haecker, G. and Strasser, A. (1994) An evolutionary perspective
on apoptosis. Cell,76, 777–779.
Sellers, A. and Woessner, J.F. Jr. (1980) The extraction of a neutral
metalloproteinase from the involuting rat uterus and its action on cartilage Vlodavsky, I.,Korner, G.,Ishai-Michaeli, R. et al. (1990) Extracellular matrix-
resident growth factors and enzymes: possible involvement in tumorproteoglycan. Biochem J.,189, 521–531. metastasis and angiogenesis. Cancer Metastasis Rev.,9, 203–226.
Shapiro, S.D., Griffin, G.L., Gilbert, D.J. et al. (1992) Molecular cloning,
chromosomal location and bacterial expression of a novel murine Warburton, M.J., Ormerod, E.J., Monaghan, P. et al. (1981) Characterization
of a myoepithelial cell line derived from a neonatal rat mammary gland.macrophage metalloelastase. J. Biol. Chem.,267, 4664–4671. J. Cell Biol.,91, 827.
Shi, Y.E., Greene, J., Wang, M. et al. (1996) Loss of expression of TIMP-4,
a novel human tissue inhibitor of metalloproteinase, in human breast Warburton, M.J., Mitchell, D., Ormerod, E.J. and Rudland, P. (1982)
Distribution of myoepithelial cells and basement membrane proteins in thecancer malignantprogression. [Abstract.]Proteases and Protease Inhibitors,
Panama City Beach, FL, March, 1996. resting, pregnant, lactating and involuting rat mammary gland. J. Histochem.
Cytochem.,30, 667–676.
Shimonovitz, S., Hurwitz, A., Dushnik, M. et al. (1994) Developmental
regulation of the expression of 72 and 92 kDa type IV collagenases in Warburton, M.J., Ferns, S.A., Hughes, C.M. et al. (1987) Generation of
cell types with myoepithelial and mesenchymal phenotypes during thehuman trophoblasts: a possible mechanism for control of trophoblast
invasion. Am. J. Obstet. Gynecol.,171, 832–838. conversion of mammary tumor epithelial stem cells into elongated cells.
J. Natl. Cancer Inst.,78, 1191.
Shipley, J.M., Wesselschmidt, R.L., Kobayashi, D.K. et al. (1996)
Metalloelastase is required for macrophage-mediated proteolysis and matrix Waterhouse, P., Denhardt, D.T. and Khokha, R. (1993) Temporal expression
of tissue inhibitors of metalloproteinases in mouse reproductive tissuesinvasion in mice. Proc. Natl. Acad. Sci. USA,93, 3942–3946. during gestation. Mol. Reprod. Dev.,35, 219–226.
Simo
´n, C., Frances, A., Piquette, G.N. et al. (1994) Embryonic implantation
in mice is blocked by interleukin-1 receptor antagonist. Endocrinology, Werb, Z., Alexander, C.M. and Adler, R.R. (1992) Expression and function
of matrix metalloproteinases in development. Matrix Suppl.,1, 337–343.134, 521–528.
Smith, G.W., McCrone, S., Petersen, S.L. and Smith, M.F. (1995) Expression Whitelock, J.M., Murdoch, A.D., Iozzo, R.V. and Underwood, P.A. (1996)
The degradation of human endothelial cell-derived perlecan and release ofof messengerribonucleic acid encodingtissue inhibitorof metalloproteinase-
2 within ovine follicles and corpora lutea. Endocrinology,136, 570–576. bound basic fibroblast growth factor by stromelysin, collagenase, plasmin
and heparanases. J. Biol. Chem., 271, 10079–10086.
Southgate, K.M., Davies, M., Booth, R.F.G. and Newby, A.C. (1992)
Involvement of extracellular-matrix-degrading metalloproteinases in rabbit Wilcox, B.D., Rydelek-Fitzgerald, L. and Jeffrey, J.J. (1992) Regulation of
collagenase gene expression by serotonin and progesterone in rat uterineaortic smooth-muscle cell proliferation. Biochem. J.,288, 93–99. smooth muscle cells. J. Biol. Chem.,267, 20752–20757.
