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Ulpu Saarialho-kere - One of the best experts on this subject based on the ideXlab platform.
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MMP-10 (Stromelysin-2) and MMP-21 in human and murine squamous cell cancer.
Experimental dermatology, 2009Co-Authors: Sonja Boyd, Susanna Virolainen, Jenita Pärssinen, Tiina Skoog, Max Van Hogerlinden, Leena Latonen, Lauri Kyllönen, Rune Toftgård, Ulpu Saarialho-kereAbstract:The squamous cell cancers (SCC) of renal transplant recipients are more aggressive and metastasize earlier than those of the non-immunocompromised population. Matrix metalloproteinases (MMPs) have a central role in tumor initiation, invasion and metastasis. Our aim was to compare the expression of MMPs-10, -12 and -21 in SCCs from immunosuppressed (IS) and control patients and the contribution of MMPs-10 and -21 to SCC development in the FVB/N-Tg(KRT5-Nfkbia)3Rto mouse line. Immunohistochemical analysis of 25 matched pairs of SCCs, nine of Bowen's disease and timed back skin biopsies of mice with selective inhibition of Rel/NF-kappaB signalling were performed. Semiquantitatively assessed stromal MMP-10 expression was higher (P = 0.009) in the control group when compared with IS patients. Tumor cell-derived MMP-10, -12 and -21 expression did not differ between the groups but stromal fibroblasts of the control SCCs tended to express MMP-21 more abundantly. MMP-10 expression was observed already in Bowen's disease while MMP-21 was absent. MMP-10 and -21 were present in inflammatory or stromal cells in ageing mice while dysplastic keratinocytes and invasive cancer were negative. Our results suggest that MMP-10 may be important in the initial stages of SCC progression and induced in the stroma relating to the general host-response reaction to skin cancer. MMP-21 does not associate with invasion of SCC but may be involved in keratinocyte differentiation.
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Temporal and spatial expression of matrix metalloproteinases during wound healing of human corneal tissue.
Experimental eye research, 2003Co-Authors: Julie T. Daniels, Gillian Murphy, Gerd Geerling, Robert A Alexander, Peng T. Khaw, Ulpu Saarialho-kereAbstract:Our understanding of MMP expression during corneal repair has previously relied upon animal models, isolated human biopsy specimens and cell culture studies. The aim of this study was to determine the temporal and spatial expression of matrix metalloproteinases following wounding of cultured human corneal tissue. Human corneas were cultured and cut into six pieces. The epithelium was removed with a corneal brush. The tissue was then re-cultured and tissue pieces were fixed up to 7 days post-wounding. Matrix metalloproteinases were detected by in situ hybridisation and immunohistochemistry. Intracellular laminin-5, a marker of migratory epithelial cells, was located immunohistologically. In the time scale studied tissue series from nine corneas achieved coverage of the stroma with epithelial cells and partial repair of damaged basement membrane, demonstrated by the Periodic acid-Schiff reaction and haematoxylin and eosin counter-staining. By day 3, migrating epithelial cells and stromal cells beneath the wounded area expressed collagenase-1 (MMP-1). Stromelysin-1 (MMP-3) was expressed only by fibroblast-like stromal cells. Stromelysin-2 (MMP-10) was detected in migrating epithelial cells and remained when the stroma was surrounded by a monolayer of epithelial cells. By day 7, development of multi-layered epithelium around the tissue coincided with cessation of MMP expression in both epithelial and stromal cells, except for MMP-9, which remained in epithelial basal cells. Tissue inhibitor of matrix metalloproteinase-1 was mainly associated with stromal cells and was reduced upon formation of a multi-layered epithelium. This study demonstrates matrix metalloproteinase expression in epithelial and fibroblast-like cells following wounding of human corneal tissue in culture where the cells remain in contact with their natural matrices.
