Reviews of Reproduction (1998) 3, 23–30

Matrix and tissue inhibitors of metalloproteinases in ovarian function

Eric W. McIntush* and Michael F. Smith

Department of Animal Sciences, University of Missouri-Columbia, Columbia, MO 65211, USA

Growth and ovulation of follicles, and development, maintenance, and regression of the cor- pus luteum depend on cyclical remodelling of the extracellular matrix. The extracellular matrix consists of proteinaceous and non-proteinaceous components and provides the tissue-specific, extracellular architecture to which cells attach, and modulates the activities of cells through cell surface receptors. Specific components of the extracellular matrix are cleaved by matrix metal- loproteinases, the activities of which are inhibited by tissue inhibitors of metalloproteinases. This review presents evidence for the involvement of matrix metalloproteinases and their in- hibitors in extracellular matrix remodelling associated with ovarian function.

The extracellular matrix (ECM) provides the ‘scaffolding’ proteolytic cleavage of an N-terminal peptide. ProMMPs are within a tissue to which cells attach, and contains domains activated in vivo by serine (plasminogen activator and that bind to specific cell surface receptors to modulate cellular kallikriens; Espey, 1992), mast cell proteases (Suzuki et al., activity. Remodelling of the ECM is a prerequisite for many 1995), and other MMPs including plasma membrane MMPs physiological and pathological processes. Examples of ECM (Sato et al., 1994). remodelling by matrix metalloproteinases (MMPs) during The expression of proMMP genes is subject to control during normal physiological processes within the reproductive system transcription, translation and by changes in mRNA stability include follicular growth, ovulation, corpus luteum formation (Fig. 1). Further control points are at the activation of secreted and regression, endometrial remodelling at menstruation, proenzymes by proteolytic cleavage of an N-terminal pro- blastocyst outgrowth, trophoblast invasion, uterine involution, peptide, and the association and dissociation of MMPs with and mammary growth and involution. Examples of MMP in- specific inhibitors (Fig. 1). Another way in which ECM re- volvement in pathological ECM remodelling include wound modelling can be regulated spatially and temporally is illus- healing, osteoarthritis, breast carcinoma, and other forms of trated by the observation that MMP-2 is localized to the plasma tumour cell metastasis. Two families of involved in membrane of invasive cells by association with an integrin remodelling of ECM are the matrix (MMP) (Brooks et al., 1996). family and the plasminogen activator–plasmin family. The role of the plasminogen activator–plasmin family in ovarian func- Tissue inhibitors of metalloproteinases tion has been reviewed by Ny et al. (1993). The focus of the present review is the role of MMPs and tissue inhibitors of Inhibitors of MMP activity include liver-derived, serum borne α metalloproteinases (TIMPs) in ovarian ECM remodelling and 2-macroglobulin and TIMPs. The activities of MMPs are regu- the subsequent effects on ovarian function. lated by a family of TIMPs, which includes TIMP-1, TIMP-2, TIMP-3 and TIMP-4 (Table 2). All TIMPs share 12 cysteine residues which are believed to form six disulfide bonds that Matrix metalloproteinases arrange the molecule into two distinct domains. Despite similar Matrix metalloproteinases are zinc- and calcium-dependent en- structural properties, TIMP-1, -2, -3, and -4 differ in size, glyco- zymes that are largely responsible for degrading ECM proteins sylation, and expression in vitro and in vivo. Although they are (Mignatti and Rifkin, 1993). While sharing certain structural separate gene products, each TIMP inhibits most members of and biochemical properties, individual family members differ the MMP family by noncovalent binding with a 1:1 stoichiom- –9 –1 in their specificity for ECM components. However, all ECM etry and high affinity (Ki value < 10 mol 1 ; Willenbrock and proteins can be degraded by an appropriate complement of Murphy, 1994). MMPs. Twelve members of the MMP family of enzymes have The extent of ECM remodelling depends upon the ratio of been characterized to date (Table 1). Although most MMPs active MMPs to TIMPs. A ratio in favour of MMP activity re- appear to be secreted, two membrane bound MMPs, which sults in ECM degradation, whereas a ratio favouring TIMPs in- preferentially activate MMP-2 ( A), are also known hibits ECM degradation and is permissive for ECM deposition. (Sato et al., 1994; Takino et al., 1995). Matrix metalloproteinases The molecular interactions between TIMPs and MMPs have are secreted as latent proenzymes which are activated by been studied extensively but much less is known about the post-secretory mechanisms regulating the activity of TIMPs. *Present address: Animal Reproduction and Biotechnology Laboratory, Colorado The mechanisms by which MMPs are liberated from complexes State University, Fort Collins, CO 80523, USA. with TIMPs or by which TIMPs are rendered inactive have not © 1998 Journals of Reproduction and Fertility 1359-6004/98 $12.50 Downloaded from Bioscientifica.com at 09/25/2021 11:14:10PM via free access 24 E. W. McIntush and M. F. Smith