Suda, T., Takahashi, T., Golstein, P. and Nagata, S. (1993) Molecular cloning
and expression of the Fas ligand, a novel member of the tumor necrosis Will, H. and Hinzmann, B. (1995) cDNA sequence and mRNA tissue
distribution of a novel human matrix metalloproteinase with a potentialfactor family. Cell,75, 1169–1178. transmembrane segment. Eur. J. Biochem.,231, 602–608.
Sympson, C.J., Talhouk, R.S., Alexander, C.M. et al. (1994) Targeted
expression of stromelysin-1 in mammary gland provides evidence for a Wilson, C.L. and Matrisian, L.M. (1996) Matrilysin: An epithelial matrix
metalloproteinase with potentially novel functions. Int. J. Biochem. Cellrole of proteinases in branching morphogenesis and the requirement for an
intact basement membrane for tissue-specific gene expression. J. Cell Biol.,Biol.,28, 123–136.
125, 681–693. Wilson, C.L., Heppner, K.J., Rudolph, L.A. and Matrisian, L.M. (1995) The
metalloproteinase matrilysin is preferentially expressed in epithelial cellsTabibzadeh, S. and Sun, X.Z. (1992) Cytokine expression in human
endometrium throughout the menstrual cycle. Hum. Reprod.,7, 1214–1221. in a tissue-restricted pattern in the mouse. Mol. Biol. Cell.,6, 851–869.
Wilson, M.J., Strasser, M., Vogel, M.M. and Sinha, A.A. (1991) Calcium-Tadakuma, H., Okamura, H., Kitaoka, M. et al. (1993) Association of
immunolocalization of matrix metalloproteinase-1 with ovulation in hCG- dependent and calcium-independent gelatinolytic proteinase activities of
the rat ventral prostate and its secretion: characterization and effect oftreated rabbit ovary. J. Reprod. Fertil.,98, 503–508. castration and testosterone treatment. Biol. Reprod.,44, 776–785.
Takino, T., Sato, H., Shinagawa, A. and Seiki, M. (1995) Identification of the
second membrane-type matrix metalloproteinase (MT-MMP-2) gene from Wilson, M.J., Garcia, B., Woodson, M. and Sinha, A.A. (1992)
Metalloproteinase activities expressed during development and maturationa human placenta cDNA library. J. Biol. Chem.,270, 23013–23020.
44
Matrix metalloproteinases in reproductive tissues
of the rat prostatic complex and seminal vesicles. Biol. Reprod.,47,
683–691.
Witty, J.P., Lempka, T., Coffey, R.J. Jr. and Matrisian, L.M. (1995a) Decreased
tumor formation in 7,12-dimethylbenzanthracene-treated stromelysin-1
transgenic mice is associated with alterations in mammary epithelial cell
apoptosis. Cancer Res.,55, 1401–1406.
Witty, J.P., Wright, J. and Matrisian, L.M. (1995b) Matrix metalloproteinases
are expressed during ductal and alveolar mammary morphogenesis and
misregulation of stromelysin-1 in transgenic mice induces unscheduled
alveolar development. Mol. Biol. Cell.,6, 1287–1303.
Woessner, J. and Taplin, C. (1988) Purification and properties of a small
latent matrix metalloproteinase of the rat uterus. J. Biol. Chem.,263,
16918–16925.
Wolfsberg, T.G., Bazan, J.F., Blobel, C.P. et al. (1993) The precursor region
of a protein active in sperm–egg fusion contains a metalloprotease and a
disintegrin domain: structural, functional and evolutionary implications.
Proc. Natl. Acad. Sci. USA,90, 10783–10787.
Wolfsberg, T.G., Straight, P.D., Gerena, R.L. et al. (1995) ADAM, a widely
distributed and developmentally regulated gene family encoding membrane
proteins with A Disintegrin And Metalloproteinase domain. Dev. Biol.,
169, 378–383.
Yagel, S., Geva, T.E., Solomon, H. et al. (1993) High levels of human
chorionic gonadotropin retard first trimester trophoblast invasion in vitro
by decreasing urokinase plasminogen activator and collagenase activities.
J. Clin. Endocrinol. Metab.,77, 1506–1511.
Yang-Yen, H.-F., Chambard, J.-C., Sun, Y.-L. et al. (1990) Transcriptional
interference between c-Jun and the glucocorticoid receptor: mutual
inhibition of DNA binding due to direct protein protein interaction. Cell,
62, 1205–1215.
Received on August 9, 1996; accepted on November 11, 1996
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