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Upregulation of matrix metalloproteinases in a model of T cell mediated tissue injury in the gut: analysis by gene array and in situ hybridisation
Gut, 2002Co-Authors: M T Salmela, Ulpu Saarialho-kere, Thomas T. Macdonald, D Black, B Irvine, T Zhuma, Sylvia L.f. PenderAbstract:Background and aim: Matrix metalloproteinases (MMPs) have been implicated in tissue remodelling and ulceration in inflammatory bowel disease and coeliac disease. Studies to date have concluded that Stromelysin 1 is functionally involved in mucosal degradation. However, there are many other MMPs whose function in the gut is currently unknown. This work had two aims: firstly, to use gene array technology to measure changes in MMP and tissue inhibitor of metalloproteinase (TIMP) expression in a model of T cell mediated injury in the gut, and secondly, to correlate data from gene arrays with that generated by in situ hybridisation. Methods: T cells in explants of human fetal gut were activated with pokeweed mitogen or anti-CD3 plus interleukin 12. Gene array analysis and in situ hybridisation were performed to investigate changes in MMP gene expression. Results: Both gene array analysis and in situ hybridisation indicated marked upregulation of Stromelysin 2 and macrophage metalloelastase expression in the explants associated with mucosal destruction. The arrays also confirmed our previous observation that interstitial collagenase (MMP-1), Stromelysin 1 (MMP-3), and gelatinase B (MMP-9) are upregulated but there was no change in MMP-2, -7, -8, -9, -11, -13, -14–17, or -19. Following T cell activation, transcripts for TIMPs were reduced. Conclusions: These results show that there is differential upregulation of MMPs during T cell responses in the gut and suggest that further studies on the role of Stromelysin 2 and macrophage metalloelastase may show that they have a functional role. In addition, the increase in MMPs and reduction in TIMPs suggest that the protease/antiprotease balance in the mucosa may determine the extent of mucosal degradation.
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Upregulation and differential expression of matrilysin (MMP-7) and metalloelastase (MMP-12) and their inhibitors TIMP-1 and TIMP-3 in Barrett's oesophageal adenocarcinoma.
British journal of cancer, 2001Co-Authors: M T Salmela, Pauli Puolakkainen, Ulpu Saarialho-kereAbstract:Oesophageal adenocarcinoma is believed to arise from metaplastic mucosa in the distal oesophagus, a condition also known as Barrett's oesophagus (BE). BE develops as a result of injury caused by refluxing gastric and duodenal contents and is associated with increased risk of malignant transformation. Matrix metalloproteinases (MMPs) have been implicated in all aspects of tumour progression; tumour growth, basement membrane degradation, invasion and metastatic spread. Using in situ hybridization, we investigated the expression patterns of collagenases-1 and -3, Stromelysin-2, matrilysin, metalloelastase and TIMPs-1 and -3 in BE, adenocarcinoma and lymph-node metastases. Matrilysin was expressed abundantly in 12/15 tumours and in 4/6 lymph-node metastases and its expression correlated with the histological aggressiveness of tumour. Matrilysin and metalloelastase were upregulated already in BE. Stromelysin-2 and collagenase-3 expression was detected only in a few tumours. Collagenase-1 was expressed by cancer and stromal cells in 9/15 tumours. Tumour-infiltrating macrophages expressed metalloelastase in 13/15 cancers. TIMPs-1 and -3 were expressed in 12/15 and 11/15 tumours, respectively. Laminin-5 and tenascin were abundantly expressed at the invasive front of poorly differentiated tumours, but not in BE. Our results indicate that matrilysin is the principal MMP expressed by tumour cells in oesophageal adenocarcinoma, and further studies are needed to investigate whether matrilysin or tenascin-C could be used as a predictive marker for progression of BE to cancer.
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Parallel expression of macrophage metalloelastase (MMP-12) in duodenal and skin lesions of patients with dermatitis herpetiformis.
Gut, 2001Co-Authors: M T Salmela, Sylvia L.f. Pender, Thomas T. Macdonald, T Reunala, Ulpu Saarialho-kereAbstract:BACKGROUND—Dermatitis herpetiformis (DH) is a specific dermatological manifestation of coeliac disease and 80% of DH patients have gluten sensitive enteropathy manifested by crypt hyperplasia and villous atrophy. Matrix degradation mediated by collagenase 1 (MMP-1) and Stromelysin 1 (MMP-3) has previously been implicated in the pathobiology of coeliac intestine and cutaneous DH blisters. AIMS—To study expression of Stromelysin 2, metalloelastase, collagenase 3, and matrilysin in the intestine and skin of DH patients. METHODS—In situ hybridisation using 35S labelled cRNA probes was performed on duodenal biopsies of 15 DH patients, three samples each of control duodenal or jejunal mucosa, fetal ileal explants, lesional DH skin, and 19 serial biopsies of experimental DH blisters. Immunostaining was used to examine type IV collagen, macrophages (CD68), and 92 kDa gelatinase (MMP-9) in the specimens. RESULTS—Metalloelastase (MMP-12) was abundantly expressed by subepithelial macrophages in both coeliac intestine and spontaneous and induced DH rash. It was also upregulated in the experimental model of coeliac disease (staphylococcal endotoxin B stimulated fetal explants). The only other MMP detected was MMP-9 which did not colocalise with MMP-12. CONCLUSIONS—Upregulation of metalloelastase is associated with T cell mediated immune responses both in the intestine and skin. In addition to modulating macrophage migration, it may contribute to degradation of proteoglycans or basement membrane components in the subepithelial mucosa. Keywords: coeliac disease; metalloproteinase; dermatitis herpetiformis
Sabine Werner - One of the best experts on this subject based on the ideXlab platform.
