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ABSTRACT: Following retrograde menstruation, shed endometrial tissue frag- ments attach to and invade the peritoneal surface to form established endo-.

Paracrine Regulation of Matrix Metalloproteinase Expression in Endometriosis KATHY L. SHARPE-TIMMS AND KATHRYN E. COX Department of Obstetrics and Gynecology, University of Missouri-Columbia, Columbia, Missouri 65212, USA

ABSTRACT: Following retrograde menstruation, shed endometrial tissue fragments attach to and invade the peritoneal surface to form established endometriotic lesions. With disease progression, the biochemically active lesions undergo remodeling and become fibrotic. Matrix metalloproteinase enzymes (MMPs) and the tissue inhibitors of metalloproteinases (TIMPs) play a significant role in normal endometrial remodeling during menses. Anomalous expression of MMPs and TIMPs has been identified in endometriotic lesions as compared to their highly regulated expression in eutopic endometrium. The paracrine mechanisms regulating misexpression of MMPs and TIMPs by endometriotic lesions are, however, not well defined. Misexpression of the MMPs and TIMPs may be due to innate anomalies in the eutopic endometrium from women with endometriosis, in the resident immune cells and peritoneal cells that juxtapose the ectopic endometrium, and/or numerous substances present in peritoneal fluid of women with endometriosis. The majority of MMPs are under strict transcriptional regulation. Steroid hormones and cytokines appear to act on the MMP promoter, either independently or in consort, to provide both positive and negative regulation of these genes. Misregulated expression of MMPs and TIMPs is associated with a more aggressive phenotype and a cascade of events facilitating peritoneal extracellular matrix degradation and establishment or remodeling of endometriotic lesions. The mechanisms by which MMP and TIMP expression are misregulated warrant further investigation as such information may provide insight into novel therapeutic modalities for endometriosis. KEYWORDS: matrix metalloproteinases; tissue inhibitors of metalloproteinases; MMP; TIMP; regulation; steroids; cytokines

CURRENT STATE OF KNOWLEDGE The pathogenic mechanisms of endometriosis are incompletely understood. The prevailing hypothesis involves that, following retrograde menstruation, shed endometrial tissues attach, invade the peritoneal surface, become vascularized, and form established endometriotic lesions.1–3 The most biochemically active lesions are the red or proposed early lesions and, with disease progression, the endometriotic lesions

Address for correspondence: K. L. Sharpe-Timms, Department of Obstetrics and Gynecology, University of Missouri-Columbia, 1 Hospital Drive, Columbia, MO 65212. Voice: 573-882-7937; fax: 573-882-9010. [email protected]

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undergo remodeling and eventually become more fibrotic and less biochemically active.4,5 Matrix metalloproteinase enzymes (MMPs) and their inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMPs), play a significant role in normal endometrial remodeling that accompanies menses.6–8 The MMP family consists of several structurally related, Zn2+-dependent secreted endopeptidases, which collectively are responsible for degrading a variety of extracellular matrix components, including several types of collagen, gelatins, proteoglycans, laminin, fibronectin, and elastin.6–12 The TIMPs are the natural inhibitors of MMPs; in combination, they inhibit all members of the MMP family.6,10–12 The expression of MMPs and TIMPs is tightly regulated in the uterine endometrium.7,9 A significant upregulation of MMP expression is coincident with tissue breakdown and remodeling occurring at menses and during the early proliferative stage of the menstrual cycle.7,9 Anomalous expression of specific members of the MMP and TIMP families has been identified in endometriotic lesions as compared to their highly regulated expression in eutopic endometrium.13–18 For example, studies of human tissues and studies using animal models have shown that MMP-1, MMP-3, and MMP-7 are constitutively expressed by endometriotic lesions, but are highly regulated in the eutopic endometrium during the menstrual cycle.9,13,18 Also, while endometriotic lesions de novo synthesize and secrete TIMP-1 protein in vitro,19 in vivo TIMP-1 protein concentrations are lower in the peritoneal fluid of women with endometriosis.20 A possible explanation for these differences is that, in vivo, TIMP-1 may be selectively localized within the endometriotic lesions or other peritoneal tissues and cells. We have previously shown that TIMP-1 protein can be immunohistochemically identified in endometriotic lesions throughout the menstrual cycle.4 Interestingly, addition of TIMP protein to the peritoneal cavity of nude mice prevented the establishment of endometriosis.21 As the expression of MMPs and TIMPs is highly regulated by steroids in the eutopic endometrium, altered biochemical characteristics in the ectopic endometrial tissue may affect production of these enzymes and their inhibitors. Endometriotic lesions are biochemically different from normal uterine endometrium in several ways, including steroid production, responsiveness, and receptor content; growth factor responsiveness and receptor content; and synthesis and secretion of several proteins such as haptoglobin, monocyte chemotactic protein-1, and complement component 3.22–25 During the past decade, a variety of studies, using various techniques, have shown that steroid receptor content in endometriotic lesions is more heterogeneous than in eutopic endometrium.22 More recently, work from Bulun and colleagues24,25 has shown that endometriotic lesions produce aromatase, which endows them with the capability to produce estrogen, and express the progesterone isoform A, but not the isoform B. Evidence is now emerging that shows the eutopic endometrial tissue of women with endometriosis may innately display some of these differences.26 In addition to the biochemical differences, endometriotic lesions also differ structurally and spatially from eutopic endometrium. They are located distally to the uterine-ovarian vasculature and are not likely receiving the same level of steroid stimulation as the eutopic endometrium. Further, the epithelial cell to stromal cell ratio is often disturbed in endometriotic lesions. As specific endometrial epithelial cell and stromal cell interactions have been shown to affect MMP production, it is