Table 1. (MMP) family of mammalian extracellular matrix degrading proteinasesa

Relative molecular massb

Group Name MMP numbers Latent form Active form

Collagenases Interstitial MMP-1 52 000 42 000 56 000 46 000 MMP-8 75 000 65 000 Collagenase 3 MMP-13 53 700 nd 72 kDa Gelatinase MMP-2 72 000 62 000 92 kDa Gelatinase MMP-9 92 000 84 000 Stromelysins Stromelysin 1 MMP-3 56 000 45 000 59 000 28 000 Matrilysin MMP-7 28 000 19 000 MMP-10 60 000 55 000 Stromelysin 3 MMP-11 nd nd Membrane-type MMPs Mt-MMP-1 MMP-14 63 000 nd Mt-MMP-2 MMP-15 ? ? Other Metalloelastase MMP-12 ? ?

aData taken from Kleiner and Stetler-Stevenson, 1993. bData taken from Salamonsen, 1996. nd, not determined. been fully investigated. Factors regulating the function of growth factor binding proteins, including insulin-like growth TIMP-1 include: (1) endothelial-stimulating angiogenesis factor factor binding protein, contain motifs that bind to components (ESAF), a low molecular mass substance that liberates active of the ECM. Growth factors bound to ECM are biologically in- MMP-1 from MMP-1–TIMP-1 complexes (McLaughlin et al., active and must be liberated, and occasionally activated, before 1991); (2) proteinases (Itoh and Nagase, 1995); and (3) peroxyni- binding to receptors (Logan and Hill, 1992). Matrix metallo- trite, a product of superoxide radicals and hydrogen peroxide proteinases have been implicated in the regulation of growth (Frears et al., 1996). factor and cytokine availability in that MMPs degrade insulin- TIMPs are multifunctional molecules that, in addition to in- like growth factor binding protein 3 (Fowlkes et al., 1994) hibiting MMP activity, stimulate proliferation of various cell and release active tumour necrosis factor α by processing its types (Edwards et al., 1996), and stimulate progesterone produc- proform (Gearing et al., 1995; Moss et al., 1997). Interactions tion by steroidogenic cells (Boujrad et al., 1995). The mechanism between components of the ECM and growth factors increase by which TIMPs stimulate cell proliferation is unknown but their stability, concentrate them near the surface of specific may involve plasma membrane receptors (Edwards et al., 1996). cells, protect them from proteolysis, and alter their biological activity (Flaumenhaft and Rifkin, 1992). Therefore, it seems that the regulated proteolytic degradation of the ECM may provide Follicular growth an important mechanism for regulating growth factor avail- Follicular growth requires proliferation of theca and granulosa ability and activity during follicular growth. cells as well as expansion of the basement membrane within the confines of the ovarian stroma. For example, the develop- Ovulation ment of a bovine primordial follicle (diameter = 0.1 mm) into a preovulatory follicle (diameter = 19 mm) requires approxi- The preovulatory gonadotrophin surge initiates a cascade of mately a 36 000-fold increase in follicular surface area. MMPs proteolytic activity within the preovulatory follicular wall that and TIMPs are obvious candidates for modulating the ex- resembles an inflammatory response (Espey, 1992, 1994). The pansion of the follicular basement membrane and ECM apex region of the preovulatory follicular wall consists of remodelling within the theca interna, including during angio- granulosa cells, basement membrane, theca interna, theca ex- genesis. The collagenous components of the ovarian stroma terna, tunica albuginea, and superficial epithelium with its include interstitial (types I and III), whereas underlying basement membrane. The tensile strength of the fol- type IV is the collagenous component of the basement mem- licular wall is determined by its collagen content. After a pre- brane (Luck, 1994). (MMP-1) occurs in ovulatory gonadotrophin surge, ovarian collagenase activity theca and granulosa cells at all stages of follicular growth from increases (Curry et al., 1985; Hirsch et al., 1993) and collagen primordial to Graafian follicles (Tadakuma et al., 1993). degradation is greatest in the apical region of the preovulatory Growth factors participate in the proliferation and differen- follicular wall (Murdoch and McCormick, 1992). Within the tiation of ovarian follicular cells and are often constitutively ex- stigma region, proteolytic degradation of collagenous fibres pressed (Logan and Hill, 1992). Growth factors, including progressively weakens the follicular wall and this, in con- fibroblast growth factor, transforming growth factor β, platelet junction with moderate and constant intrafollicular pressure, derived growth factor and hepatocyte growth factor, and culminates in follicular rupture (Espey, 1994).