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Activities of the Matrix Metalloproteinase Stromelysin-2 (MMP-10) in Matrix Degradation and Keratinocyte Organization in Wounded Skin
Molecular biology of the cell, 2004Co-Authors: Monika Krampert, Wilhelm Bloch, Takako Sasaki, Philippe Bugnon, Thomas Rülicke, Eckhard Wolf, Monique Aumailley, William C. Parks, Sabine WernerAbstract:The matrix metalloproteinase Stromelysin-2 is expressed in keratinocytes of the epithelial tongue of skin wounds, suggesting a role in keratinocyte migration. Here, we show that Stromelysin-2 enhances migration of cultured keratinocytes. To gain insight into the in vivo activities of Stromelysin-2 in epithelial repair, we generated transgenic mice expressing a constitutively active Stromelysin-2 mutant in keratinocytes. These animals had no alterations in skin architecture, and the healing rate of skin wounds was normal. Histologically, however, we found abnormalities in the organization of the wound epithelium. Keratinocytes at the migrating epidermal tip were scattered in most sections of mice with high expression level, and there was a reduced deposition of new matrix. In particular, the staining pattern of laminin-5 at the wound site was altered. This may be due to proteolytic processing of laminin-5 by Stromelysin-2, because degradation of laminin-5 by this enzyme was observed in vitro. The inappropriate matrix contact of keratinocytes was accompanied by aberrant localization of β1-integrins and phosphorylated focal adhesion kinase, as well as by increased apoptosis of wound keratinocytes. These results suggest that a tightly regulated expression level of Stromelysin-2 is required for limited matrix degradation at the wound site, thereby controlling keratinocyte migration.
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Glucocorticoid-regulated gene expression during cutaneous wound repair.
Vitamins and hormones, 2000Co-Authors: Hans-dietmar Beer, Reinhard Fässler, Sabine WernerAbstract:Glucocorticoids exert a deleterious effect on the wound healing process, which has been suggested to result from the anti-inflammatory action of these steroids. In addition, recent studies have demonstrated that glucocorticoids regulate the expression of various genes at the wound site which are likely to encode key players in the wound repair process. Using a murine full-thickness excisional wound healing model, we analyzed the effect of dexamethasone on the expression of various cytokines, growth factors, enzymes, and extracellular matrix molecules in normal and wounded skin. We demonstrate that the proinflammatory cytokines interleukin-1 alpha and -beta, tumor necrosis factor alpha, keratinocyte growth factor, transforming growth factors beta 1, beta 2, and beta 3 and their receptors, platelet-derived growth factors and their receptors, tenascin-C, Stromelysin-2, macrophage metalloelastase, and enzymes involved in the generation of nitric oxide are targets of glucocorticoid action in wounded skin. These results indicate that anti-inflammatory steroids inhibit wound repair at least in part by influencing the expression of these key regulatory molecules.
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cDNA cloning and expression of the gene encoding murine Stromelysin-2 (MMP-10).
Gene, 1997Co-Authors: Marianne Madlener, Sabine WernerAbstract:Recently, we demonstrated a biphasic induction of the epithelial broad-spectrum matrix metalloproteinase (MMP) Stromelysin-2 during cutaneous wound healing. Now we have generated a murine wound cDNA libary and have used it to isolate the putative cDNA of this murine matrix metalloproteinase. The predicted sequence of the protein shows 76 and 89% identity with its human and rat analogues, respectively. Stromelysin-2 and Stromelysin-1 transcripts were both detected at very low levels in the lung and the heart of adult Balb/c mice, whereas Stromelysin-2 mRNA expression alone was found at comparatively high levels in the small intestine, a tissue characterized by continuous epithelial renewal. Recombinant forms of murine Stromelysin-1 and -2 produced in transfected COS cells were secreted and could be induced to undergo autocatalytic processing by addition of the organomercurial salt 4-aminophenylmercuric acetate (APMA).