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possible that this altered ratio may change the response of the ectopic tissues to particular stimuli as compared to the response of the uterine endometrium. For example, progesterone acts on endometrial stromal cells to increase production of TGF-β. In turn, the TGF-β acts on the endometrial epithelial cells to decrease MMP-7 production.4 If the stromal component of the endometriotic lesion is reduced, progesteroneinduced TGF-β stimulus may be lessened and may subsequently alter MMP-7 expression by the ectopic lesion. Endometriotic lesions also differ in the number and activity of their resident immune cells and are juxtaposed among peritoneal mesothelial and subserosal cells. Both resident endometrial and endometriotic immune cells and peritoneal immune cells produce growth factors and cytokines that alter MMP and TIMP expression.2,22,27–29 Further, the immune cells also produce certain MMPs.30–32 Human mesothelial cells synthesize and secrete MMPs and TIMP-1 too.33 The state of the mesothelial cell differentiation has a striking influence on the expression of these enzymes and their inhibitors. Characteristic of the normal early response to serosal injury, reactive cuboidal mesothelium may manifest a matrix-degrading phenotype favoring normal repair as opposed to fibrosis. It is not known how the combination of MMPs and TIMPs produced by endometrial tissue fragments, immune cells, and peritoneal cells might alter the balance of these substances in the peritoneal cavity and subsequently contribute to the development of endometriosis. Endometriotic lesions are also bathed in peritoneal fluid. Numerous substances are present in peritoneal fluid of women with endometriosis and may originate from a variety of sources.3,22 These substances might originate from the ovary, peritoneal mesothelial or subserosal cells, or peritoneal immune cells, or from the shed endometrial tissue fragments or endometriotic epithelial and stromal cells. They include gonadal hormones, prostaglandins, enzymes and inhibitors, growth factors, inflammatory mediators, and various other proteins. Many of these factors are known regulators of MMP and TIMP production. Both epidermal growth factor (EGF) and transforming growth factor-α (TGF-α), known upregulators of MMPs, have been found in endometriotic lesions of rats with surgically induced disease.34 Rat lesions also express TGF-β, a downregulator of MMP expression.35 Women with endometriosis have elevated levels of interleukin-1α (IL-1α), another well-recognized upregulator of MMP, in their peritoneal fluid.36–38 This IL-1α is believed to originate from activated peritoneal immune cells, macrophages, and T cells, which are responding to the inflammation of the peritoneal cavity.39 We recently found that IL-1α mRNA and protein are expressed in increasing amounts over time when rat uterine tissues are placed into tissue explant culture. The increased IL-α specifically coincides with an increase in MMP-3 mRNA levels and protein synthesis, but not MMP-2 nor TIMP-1 mRNA or protein (FIG . 1). The majority of MMPs are under strict transcriptional regulation by certain growth factors, tumor promoters, hormones, and oncogenes.40 Transcriptional activation can result in up to 50-fold changes in MMP mRNA expression. There are both positive and negative transcriptional regulators upstream from the transcription site and include AP-1, PEA, TIE, and TATA box consensus sequences for transcription factor binding. There are differences in promoter regions between members of the MMP family.41–45 Factors, including IL-1α, IL-1β, tumor necrosis factor-α (TNF-α), platelet-derived growth factor (PDGF), TGF-α, EGF, basic fibroblast growth factor