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Activators tPA uPA 1 Plasminogen

Plasmin 2 mRNA MMP proMMP 4 3

proMMP mtMMP Inhibitors 5 TIMPs α 2-MG

6 MMP-2 ECM

Fig. 1. Pathways for matrix metalloproteinase (MMP) production, activation and inhibition during remodelling of the extracellular matrix (ECM). The production of MMPs is regulated at gene activation and transcription (1), stability of mRNA (2) and translation of mRNA encoding pro-MMPs (3). Activation of proMMPs (4) involves proteolytic processing by plasmin generated by serum-derived plasminogen from locally produced activators, tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA). Proteolytically active MMPs (proMMPs) and membrane bound MMPs (membrane type MMPs, mtMMP) also activate proMMPs. MMPs degrade the pro- teinaceous components of the extracellular matrix (ECM) and the degree of ECM degradation is regulated primarily by locally produced in- α α hibitors (5), including tissue inhibitors of metalloproteinases (TIMPs) and, possibly, the serum-derived inhibitor 2-macroglobulin ( 2-MG). Degradation of the ECM can be localized to the cell surface by the association of MMP-2 with an integrin (6).

Role of matrix metalloproteinases membranes underlying the granulosa layer and superficial epithelium. Proteolytic enzymes that degrade collagen type IV The synthesis of proteolytic enzymes (MMPs and plasmino- include type IV gelatinases (72 kDa gelatinase (MMP-2) and gen activators), which degrade ECM components of the pre- 92 kDa gelatinase (MMP-9)) and stromelysin-1 (MMP-3). ovulatory follicular wall, increases after the preovulatory Gelatinase activity has been detected within preovulatory fol- gonadotrophin surge (Espey, 1992, 1994). In rodents, there is licles of several species (Curry et al., 1992; Russell et al., 1995). In evidence that only increased MMP activity is required for fol- rats, the expression (Reich et al., 1991) and activity (Curry et al., licular rupture since ovulation occurs in the absence of plas- 1992) of the gene encoding MMP-2 increases after hCG in- minogen activator activity (Carmeliet et al., 1994) and inhibitors jection, and treatment with interleukin 1β (which has been im- of MMPs block follicular rupture (Woessner et al., 1989). Since plicated in the ovulatory process) increases MMP-9 activity the triple helical structure of interstitial collagen fibres (type I within preovulatory follicles (Hurwitz et al., 1993). To our and III) is resistant to proteolytic degradation, interstitial colla- genase (MMP-1) is probably essential for the initial degradation a of fibrillar collagen in the tunica albuginea and theca layer. In Table 2. Tissue inhibitors of metalloproteinase (TIMP) family support of this view, expression of the gene encoding ovarian MMP-1 increases after treatment with hCG or LH (Reich et al., Inhibitor Relative Glycosylation Extracellular 1991) and is related to collagen breakdown within the wall of molecular mass location the preovulatory follicle (Reich et al., 1985). Furthermore, im- munocytochemical studies in rabbits have shown that after TIMP-1 28 000 Glycosylated Soluble in ECM and body fluids hCG treatment the intensity of pro-MMP-1 labelling increases TIMP-2 21 000 Not glycosylated Soluble in ECM within theca and granulosa cells surrounding the orifice of the and body fluids ruptured follicle. Immunoreactive proMMP-1 is localized to TIMP-3 24 000 Not glycosylated Bound to ECM capillary lumina within the apex but not the basal regions of TIMP-4 22 000 nd nd periovulatory follicles (Tadakuma et al., 1993). In addition to fibrillar collagen, the follicular wall contains a aData taken from Greene et al., 1996; Salamonsen, 1996. mesh-like network of collagen type IV within the basement nd, not determined.

