Abstract
Programmed expression of matrix metalloproteinases is involved in wound healing in various organs. We have previously demonstrated enhanced expression of collagenase-1, stromelysin-1, matrilysin, and tissue inhibitor of metalloproteinases (TIMP-1) in gastrointestinal ulcerations. To further define the role of matrix-degrading enzymes and their inhibitors in intestinal inflammation and ulcerations, the expression of stromelysin-2 (MMP-10), collagenase-3 (MMP-13), macrophage metalloelastase (HME, MMP-12), and TIMP-3 mRNAs was studied using in situ hybridization and immunohistochemistry in 38 samples representing ulcerative colitis, Crohn's disease, ischemic colitis, and normal intestine. As controls for normally healing intestinal wounds, 12 postoperative samples of rat experimental jejunal anastomoses were also examined. The colitis types studied did not essentially differ in their MMP expression. We found stromelysin-2 mRNA in laminin-5-positive and Ki-67-negative enterocytes bordering the ulcerations. HME was abundantly expressed by macrophages in the vicinity of shedding mucosal epithelium and beneath the necrotic surface of the ulcers. Collagenase-3 and TIMP-3 were expressed by fibroblast-like cells deeper in the remodeling intestinal wall. Expression for stromelysin-2 and collagenase-3 was observed in granulation tissue, but not the epithelium, of the rat anastomoses. Our results suggest a role for stromelysin-2 in epithelial migration and for metalloelastase in macrophage movement and epithelial cell shedding.
Full text
PDF









Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Airola K., Ahonen M., Johansson N., Heikkilä P., Kere J., Kähäri V. M., Saarialho-Kere U. K. Human TIMP-3 is expressed during fetal development, hair growth cycle, and cancer progression. J Histochem Cytochem. 1998 Apr;46(4):437–447. doi: 10.1177/002215549804600403. [DOI] [PubMed] [Google Scholar]
- Airola K., Reunala T., Salo S., Saarialho-Kere U. K. Urokinase plasminogen activator is expressed by basal keratinocytes before interstitial collagenase, stromelysin-1, and laminin-5 in experimentally induced dermatitis herpetiformis lesions. J Invest Dermatol. 1997 Jan;108(1):7–11. doi: 10.1111/1523-1747.ep12285610. [DOI] [PubMed] [Google Scholar]
- Anand-Apte B., Pepper M. S., Voest E., Montesano R., Olsen B., Murphy G., Apte S. S., Zetter B. Inhibition of angiogenesis by tissue inhibitor of metalloproteinase-3. Invest Ophthalmol Vis Sci. 1997 Apr;38(5):817–823. [PubMed] [Google Scholar]
- Apte S. S., Mattei M. G., Olsen B. R. Cloning of the cDNA encoding human tissue inhibitor of metalloproteinases-3 (TIMP-3) and mapping of the TIMP3 gene to chromosome 22. Genomics. 1994 Jan 1;19(1):86–90. doi: 10.1006/geno.1994.1016. [DOI] [PubMed] [Google Scholar]
- Babyatsky M. W., Rossiter G., Podolsky D. K. Expression of transforming growth factors alpha and beta in colonic mucosa in inflammatory bowel disease. Gastroenterology. 1996 Apr;110(4):975–984. doi: 10.1053/gast.1996.v110.pm8613031. [DOI] [PubMed] [Google Scholar]
- Bailey C. J., Hembry R. M., Alexander A., Irving M. H., Grant M. E., Shuttleworth C. A. Distribution of the matrix metalloproteinases stromelysin, gelatinases A and B, and collagenase in Crohn's disease and normal intestine. J Clin Pathol. 1994 Feb;47(2):113–116. doi: 10.1136/jcp.47.2.113. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Baragi V. M., Qiu L., Gunja-Smith Z., Woessner J. F., Jr, Lesch C. A., Guglietta A. Role of metalloproteinases in the development and healing of acetic acid-induced gastric ulcer in rats. Scand J Gastroenterol. 1997 May;32(5):419–426. doi: 10.3109/00365529709025075. [DOI] [PubMed] [Google Scholar]
- Brauchle M., Madlener M., Wagner A. D., Angermeyer K., Lauer U., Hofschneider P. H., Gregor M., Werner S. Keratinocyte growth factor is highly overexpressed in inflammatory bowel disease. Am J Pathol. 1996 Aug;149(2):521–529. [PMC free article] [PubMed] [Google Scholar]