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FIGURE 1. Increased endometrial MMP-3 mRNA levels coincide with increased endometrial IL-1α mRNA levels in vitro. To study the effects of an ectopic location free from confounding peritoneal influences, rat uterine tissues were placed into tissue explant culture for 48 hours. Tissues were harvested and snap-frozen. The mRNA was isolated and reverse-transcribed. RT-PCR was performed with gene-specific primers. GAPDH levels were evaluated as load controls. IL-1α mRNA was expressed in increasing amounts over time when rat uterine tissues were placed into tissue explant culture. The increased IL-1α specifically coincided with an increase in MMP-3 mRNA levels, but not MMP-2 nor TIMP-1 mRNA levels.

(bFGF), and phorbol esters, induce MMP gene by increasing the levels of c-fos and c-jun, two transcription factors.10,40,46 With the exception of MMP-2, MMP genes contain an AP-1-binding site, 5′ to the translation start site.42,44 It is at this AP-1 consensus sequence where c-fos and c-jun heterodimers bind.47–51 This site is also where most growth factor and cytokine regulatory pathways converge for both positive and negative regulation.40,52 The AP-1 site is a necessary, but not sufficient, element for transcriptional activation and basal MMP expression.53–55 The MMP-3 promoter also contains a binding site where Ets family transcription factors bind. This Ets (or PEA3) site acts synergistically with the AP-1 site to result in maximal positive transcriptional induction.50,56–58 There are also negative regulatory elements in the MMP promoter.10,51,59 Whereas IL-1α-induced c-fos binding at the AP-1 site results in positive MMP transcription, c-fos also plays a role in the AP-1-independent downregulation of MMPs by TGF-β at the TGF-β inhibitory element (TIE) site of the promoter.10,60,61 While

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TGF-β downregulation of MMPs is independent of AP-1, the downregulation of MMPs by glucocorticoids and retinoic acid occurs through the AP-1 site and binding of the Jun/Fos complex.62–68 It has also recently been shown that MMP-1 and MMP3 mRNAs can be inhibited by urinary trypsin inhibitor (UTI), a member of the Kunitz-type proteinase inhibitors, although the method of action has not yet been elucidated.69 The novel discovery of a cytokine-induced repressor of IL-1-stimulated expression of MMP-3 in that promoter suggests that activation and repression are tightly controlled and in some cases intertwined.59 As previously noted, progesterone is a potent inhibitor of MMP-3 expression in endometrial stromal cells and MMP-7 in endometrial epithelial cells both in vivo and in vitro.70,71 Curiously, IL-1α is a potent stimulator of MMP-3 in proliferative-phase endometrium in organ culture, yet progesterone exposure in vivo reduces the IL-1α stimulation of MMP-3 in secretory-phase tissue.70 This loss of sensitivity to IL-1α was duplicated in isolated stromal cells treated with progesterone in vitro, and IL-1α stimulation of MMP-3 was restored in a dose-dependent manner with progesterone withdrawal. It has been proposed that inflammatory cytokines, such as IL-1α, may block or interfere with steroid-mediated MMP regulation at ectopic sites.72 We repeated these experiments with cells from a rat model for endometriosis. Purified rat uterine and endometriotic stromal cells were cultured with 0, 0.1, 1.0, and 10 × 10−8 M concentrations of medroxyprogesterone for 48 hours. Compared to the cultured endometriotic cells, MMP-3 mRNA levels were lower in the cultured endometrial stromal cells (FIG . 2). The elevated and persistent MMP-3 expression by endometriotic stromal cells cultured in the presence of progesterone was correlated with elevated levels of IL-1α mRNA detected in the endometriotic cells (FIG . 2) and IL-1α protein in their culture media. Little or no IL-1α expression was found in the uterine stromal cells, except for the highest dose of progesterone tested (10 × 10−8 M, FIG . 2). Thus, we hypothesize that production of IL-1α by the endometriotic lesions was able to overcome the progesterone-induced suppression of MMP-3 in these cells, a phenomenon that was not observed in the cultured uterine stromal cells. Preliminary studies from our laboratory suggest that IL-1α and progesterone act in consort to change binding at the AP-1 site on the MMP-3 promoter, the site required for upregulation of MMP expression, and that this phenomenon is different comparing uterine and endometriotic MMP-3. While further work is mandated, these preliminary data offer a plausible IL-1α-related mechanism for the perpetuation of MMP-3 production by endometriotic cells in the presence of progesterone. Overall, these studies support the hypothesis that misregulated expression of MMPs and TIMPs in women with endometriosis is associated with a more aggressive phenotype and a cascade of events facilitating degradation and remodeling of the peritoneal extracellular matrix and establishment or remodeling of endometriotic lesions in the peritoneal cavity. The mechanisms by which MMP and TIMP expression are misregulated in endometriosis are, however, not well understood.