Downloaded from Bioscientifica.com at 09/25/2021 11:14:10PM via free access 26 E. W. McIntush and M. F. Smith knowledge, MMP-3 has not been detected within ovarian may enter the extracellular spaces within the preovulatory fol- follicles. A preovulatory increase in gelatinase activity within licle to assist in the regulation of collagenolysis. follicular fluid may be important for follicular rupture. After the preovulatory gonadotrophin surge in sheep, ex- Immunization of ewes against the N-terminal peptide of the pression of the mRNA encoding TIMP-1 (Smith et al., 1994a) in- 43 kDa inhibin α subunit (αN) is associated with reduced ovi- creases approximately tenfold and immunolabelled TIMP-1 is ductal recovery of oocytes and formation of corpora lutea localized primarily in the granulosa cells of preovulatory fol- possessing a morphology consistent with incomplete basement licles (McIntush et al., 1996). Follicular fluid concentrations of membrane breakdown (Russell et al., 1995). Inadequate break- TIMP-1 increase approximately tenfold after a gonadotrophin down of the basement membrane is associated with decreased surge (McIntush et al., in press). Conversely, expression of gelatinase activity and MMP-2 concentrations within the fol- mRNA encoding TIMP-2 within ovine preovulatory follicles is licular fluid of ewes immunized against αN (Russell et al., not affected by the gonadotrophin surge, and TIMP-2 is local- 1995). Basement membrane breakdown around the time of fol- ized to the thecal layer (Smith et al., 1995). These differences in licular rupture is necessary for migration of endothelial cells the localization and temporal expression of ovine TIMP-1 and (angiogenesis), fibroblasts, and luteinizing thecal cells during -2 suggest that the regulation and potential functions of these corpus luteum formation. MMP inhibitors differ, thus adding to the complexity of the control of proteolytic degradation within the follicular wall. Role of inhibitors of matrix metalloproteinases Regulation of follicular rupture Initial attempts to detect MMP activity within periovulatory ovarian tissues were unsuccessful owing to the presence of Before follicular rupture, collagen degradation occurs at the α α MMP inhibitors, including TIMPs and 2-macroglobulin. 2- apex of the preovulatory follicular wall (Espey, 1967; Murdoch Macroglobulin is a large protein (720 000 kDa) that inhibits four and McCormick, 1992). This increase in collagen degradation major classes of proteinases, including MMPs, and is found in may be caused by an increase in the ratio of MMP activity: in- serum. During the periovulatory period, as a result of increased hibitor activity. At the time of follicular rupture, high concen- α α capillary permeability, 2-macroglobulin derived from serum trations of TIMP-1, and possibly 2-macroglobulin, within follicular fluid may neutralize MMP activity within the apex re- gion of the follicular wall (Curry et al., 1989). A more complete Box 1. The extracellular matrix actively modulates cell understanding of connective tissue remodelling within the function stigma region of the preovulatory follicle awaits further investi- gation of the temporal and spatial expression, production and Collagens, of which there are at least 18 types, are the major regulation of follicular MMPs and TIMPs. protein components of most extracellular matrices and form the primary scaffold to which other proteinaceous and non- Oocyte maturation and early embryonic development proteinaceous components associate. Laminins, fibronectin, vitronectin, nigoden, perlecan and fubulin-1 are some of the In addition to regulating collagenolysis, increased concen- proteins that associate either directly or indirectly with col- trations of TIMP-1 in follicular fluid during the periovulatory lagens. The collagen type(s) and the mixture of other pro- period may affect oocyte maturation and early embryonic de- teinaceous and non-proteinaceous components vary between velopment. Collagenase, stromelysin and TIMP expression have and within tissues and, thereby, provide for the requirements of specific cells within tissues. been detected in unfertilized oocytes, zygotes, cleavage stage Extracellular matrices are not inert. They modulate cell embryos and blastocysts (Brenner et al., 1989). Furthermore, the function actively through cell surface receptors for extra- addition of TIMP-1 during maturation of pig oocytes in vitro cellular matrix components. Integrins are one class of cell (Funahashi et al., 1997) or development of bovine embryos surface receptors. Integrins are heterodimers containing an α- in vitro (Satoh et al., 1994) enhances early embryonic develop- β α α α α α α and -subunit. There are 14 -subunits ( 1– 8, E, iib, L, ment. Mechanisms by which TIMP-1 enhances early embryonic α α α β β β M, V and X) and eight -subunits ( 1– 8) that associate in development are unclear but may include regulation of ECM different combinations to form at least 20 distinct integrins remodelling and stimulation of cellular proliferation. which differ in ligand binding. Interactions between integrins and extracellular matrix ligands activate a variety of intra- cellular signalling molecules including tyrosine, serine- Luteal development threonine, and lipid kinases and phospholipases. In addition, binding of integrins to their respective ligands modulates the The transition of the postovulatory follicle into a corpus luteum generation of second messengers by growth factors, cytokines involves extensive ECM remodelling to accommodate the rapid and hormones. proliferation (Jablonka-Shariff et al., 1993), differentiation (Smith The influence of the extracellular matrix on cell function et al., 1994b), and migration (O’Shea et al., 1980) of cells during is pronounced in tissues undergoing remodelling. Within luteal development (Box 1). Many migrating and proliferating these tissues, cells are exposed to different ligands for inte- cells are endothelial cells (Jablonka-Shariff et al., 1993). In addi- grins as extracellular matrix components are degraded and re- tion to endothelial cells and fibroblasts (Farin et al., 1986), the placed. Differentiation of cells into subsequent cell types, corpus luteum contains two biochemically, physiologically, such as granulosa cells into large luteal cells, is likely to re- and morphologically distinct steroidogenic cell types: large quire sequential exposure to different extracellular matrix environments. luteal cells (LLCs), presumably derived from follicular granu- losa cells, and small luteal cells (SLCs), presumably derived from follicular theca cells (Alila and Hansel, 1984). The bulk of