- Busiek D. F., Ross F. P., McDonnell S., Murphy G., Matrisian L. M., Welgus H. G. The matrix metalloprotease matrilysin (PUMP) is expressed in developing human mononuclear phagocytes. J Biol Chem. 1992 May 5;267(13):9087–9092. [PubMed] [Google Scholar]
- Cattoretti G., Becker M. H., Key G., Duchrow M., Schlüter C., Galle J., Gerdes J. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol. 1992 Dec;168(4):357–363. doi: 10.1002/path.1711680404. [DOI] [PubMed] [Google Scholar]
- Chandler S., Cossins J., Lury J., Wells G. Macrophage metalloelastase degrades matrix and myelin proteins and processes a tumour necrosis factor-alpha fusion protein. Biochem Biophys Res Commun. 1996 Nov 12;228(2):421–429. doi: 10.1006/bbrc.1996.1677. [DOI] [PubMed] [Google Scholar]
- Conca W., Willmroth F. Human T lymphocytes express a member of the Matrix Metalloproteinase gene family. Arthritis Rheum. 1994 Jun;37(6):951–956. doi: 10.1002/art.1780370626. [DOI] [PubMed] [Google Scholar]
- Fariss R. N., Apte S. S., Olsen B. R., Iwata K., Milam A. H. Tissue inhibitor of metalloproteinases-3 is a component of Bruch's membrane of the eye. Am J Pathol. 1997 Jan;150(1):323–328. [PMC free article] [PubMed] [Google Scholar]
- Fini M. E., Parks W. C., Rinehart W. B., Girard M. T., Matsubara M., Cook J. R., West-Mays J. A., Sadow P. M., Burgeson R. E., Jeffrey J. J. Role of matrix metalloproteinases in failure to re-epithelialize after corneal injury. Am J Pathol. 1996 Oct;149(4):1287–1302. [PMC free article] [PubMed] [Google Scholar]
- Freije J. M., Díez-Itza I., Balbín M., Sánchez L. M., Blasco R., Tolivia J., López-Otín C. Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas. J Biol Chem. 1994 Jun 17;269(24):16766–16773. [PubMed] [Google Scholar]
- Gronski T. J., Jr, Martin R. L., Kobayashi D. K., Walsh B. C., Holman M. C., Huber M., Van Wart H. E., Shapiro S. D. Hydrolysis of a broad spectrum of extracellular matrix proteins by human macrophage elastase. J Biol Chem. 1997 May 2;272(18):12189–12194. doi: 10.1074/jbc.272.18.12189. [DOI] [PubMed] [Google Scholar]
- Johansson N., Westermarck J., Leppä S., Häkkinen L., Koivisto L., López-Otín C., Peltonen J., Heino J., Kähäri V. M. Collagenase 3 (matrix metalloproteinase 13) gene expression by HaCaT keratinocytes is enhanced by tumor necrosis factor alpha and transforming growth factor beta. Cell Growth Differ. 1997 Feb;8(2):243–250. [PubMed] [Google Scholar]
- Leco K. J., Apte S. S., Taniguchi G. T., Hawkes S. P., Khokha R., Schultz G. A., Edwards D. R. Murine tissue inhibitor of metalloproteinases-4 (Timp-4): cDNA isolation and expression in adult mouse tissues. FEBS Lett. 1997 Jan 20;401(2-3):213–217. doi: 10.1016/s0014-5793(96)01474-3. [DOI] [PubMed] [Google Scholar]
- Leco K. J., Khokha R., Pavloff N., Hawkes S. P., Edwards D. R. Tissue inhibitor of metalloproteinases-3 (TIMP-3) is an extracellular matrix-associated protein with a distinctive pattern of expression in mouse cells and tissues. J Biol Chem. 1994 Mar 25;269(12):9352–9360. [PubMed] [Google Scholar]
- Leivo I., Tani T., Laitinen L., Bruns R., Kivilaakso E., Lehto V. P., Burgeson R. E., Virtanen I. Anchoring complex components laminin-5 and type VII collagen in intestine: association with migrating and differentiating enterocytes. J Histochem Cytochem. 1996 Nov;44(11):1267–1277. doi: 10.1177/44.11.8918902. [DOI] [PubMed] [Google Scholar]
- Lotz M. M., Nusrat A., Madara J. L., Ezzell R., Wewer U. M., Mercurio A. M. Intestinal epithelial restitution. Involvement of specific laminin isoforms and integrin laminin receptors in wound closure of a transformed model epithelium. Am J Pathol. 1997 Feb;150(2):747–760. [PMC free article] [PubMed] [Google Scholar]