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Regulation of the expression of Stromelysin-2 by growth factors in keratinocytes: implications for normal and impaired wound healing
Biochemical Journal, 1996Co-Authors: Marianne Madlener, William C. Parks, Cornelia Mauch, Walter Conca, Maria Brauchle, Sabine WernerAbstract:Keratinocyte growth factor (KGF) has been implicated in wound re-epithelialization and branching morphogenesis of several organs. To determine whether KGF induces these effects via induction of matrix metalloproteinase expression we have analysed the effect of KGF on the expression of Stromelysin-2 in cultured HaCaT keratinocytes. Here we show a strong induction of Stromelysin-2 mRNA within 5-8 h of stimulation of these cells with KGF. The degree of induction was similar to that achieved by treatment with epidermal growth factor or tumour necrosis factor alpha, whereas the stimulatory effect of transforming growth factor beta 1 was even stronger. To determine whether the induction of Stromelysin-2 expression by growth factors and cytokines might be important for wound healing, we analysed the expression of this gene during the healing process of full-thickness excisional wounds in mice. Whereas Stromelysin-2 mRNA could hardly be detected in unwounded skin, a biphasic induction was seen after injury and highest levels were found at days 1 and 5 after wounding. Hybridization in situ revealed the presence of Stromelysin-2 mRNA in basal keratinocytes at the wound edge but not in the underlying mesenchymal tissue. During impaired wound healing as seen in glucocorticoid-treated mice, Stromelysin-2 expression was significantly increased compared with untreated control mice. Taken together, these results suggest that correct regulation of this broad-spectrum metalloproteinase might be important for normal repair.
William C. Parks - One of the best experts on this subject based on the ideXlab platform.
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Stromelysin-2 (MMP-10) facilitates clearance and moderates inflammation and cell death following lung exposure to long multiwalled carbon nanotubes.
International journal of nanomedicine, 2017Co-Authors: Tyler C. Vandivort, Timothy P. Birkland, Talita P. Domiciano, Somenath Mitra, Terrance J. Kavanagh, William C. ParksAbstract:Multiwalled carbon nanotubes (MWCNTs) are nanomaterials composed of multiple layers of graphene cylinders with unique properties that make them valuable for a number of industries. However, rising global production has led to concerns regarding potential occupational exposures to them as raw materials during handling. This is especially true for long MWCNT fibers, whose aspect ratio has been posited to initiate pathology similar to that of asbestos. Matrix metalloproteinases (MMPs) are a class of extracellular endopeptidases that control various processes related to tissue repair, inflammation, and more. Stromelysin-2 (MMP-10) has roles in modulating macrophage activation and function, and hence, we used an MMP-10 null (Mmp10-/-) mouse model to assess its role in controlling lung responses to inhaled long MWCNTs. Oropharyngeal aspiration of long MWCNTs (80 µg/mouse) by wild-type mice induced expression of Mmp10 mRNA, which was accompanied by a robust inflammatory response characterized by elevated expression of Tnfa, Il6, and Il1b. In Mmp10-/- mice, we found that absence of MMP-10 led to impaired pulmonary clearance of MWCNTs and reduced macrophage cell survival. Exposure of wild-type bone marrow-derived macrophages (BMDMs) and alveolar macrophages to MWCNTs caused a rapid, dose-dependent upregulation of Mmp10 mRNA expression, which was accompanied by expression of pro-inflammatory products (Il6 and Il1b). These products were further enhanced in Mmp10-/- macrophages, resulting in increased caspase-3-dependent cell death compared with wild-type cells. These findings indicate that MMP-10 facilitates the clearance of MWCNTs and moderates the pro-inflammatory response of exposed alveolar and infiltrated macrophages.