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(a) In vivo

Deposition of extracellular Progesterone matrix PGF2α Apoptopic cell death Loss of ECM and Large luteal cell integrity?

Loss of P4 secretion Granulosa cell Luteal development Luteal regression

(b) In vitro

Exposure to Progesterone extracellular Enzymatic dissociation of matrix luteal tissue

or Large luteal cell Dedifferentiation Apoptosis Granulosa cell Luteinization ECM degradation

Fig. 2. Hypothesized relationship between extracellular matrix (ECM) and luteal cell function in vivo (a) and in vitro (b). (a) The relationship of luteal development and regression to changes in ECM in vivo. Differentiation of follicular cells into large luteal cells is associated with net accumulation of ECM during luteal development. Likewise, reduction in progesterone secretion and apoptotic cell death is associated with loss of ECM integrity. (b) Granulosa cell luteinization in vitro is enhanced by exposure to basal lamina components (laminin and fibronectin). In addition, enzymatic dissociation of luteal tissue leads to apoptosis or dedifferentiation of luteal cells. luteal progesterone (80%) is derived from LLCs (Niswender differentiation of follicular-derived cells into luteal cells, and et al., 1985). The construction and degradation of the ECM the maintenance of the phenotype of luteal cells. associated with luteal cell differentiation and regression in vivo, Differentiation of granulosa cells into luteal cells is pro- together with the experimental evidence that ECM components moted by two components of the basal lamina, fibronectin or β enhance luteinization of follicular cells and that loss of ECM laminin, and blocked by an antibody to the integrin 1 subunit results in luteal cell death or loss of differentiated phenotype, (Aten et al., 1995). Thus, it is likely that the luteal ECM is in- are summarized (Fig. 2). Remodelling of the ECM involves volved in manifestation of the phenotype of LLCs. In addition, expression of genes encoding MMPs and inhibitors of ECM inhibition of ECM degradation by inhibitors of MMPs can degrading proteases (TIMP-1, TIMP-2, TIMP-3 and PAI-1). The maintain the differentiated phenotype of epithelia (Alexander production of mRNA encoding TIMP-1 (Hampton et al., 1995) et al., 1996). Thus, inhibitors may maintain the proper and TIMP-1 (McIntush and Smith, 1997) by the corpus luteum contacts between luteal cells and the ECM. is 30–3 000 times greater than that of other tissues. Although re- The mRNA encoding TIMP-1 is expressed in abundance ports of growth- (Edwards et al., 1996) and steroidogenesis- during luteal development (Smith et al., 1994a), a time when promoting (Boujrad et al., 1995) activities of TIMP-1 suggest that neovascularization and cell migration is rapid (Jablonka-Shariff it may also modulate these processes within the corpus luteum, et al., 1993). These data indicate an apparent paradox since the potential role of these activities will not be addressed here. TIMP-1 inhibits neovascularization and cell migration (Khokha, TIMP-1, TIMP-2 and PAI-1 are expressed specifically by one 1994) presumably by inhibiting MMPs. An explanation might be of the several types of luteal cell, and may be important in that the concentration of mRNA encoding TIMP-1 is not indica- maintaining an ECM microenvironment conducive to the tive of the concentration of TIMP-1 protein in the extracellular