- Madlener M., Mauch C., Conca W., Brauchle M., Parks W. C., Werner S. Regulation of the expression of stromelysin-2 by growth factors in keratinocytes: implications for normal and impaired wound healing. Biochem J. 1996 Dec 1;320(Pt 2):659–664. doi: 10.1042/bj3200659. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Muller D., Quantin B., Gesnel M. C., Millon-Collard R., Abecassis J., Breathnach R. The collagenase gene family in humans consists of at least four members. Biochem J. 1988 Jul 1;253(1):187–192. doi: 10.1042/bj2530187. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Murch S. H., Braegger C. P., Walker-Smith J. A., MacDonald T. T. Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease. Gut. 1993 Dec;34(12):1705–1709. doi: 10.1136/gut.34.12.1705. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Murphy G., Cockett M. I., Ward R. V., Docherty A. J. Matrix metalloproteinase degradation of elastin, type IV collagen and proteoglycan. A quantitative comparison of the activities of 95 kDa and 72 kDa gelatinases, stromelysins-1 and -2 and punctuated metalloproteinase (PUMP). Biochem J. 1991 Jul 1;277(Pt 1):277–279. doi: 10.1042/bj2770277. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Newell K. J., Witty J. P., Rodgers W. H., Matrisian L. M. Expression and localization of matrix-degrading metalloproteinases during colorectal tumorigenesis. Mol Carcinog. 1994 Aug;10(4):199–206. doi: 10.1002/mc.2940100404. [DOI] [PubMed] [Google Scholar]
- Okada A., Tomasetto C., Lutz Y., Bellocq J. P., Rio M. C., Basset P. Expression of matrix metalloproteinases during rat skin wound healing: evidence that membrane type-1 matrix metalloproteinase is a stromal activator of pro-gelatinase A. J Cell Biol. 1997 Apr 7;137(1):67–77. doi: 10.1083/jcb.137.1.67. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pender S. L., Tickle S. P., Docherty A. J., Howie D., Wathen N. C., MacDonald T. T. A major role for matrix metalloproteinases in T cell injury in the gut. J Immunol. 1997 Feb 15;158(4):1582–1590. [PubMed] [Google Scholar]
- Polette M., Clavel C., Muller D., Abecassis J., Binninger I., Birembaut P. Detection of mRNAs encoding collagenase I and stromelysin 2 in carcinomas of the head and neck by in situ hybridization. Invasion Metastasis. 1991;11(2):76–83. [PubMed] [Google Scholar]
- Powe D. G., Brough J. L., Carter G. I., Bailey E. M., Stetler-Stevenson W. G., Turner D. R., Hewitt R. E. TIMP-3 mRNA expression is regionally increased in moderately and poorly differentiated colorectal adenocarcinoma. Br J Cancer. 1997;75(11):1678–1683. doi: 10.1038/bjc.1997.285. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Prosser I. W., Stenmark K. R., Suthar M., Crouch E. C., Mecham R. P., Parks W. C. Regional heterogeneity of elastin and collagen gene expression in intralobar arteries in response to hypoxic pulmonary hypertension as demonstrated by in situ hybridization. Am J Pathol. 1989 Dec;135(6):1073–1088. [PMC free article] [PubMed] [Google Scholar]
- Pulford K. A., Rigney E. M., Micklem K. J., Jones M., Stross W. P., Gatter K. C., Mason D. Y. KP1: a new monoclonal antibody that detects a monocyte/macrophage associated antigen in routinely processed tissue sections. J Clin Pathol. 1989 Apr;42(4):414–421. doi: 10.1136/jcp.42.4.414. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Pyke C., Rømer J., Kallunki P., Lund L. R., Ralfkiaer E., Danø K., Tryggvason K. The gamma 2 chain of kalinin/laminin 5 is preferentially expressed in invading malignant cells in human cancers. Am J Pathol. 1994 Oct;145(4):782–791. [PMC free article] [PubMed] [Google Scholar]
- Rodgers W. H., Matrisian L. M., Giudice L. C., Dsupin B., Cannon P., Svitek C., Gorstein F., Osteen K. G. Patterns of matrix metalloproteinase expression in cycling endometrium imply differential functions and regulation by steroid hormones. J Clin Invest. 1994 Sep;94(3):946–953. doi: 10.1172/JCI117461. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Saarialho-Kere U. K., Kovacs S. O., Pentland A. P., Olerud J. E., Welgus H. G., Parks W. C. Cell-matrix interactions modulate interstitial collagenase expression by human keratinocytes actively involved in wound healing. J Clin Invest. 1993 Dec;92(6):2858–2866. doi: 10.1172/JCI116906. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Saarialho-Kere U. K., Pentland A. P., Birkedal-Hansen H., Parks W. C., Welgus H. G. Distinct populations of basal keratinocytes express stromelysin-1 and stromelysin-2 in chronic wounds. J Clin Invest. 1994 Jul;94(1):79–88. doi: 10.1172/JCI117351. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Saarialho-Kere U. K., Vaalamo M., Puolakkainen P., Airola K., Parks W. C., Karjalainen-Lindsberg M. L. Enhanced expression of matrilysin, collagenase, and stromelysin-1 in gastrointestinal ulcers. Am J Pathol. 1996 Feb;148(2):519–526. [PMC free article] [PubMed] [Google Scholar]
- Shapiro S. D., Kobayashi D. K., Ley T. J. Cloning and characterization of a unique elastolytic metalloproteinase produced by human alveolar macrophages. J Biol Chem. 1993 Nov 15;268(32):23824–23829. [PubMed] [Google Scholar]
- Shipley J. M., Wesselschmidt R. L., Kobayashi D. K., Ley T. J., Shapiro S. D. Metalloelastase is required for macrophage-mediated proteolysis and matrix invasion in mice. Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):3942–3946. doi: 10.1073/pnas.93.9.3942. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tani T., Karttunen T., Kiviluoto T., Kivilaakso E., Burgeson R. E., Sipponen P., Virtanen I. Alpha 6 beta 4 integrin and newly deposited laminin-1 and laminin-5 form the adhesion mechanism of gastric carcinoma. Continuous expression of laminins but not that of collagen VII is preserved in invasive parts of the carcinomas: implications for acquisition of the invading phenotype. Am J Pathol. 1996 Sep;149(3):781–793. [PMC free article] [PubMed] [Google Scholar]
- Uría J. A., Ferrando A. A., Velasco G., Freije J. M., López-Otín C. Structure and expression in breast tumors of human TIMP-3, a new member of the metalloproteinase inhibitor family. Cancer Res. 1994 Apr 15;54(8):2091–2094. [PubMed] [Google Scholar]
- Vaalamo M., Mattila L., Johansson N., Kariniemi A. L., Karjalainen-Lindsberg M. L., Kähäri V. M., Saarialho-Kere U. Distinct populations of stromal cells express collagenase-3 (MMP-13) and collagenase-1 (MMP-1) in chronic ulcers but not in normally healing wounds. J Invest Dermatol. 1997 Jul;109(1):96–101. doi: 10.1111/1523-1747.ep12276722. [DOI] [PubMed] [Google Scholar]
- Vaalamo M., Weckroth M., Puolakkainen P., Kere J., Saarinen P., Lauharanta J., Saarialho-Kere U. K. Patterns of matrix metalloproteinase and TIMP-1 expression in chronic and normally healing human cutaneous wounds. Br J Dermatol. 1996 Jul;135(1):52–59. [PubMed] [Google Scholar]
- Welgus H. G., Fliszar C. J., Seltzer J. L., Schmid T. M., Jeffrey J. J. Differential susceptibility of type X collagen to cleavage by two mammalian interstitial collagenases and 72-kDa type IV collagenase. J Biol Chem. 1990 Aug 15;265(23):13521–13527. [PubMed] [Google Scholar]
- Welgus H. G., Jeffrey J. J., Eisen A. Z. The collagen substrate specificity of human skin fibroblast collagenase. J Biol Chem. 1981 Sep 25;256(18):9511–9515. [PubMed] [Google Scholar]
- Windsor L. J., Grenett H., Birkedal-Hansen B., Bodden M. K., Engler J. A., Birkedal-Hansen H. 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. J Biol Chem. 1993 Aug 15;268(23):17341–17347. [PubMed] [Google Scholar]
- Yamamoto H., Itoh F., Hinoda Y., Senota A., Yoshimoto M., Nakamura H., Imai K., Yachi A. Expression of matrilysin mRNA in colorectal adenomas and its induction by truncated fibronectin. Biochem Biophys Res Commun. 1994 Jun 15;201(2):657–664. doi: 10.1006/bbrc.1994.1751. [DOI] [PubMed] [Google Scholar]
- Zhang K., Kramer R. H. Laminin 5 deposition promotes keratinocyte motility. Exp Cell Res. 1996 Sep 15;227(2):309–322. doi: 10.1006/excr.1996.0280. [DOI] [PubMed] [Google Scholar]
- von Boguslawsky K. Immunohistochemical detection of progesterone receptors in paraffin sections. A novel method using microwave oven pretreatment. APMIS. 1994 Sep;102(9):641–646. doi: 10.1111/j.1699-0463.1994.tb05215.x. [DOI] [PubMed] [Google Scholar]