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Stromelysin-2 (MMP10) Moderates Inflammation by Controlling Macrophage Activation
Journal of immunology (Baltimore Md. : 1950), 2016Co-Authors: Ryan S. Mcmahan, Timothy P. Birkland, Kate S. Smigiel, Tyler C. Vandivort, Maryam G. Rohani, Anne M. Manicone, John K. Mcguire, Sina A. Gharib, William C. ParksAbstract:Several members of the matrix metalloproteinase (MMP) family control a range of immune processes, such as leukocyte influx and chemokine activity. Stromelysin-2 (MMP10) is expressed by macrophages in numerous tissues after injury; however, little is known of its function. In this study, we report that MMP10 is expressed by macrophages in human lungs from patients with cystic fibrosis and induced in mouse macrophages in response to Pseudomonas aeruginosa infection both in vivo and by isolated resident alveolar and bone marrow–derived macrophages (BMDM). Our data indicates that macrophage MMP10 serves a beneficial function in response to acute infection. Whereas wild-type mice survived infection with minimal morbidity, 50% of Mmp10 −/− mice died and all showed sustained weight loss (morbidity). Although bacterial clearance and neutrophil influx did not differ between genotypes, macrophage numbers were ∼3-fold greater in infected Mmp10 −/− lungs than in wild-types. Adoptive transfer of wild-type BMDM normalized infection-induced morbidity in Mmp10 −/− recipients to wild-type levels, demonstrating that the protective effect of MMP10 was due to its production by macrophages. Both in vivo and in cultured alveolar macrophages and BMDM, expression of several M1 macrophage markers was elevated, whereas M2 markers were reduced in Mmp10 −/− tissue and cells. Global gene expression analysis revealed that infection-mediated transcriptional changes persisted in Mmp10 −/− BMDM long after they were downregulated in wild-type cells. These results indicate that MMP10 serves a beneficial role in response to acute infection by moderating the proinflammatory response of resident and infiltrating macrophages.
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Macrophage migration and invasion is regulated by MMP10 expression.
PloS one, 2013Co-Authors: Megan Y. Murray, William C. Parks, Timothy P. Birkland, Jonathan D. Howe, Andrew D. Rowan, Mark Fidock, Jelena GavrilovicAbstract:This study was designed to identify metalloproteinase determinants of macrophage migration and led to the specific hypothesis that matrix metalloproteinase 10 (MMP10/Stromelysin-2) facilitates macrophage migration. We first profiled expression of all MMPs in LPS-stimulated primary murine bone marrow-derived macrophages and Raw264.7 cells and found that MMP10 was stimulated early (3 h) and down-regulated later (24 h). Based on this pattern of expression, we speculated that MMP10 plays a role in macrophage responses, such as migration. Indeed, using time lapse microscopy, we found that RNAi silencing of MMP10 in primary macrophages resulted in markedly reduced migration, which was reversed with exogenous active MMP10 protein. Mmp10−/− bone marrow-derived macrophages displayed significantly reduced migration over a two-dimensional fibronectin matrix. Invasion of primary wild-type macrophages into Matrigel supplemented with fibronectin was also markedly impaired in Mmp10−/− cells. MMP10 expression in macrophages thus emerges as an important moderator of cell migration and invasion. These findings support the hypothesis that MMP10 promotes macrophage movement and may have implications in understanding the control of macrophages in several pathologies, including the abnormal wound healing response associated with pro-inflammatory conditions.
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Individual Matrix Metalloproteinases Control Distinct Transcriptional Responses in Airway Epithelial Cells Infected with Pseudomonas aeruginosa
Infection and immunity, 2007Co-Authors: Sean Y. Kassim, William C. Parks, Timothy P. Birkland, Sina A. Gharib, Brighain H. Mecham, John K. McguireAbstract:Airway epithelium is the initial point of host-pathogen interaction in Pseudomonas aeruginosa infection, an important pathogen in cystic fibrosis and nosocomial pneumonia. We used global gene expression analysis to determine airway epithelial transcriptional responses dependent on matrilysin (matrix metalloproteinase 7 [MMP-7]) and Stromelysin-2 (MMP-10), two MMPs induced by acute P. aeruginosa pulmonary infection. Extraction of differential gene expression (EDGE) analysis of gene expression changes in P. aeruginosa-infected organotypic tracheal epithelial cell cultures from wild-type, Mmp7−/−, and Mmp10−/− mice identified 2,091 matrilysin-dependent and 1,628 Stromelysin-2-dependent genes that were differentially expressed. Key node network analysis showed that these MMPs controlled distinct gene expression programs involved in proliferation, cell death, immune responses, and signal transduction, among other host defense processes. Our results demonstrate discrete roles for these MMPs in regulating epithelial responses to Pseudomonas infection and show that a global genomics strategy can be used to assess MMP function.