Downloaded from Bioscientifica.com at 09/25/2021 11:14:10PM via free access 28 E. W. McIntush and M. F. Smith milieu at this time. While the concentration of the mRNA en- progesterone (Niswender and Nett, 1994), and apoptosis coding TIMP-1 per unit of DNA decreases (Freudenstein et al., (Juengel et al., 1993). Changes in luteal gene expression in re- 1990; Smith et al., 1994a, 1996) from the early to the mid-luteal sponse to PGF2α, the natural luteolysin, are similar to changes phase, TIMP-1 mg-1 of luteal tissue increases approximately in luteal gene expression induced by enzymatic dissociation threefold from the early to the mid-luteal phase (McIntush and (G. Niswender, personal communication; Fig. 2). Ovine LLCs Smith, 1997). Morphologically, the secretory granules in LLCs are the luteal cell type that possess receptors for and respond to in which TIMP-1 is localized (McIntush et al., 1996) fit the cri- PGF2α. It is proposed that extracellular matrix degradation is teria for dense core secretory granules, which are often associ- an important component of the physiological response of LLCs ated with a regulated pathway of protein secretion (Kelly, to PGF2α, which allows the corpus luteum to regress. In sup- 1985). Thus, increasing TIMP-1 protein, decreasing mRNA en- port of this view, microtubules within LLCs disappear within coding TIMP-1 and the localization of TIMP-1 to secretory 2 h after administration of PGF2α (Murdoch, 1996). These data granules are consistent with the hypothesis that, although some indicate that contacts between LLCs and the ECM are dis- TIMP-1 may be secreted, much of it accumulates within the rupted during luteal regression. Thus, maintenance of corpora secretory granules of LLCs. This suggestion explains why high lutea may be dependent upon the establishment and mainten- TIMP-1 expression during luteal development does not inhibit ance of contacts between the ECM and LLCs. It is suggested the rapid pace of neovascularization. that luteal tissue produces TIMP-1, TIMP-2, TIMP-3 and PAI-1 to preserve the integrity of the ECM components required to maintain the function of luteal cells until the induction of Luteal maintenance luteolysis. Large luteal cell-derived protease inhibitors may be seques- In humans, the corpus luteum is ‘rescued’ by hCG during tered within LLCs until they are needed to slow the rate of cell early pregnancy. Although the specific mechanisms associated proliferation and migration as the corpus luteum matures. The with luteal rescue are unknown, there is increasing evidence concentration of TIMP-1 in luteal tissue reaches a plateau be- that human granulosa–lutein cells depend on contact with the fore the mid-luteal and late-luteal phase (McIntush and Smith, ECM for cell survival and that hCG decreases gelatinase pro- 1997), while expression of mRNA encoding TIMP-1 is main- duction (Stamouli et al., 1996) and increases TIMP-1 production tained or increased over the same period (Smith et al., 1994a, (O’Sullivan et al., 1997). Stabilization of ECM–luteal cell con- 1996). These observations indicate that, although TIMP-1 is tacts may enhance steroidogenesis and promote cell survival. packaged within secretory granules, it ceases to accumulate. A If inhibitors of ECM proteases are important for luteal main- plateau in TIMP-1 accumulation while production of mRNA tenance, then destruction of TIMP-1 may be important for luteal encoding TIMP-1 continues indicates that