EMERGING ISSUES AND CONTINUING GAPS IN KNOWLEDGE It has been established that ectopic endometrial tissue fragments possess the mechanisms by which they can attach to and invade an intact peritoneal surface.73–75

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FIGURE 2. An IL-1α-induced mechanism for the perpetuation of MMP-3 production by endometriotic cells in the presence of progesterone. Purified rat uterine stromal cells and rat endometriotic stromal cells were cultured with 0, 0.1, 1.0, and 10 × 10−8 M concentrations of medroxyprogesterone (MPA) for 48 hours. Compared to the cultured endometriotic cells, MMP-3 mRNA levels were lower in the cultured endometrial stromal cells. The elevated and persistent MMP-3 expression by endometriotic stromal cells cultured in the presence of progesterone was correlated with elevated levels of IL-1α mRNA detected in the endometriotic cells. Little or no IL-1α mRNA was found in the uterine stromal cells, except at the highest dose of progesterone tested (10 × 10−8 M). The production of IL-1α by the endometriotic lesions offers a plausible mechanism by which MMP-3 mRNA levels remain elevated in endometriotic lesions in the presence of progesterone, a phenomenon that is not observed in cultured uterine stromal cells.

It is evident that products of endometrial and endometriotic tissues, including MMPs and TIMPs as well as cytokines that regulate production of these enzymes and inhibitors, may actively participate in establishment and remodeling of endometriotic lesions.4 Also, while studies have recognized that eutopic endometrium from women with endometriosis is innately aberrant compared to women without endometriosis,26 it is unclear if this is true for the expression of MMPs and/or TIMPs. It would also be of interest to know if immune cells or peritoneal cells from women with endometriosis have defects in MMP and TIMP expression and if these cells alter such expression by ectopic endometrial cells. Either of these mechanisms could contribute to the establishment of the disease or remodeling of the lesions during disease progression. There are still many questions to be answered. Is misexpression of MMPs and TIMPs caused by an innate anomaly in endometrial, immune, or peritoneal components in women with endometriosis or a consequence of tangential and highly interrelated factors that elicit this aberrant expression in the peritoneal cavity? Why, when MMP and TIMP expression is altered to a more invasive phenotype, are endometriotic lesions not more like cancer and more aggressive in their invasion? As