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Activities of the Matrix Metalloproteinase Stromelysin-2 (MMP-10) in Matrix Degradation and Keratinocyte Organization in Wounded Skin
Molecular biology of the cell, 2004Co-Authors: Monika Krampert, Wilhelm Bloch, Takako Sasaki, Philippe Bugnon, Thomas Rülicke, Eckhard Wolf, Monique Aumailley, William C. Parks, Sabine WernerAbstract:The matrix metalloproteinase Stromelysin-2 is expressed in keratinocytes of the epithelial tongue of skin wounds, suggesting a role in keratinocyte migration. Here, we show that Stromelysin-2 enhances migration of cultured keratinocytes. To gain insight into the in vivo activities of Stromelysin-2 in epithelial repair, we generated transgenic mice expressing a constitutively active Stromelysin-2 mutant in keratinocytes. These animals had no alterations in skin architecture, and the healing rate of skin wounds was normal. Histologically, however, we found abnormalities in the organization of the wound epithelium. Keratinocytes at the migrating epidermal tip were scattered in most sections of mice with high expression level, and there was a reduced deposition of new matrix. In particular, the staining pattern of laminin-5 at the wound site was altered. This may be due to proteolytic processing of laminin-5 by Stromelysin-2, because degradation of laminin-5 by this enzyme was observed in vitro. The inappropriate matrix contact of keratinocytes was accompanied by aberrant localization of β1-integrins and phosphorylated focal adhesion kinase, as well as by increased apoptosis of wound keratinocytes. These results suggest that a tightly regulated expression level of Stromelysin-2 is required for limited matrix degradation at the wound site, thereby controlling keratinocyte migration.
Henning Birkedal-hansen - One of the best experts on this subject based on the ideXlab platform.
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Distinct populations of basal keratinocytes express Stromelysin-1 and Stromelysin-2 in chronic wounds.
The Journal of clinical investigation, 1994Co-Authors: Ulpu Saarialho-kere, William C. Parks, Alice P. Pentland, Henning Birkedal-hansen, Howard G. WelgusAbstract:Wound repair involves cell migration and tissue remodeling, and these ordered and regulated processes are facilitated by matrix-degrading proteases. We reported that interstitial collagenase is invariantly expressed by basal keratinocytes at the migrating front of healing epidermis (Saarialho-Kere, U. K., E. S. Chang, H. G. Welgus, and W. C. Parks, 1992. J. Clin. Invest. 90:1952-1957). Because of the limited substrate specificity of collagenase, principally for interstitial fibrillar collagens, other enzymes must also be produced in the wound environment to effectively restructure tissues with a complex matrix composition. Stromelysins-1 and -2 are closely related, yet distinct metalloproteinases, and both can degrade many noncollagenous connective tissue macromolecules. Using in situ hybridization and immunohistochemistry, we found that both Stromelysins are produced by distinct populations of keratinocytes in a variety of chronic ulcers. Stromelysin-1 mRNA and protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of proliferating epidermis. In contrast, Stromelysin-2 mRNA was seen only in basal keratinocytes at the migrating front, in the same epidermal cell population that expresses collagenase. Stromelysin-1-producing keratinocytes resided on the basement membrane, whereas Stromelysin-2-producing keratinocytes were in contact with the dermal matrix. Furthermore, Stromelysin-1 expression was prominent in dermal fibroblasts, whereas no signal for Stromelysin-2 was seen in any dermal cell. These findings demonstrate that Stromelysins-1 and -2 are produced by different populations of basal keratinocytes in response to wounding and suggest that these two matrix metalloproteinases serve distinct roles in tissue repair.
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Cell type-specific regulation of SL-1 and SL-2 genes. Induction of the SL-2 gene but not the SL-1 gene by human keratinocytes in response to cytokines and phorbolesters.