additional TIMP-1 is regression. Inactivation of TIMP-1 could be accomplished by released. It is interesting to note that the rate of cell prolifer- mechanisms that have been implicated in luteolysis. For ation, primarily of endothelial cells associated with neovascu- example, leukocytes, which are involved in luteolysis, inactivate larization, begins to plateau in the mid-luteal phase (Jablonka- TIMP-1 by proteolytic degradation (Itoh and Nagase, 1995). In Shariff et al., 1993). Abundant TIMP-1 expression, coupled with addition, highly reactive peroxynitrite, ONOO– (generated by ⊄– ⊄ accumulation within the developing corpus luteum and in- the reaction of superoxide (O2 ) with nitric oxide ( NO)), creased secretion as the corpus luteum matures, provides an which inactivates TIMP-1 (Frears et al., 1996), may be generated explanation of the mechanism for slowing neovascularization. by luteal tissue during the generation of oxygen radicals associ- Tissue inhibitor of metalloproteinases-1 may maintain critical ated with luteolysis (Sawada and Carlson, 1994). ECM integrity during luteal maintenance. Large luteal cells ap- pear to be the primary cell type responsible for controlling the Conclusion extent of luteal ECM remodelling since they produce TIMP-1 (Smith et al., 1994a; McIntush et al., 1996), TIMP-2 (Smith et al., In conclusion, growth of an ovarian follicle culminating in ovu- 1995; McIntush et al., 1996), and plasminogen activator inhibitor- lation or atresia and the development, maintenance and re- 1 (G. W. Smith and M. F. Smith, unpublished). A distinguishing gression of a corpus luteum are cyclic events that depend upon characteristic of ovine LLCs is the presence of a basal lamina extensive remodelling of the ECM. Components of the ECM around their periphery except at points of microvillous pro- modulate cellular processes (including gene expression; cellu- jections (Farin et al., 1986). Furthermore, if LLCs are as depen- lar proliferation, migration and differentiation; and apoptosis) dent upon ECM as are mammary epithelial cells, keratinocytes, via cell surface receptors and serve as a reservoir for a number and hepatocytes (Lin and Bissell, 1993), then they may produce of biologically active factors. Consequently, the controlled inhibitors of proteases to preserve their own basal lamina and, degradation of ECM proteins by MMPs and TIMPs may be in so doing, preserve their differentiated phenotype. The pat- essential for preserving a microenvironment conducive to tern of collagen type IV gene expression in the corpus luteum follicular and luteal function. (Zhao and Luck, 1995) is consistent with the hypothesis that granulosa cells are exposed to some components of basal lami- This manuscript is a contribution of the Missouri Agricultural Experiment Station (Journal Series 12 688). This work was partially nae early in the process of differentiating into LLCs. funded by USDA Grant, USDA CSRS 92-37203-7950. E. W. McIntush and M. F. Smith were supported by a USDA National Needs Luteolysis Fellowship and a National Institutes of Health Senior International Fellowship, respectively. The authors thank H. Nagase (University of Regression of corpora lutea is marked by loss of cell adhesion Kansas Medical School, Kansas City) for his contributions to the design to matrix (Nett et al., 1976), loss of the capacity to synthesize and conduct of their research.

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