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endometriotic lesions undergo remodeling much like the eutopic endometrium, why do the lesions progress through a series of phenotypes and become fibrotic and scarlike? As it is plausible that MMPs and TIMPs participate in these events, what mechanisms control their expression? Are defects in the peritoneal surface architecture important for MMP activity to be effective in extracellular matrix breakdown? Further research is required to answer these questions. REFERENCES 1. SAMPSON, J.A. 1927. Peritoneal endometriosis due to menstrual dissemination of endometrial tissue into the peritoneal cavity. Am. J. Obstet. Gynecol. 14: 422–469. 2. SAMPSON, J.A. 1940. The development of the implantation theory for the origin of peritoneal endometriosis. Am. J. Obstet. Gynecol. 40: 549–557. 3. GIUDICE, L.C., S.I. TAZUKE & L. SWIERSZ. 1998. Status of current research on endometriosis. J. Reprod. Med. 43(suppl. 3): 252–262. 4. OSTEEN, K.G., K.L. BRUNER & K.L. SHARPE-TIMMS. 1996. Steroid and growth factor regulation of matrix metalloproteinase expression and endometriosis. Semin. Reprod. Endocrinol. 14: 247–255. 5. D’HOOGHE, T.M., C.S. BAMBRA, B.M. RAEYMAEKERS & P.R. KONINCKX. 1996. Serial laparoscopies over 30 months show that endometriosis in captive baboons (Papio anubis, Papio cynocephalus) is a progressive disease. Fertil. Steril. 65(3): 645–649. 6. WOESSNER, J.F. 1991. Matrix metalloproteinases and their inhibitors in connective tissue remodeling. FASEB J. 5: 2145–2154. 7. SALAMONSEN, L.A. & D.E. WOOLLEY. 1996. Matrix metalloproteinases in normal menstruation. Hum. Reprod. 11(suppl. 2): 124–133. 8. HULBOY, D.L., L.A. RUDOLPH & L.M. MATRISIAN. 1997. Matrix metalloproteinases as mediators of reproductive function. Mol. Hum. Reprod. 3(1): 27–45. 9. RODGERS, W.H., K.G. OSTEEN, L.M. MATRISIAN et al. 1993. Expression and localization of matrilysin, a matrix metalloproteinase, in human endometrium during the reproductive cycle. Am. J. Obstet. Gynecol. 168: 253–260. 10. MATRISIAN, L.M. 1990. Metalloproteinases and their inhibitors in matrix remodeling. Trends Genet. 6(4): 121–125. 11. BIRKEDAL-HANSEN, H., W.G.I. MOORE, M.K. BODDEN et al. 1993. Matrix metalloproteinases: a review. Crit. Rev. Oral Biol. Med. 4(2): 197–250. 12. MATRISIAN, L. 1992. The matrix-degrading metalloproteinases. Bioessays 14(7): 455– 463. 13. KOKORINE, I., M. NISOLLE, J. DONNEZ et al. 1997. Expression of interstitial collagenase (matrix metalloproteinase-1) is related to the activity of human endometriotic lesions. Fertil. Steril. 68: 246–251. 14. SPUIJBROEK, M.D.E.H., G.J. DUNSELMAN, P.P.C.A. MENHEERE & J.L.H. EVERS. 1992. Early endometriosis invades the extracellular matrix. Fertil. Steril. 58: 929–933. 15. SAITO, T., H. MIZUMOTO et al. 1995. Expression of MMP-3 and TIMP-1 in the endometriosis and the influence of danazol. Acta Obstet. Gynecol. Jpn. 47: 495–496. 16. KOKS, C.A., P.G. GROOTHUIS et al. 2000. Matrix metalloproteinases and their tissue inhibitors in antegradely shed menstruum and peritoneal fluid. Fertil. Steril. 73(3): 604–612. 17. MARBAIX, E., J. DONNEZ, P.J. COURTOY & Y. EECKHOUT. 1992. Progesterone regulates the activity of collagenase and related gelatinases A and B in human endometrial explants. Proc. Natl. Acad. Sci. U.S.A. 89: 11789–11793. 18. COX, K.E., M. PIVA & K.L. SHARPE-TIMMS. 2001. Differential regulation of matrix metalloproteinase-3 (MMP-3) gene expression in endometriotic lesions as compared to endometrium. Biol. Reprod. In press. 19. SHARPE-TIMMS, K.L., L.L. PENNEY, R.L. ZIMMER et al. 1995. Partial purification and amino acid sequence analysis of endometriosis protein-II (ENDO-II) reveal homology with tissue inhibitor of metalloproteinases-1 (TIMP-1). J. Clin. Endocrinol. Metab. 80(12): 3784–3787.

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