The Journal of biological chemistry, 1993Co-Authors: L J Windsor, Jeffrey A. Engler, H E Grenett, B. Birkedal-hansen, M.k. Bodden, Henning Birkedal-hansenAbstract:The Stromelysin-2 (SL-2) gene is transcriptionally active in normal human keratinocytes and encodes a secreted, catalytically competent but latent matrix metalloproteinase. Phorbolester induction resulted in the emergence of SL-2 (but not SL-1 transcripts), whereas the opposite was true for human mucosal fibroblasts. Expression of keratinocyte SL-2 was also induced by the two keratinocyte growth factors, transforming growth factor-alpha and epidermal growth factor, by the proinflammatory cytokine, tumor necrosis factor-alpha, but, somewhat surprisingly, not by interleukin-1 beta. The latent SL-2 proenzyme was isolated from 12-O-tetradecanoylphorbol-13-acetate-induced keratinocytes by immunoaffinity chromatography using a cross-reactive antibody raised against human SL-1. This procedure led to the recovery of a single M(r) 54,000 molecular species at a level of approximately 0.2 microgram/ml of culture medium. Amino-terminal sequencing identified the protein as SL-2 and verified the predicted signal sequence cleavage site. Conformational activation of latent SL-2 precursor by SDS gave rise to a full-length, uncleaved (M(r) 54,000) active form and at the same time exposed a cryptic thiol group. By contrast, organomercurial activation resulted in autolytic truncation of the molecule with loss of M(r) approximately 10,000 propeptide. SL-2 shared with (human fibroblast) SL-1 the ability to cleave casein, to "superactivate" fibroblast type procollagenase, and to form apparently binary, SDS-resistant complexes with tissue inhibitor of metalloproteinases-1.
M T Salmela - One of the best experts on this subject based on the ideXlab platform.
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Collagenase-1 (MMP-1), matrilysin-1 (MMP-7), and Stromelysin-2 (MMP-10) are expressed by migrating enterocytes during intestinal wound healing.
Scandinavian journal of gastroenterology, 2004Co-Authors: M T Salmela, Pauli Puolakkainen, Sylvia L.f. Pender, M.-l. Karjalainen-lindsberg, Thomas T. Macdonald, U. Saarialho-kereAbstract:Background: Matrix metalloproteinases (MMPs) play a crucial role in wound healing of the skin, airways, and cornea, but data on MMPs in normal intestinal wound healing is limited. The aim of this study was to clarify the role of collagenase-1 (MMP-1), matrilysin-1 (MMP-7), and Stromelysin-2 (MMP-10) in intestinal wound repair and to determine the effect of cytokines on the expression of these MMPs in intestinal epithelial cell lines. Methods: Surgical specimens from patients with ischemic colitis (n = 5) were used as an in vivo model of intestinal re-epithelialization. Fetal ileal explants were used as an ex vivo model. In situ hybridization for MMPs -1, -3, -7, and -10 was performed and immunohistochemical stainings were used to localize MMP-7 and -9 expressing cells. Stainings for cytokeratin and laminin-5 were performed to identify epithelial cells and migrating enterocytes, respectively. Caco-2, HT-29, and WiDr cell lines were treated for 6-48 h with different cytokines (e.g. EGF, KGF, IL-1β, TGF-α, T...
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Upregulation of matrix metalloproteinases in a model of T cell mediated tissue injury in the gut: analysis by gene array and in situ hybridisation
Gut, 2002Co-Authors: M T Salmela, Ulpu Saarialho-kere, Thomas T. Macdonald, D Black, B Irvine, T Zhuma, Sylvia L.f. PenderAbstract:Background and aim: Matrix metalloproteinases (MMPs) have been implicated in tissue remodelling and ulceration in inflammatory bowel disease and coeliac disease. Studies to date have concluded that Stromelysin 1 is functionally involved in mucosal degradation. However, there are many other MMPs whose function in the gut is currently unknown. This work had two aims: firstly, to use gene array technology to measure changes in MMP and tissue inhibitor of metalloproteinase (TIMP) expression in a model of T cell mediated injury in the gut, and secondly, to correlate data from gene arrays with that generated by in situ hybridisation. Methods: T cells in explants of human fetal gut were activated with pokeweed mitogen or anti-CD3 plus interleukin 12. Gene array analysis and in situ hybridisation were performed to investigate changes in MMP gene expression. Results: Both gene array analysis and in situ hybridisation indicated marked upregulation of Stromelysin 2 and macrophage metalloelastase expression in the explants associated with mucosal destruction. The arrays also confirmed our previous observation that interstitial collagenase (MMP-1), Stromelysin 1 (MMP-3), and gelatinase B (MMP-9) are upregulated but there was no change in MMP-2, -7, -8, -9, -11, -13, -14–17, or -19. Following T cell activation, transcripts for TIMPs were reduced. Conclusions: These results show that there is differential upregulation of MMPs during T cell responses in the gut and suggest that further studies on the role of Stromelysin 2 and macrophage metalloelastase may show that they have a functional role. In addition, the increase in MMPs and reduction in TIMPs suggest that the protease/antiprotease balance in the mucosa may determine the extent of mucosal degradation.
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Upregulation and differential expression of matrilysin (MMP-7) and metalloelastase (MMP-12) and their inhibitors TIMP-1 and TIMP-3 in Barrett's oesophageal adenocarcinoma.
British journal of cancer, 2001Co-Authors: M T Salmela, Pauli Puolakkainen, Ulpu Saarialho-kereAbstract:Oesophageal adenocarcinoma is believed to arise from metaplastic mucosa in the distal oesophagus, a condition also known as Barrett's oesophagus (BE). BE develops as a result of injury caused by refluxing gastric and duodenal contents and is associated with increased risk of malignant transformation. Matrix metalloproteinases (MMPs) have been implicated in all aspects of tumour progression; tumour growth, basement membrane degradation, invasion and metastatic spread. Using in situ hybridization, we investigated the expression patterns of collagenases-1 and -3, Stromelysin-2, matrilysin, metalloelastase and TIMPs-1 and -3 in BE, adenocarcinoma and lymph-node metastases. Matrilysin was expressed abundantly in 12/15 tumours and in 4/6 lymph-node metastases and its expression correlated with the histological aggressiveness of tumour. Matrilysin and metalloelastase were upregulated already in BE. Stromelysin-2 and collagenase-3 expression was detected only in a few tumours. Collagenase-1 was expressed by cancer and stromal cells in 9/15 tumours. Tumour-infiltrating macrophages expressed metalloelastase in 13/15 cancers. TIMPs-1 and -3 were expressed in 12/15 and 11/15 tumours, respectively. Laminin-5 and tenascin were abundantly expressed at the invasive front of poorly differentiated tumours, but not in BE. Our results indicate that matrilysin is the principal MMP expressed by tumour cells in oesophageal adenocarcinoma, and further studies are needed to investigate whether matrilysin or tenascin-C could be used as a predictive marker for progression of BE to cancer.
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Parallel expression of macrophage metalloelastase (MMP-12) in duodenal and skin lesions of patients with dermatitis herpetiformis.
Gut, 2001Co-Authors: M T Salmela, Sylvia L.f. Pender, Thomas T. Macdonald, T Reunala, Ulpu Saarialho-kereAbstract:BACKGROUND—Dermatitis herpetiformis (DH) is a specific dermatological manifestation of coeliac disease and 80% of DH patients have gluten sensitive enteropathy manifested by crypt hyperplasia and villous atrophy. Matrix degradation mediated by collagenase 1 (MMP-1) and Stromelysin 1 (MMP-3) has previously been implicated in the pathobiology of coeliac intestine and cutaneous DH blisters. AIMS—To study expression of Stromelysin 2, metalloelastase, collagenase 3, and matrilysin in the intestine and skin of DH patients. METHODS—In situ hybridisation using 35S labelled cRNA probes was performed on duodenal biopsies of 15 DH patients, three samples each of control duodenal or jejunal mucosa, fetal ileal explants, lesional DH skin, and 19 serial biopsies of experimental DH blisters. Immunostaining was used to examine type IV collagen, macrophages (CD68), and 92 kDa gelatinase (MMP-9) in the specimens. RESULTS—Metalloelastase (MMP-12) was abundantly expressed by subepithelial macrophages in both coeliac intestine and spontaneous and induced DH rash. It was also upregulated in the experimental model of coeliac disease (staphylococcal endotoxin B stimulated fetal explants). The only other MMP detected was MMP-9 which did not colocalise with MMP-12. CONCLUSIONS—Upregulation of metalloelastase is associated with T cell mediated immune responses both in the intestine and skin. In addition to modulating macrophage migration, it may contribute to degradation of proteoglycans or basement membrane components in the subepithelial mucosa. Keywords: coeliac disease; metalloproteinase; dermatitis herpetiformis
