Increased Inflammation Delays Wound Healing in Mice Deficient in Collagenase-2 (MMP-8)

[en] Matrix metalloproteinases (MMPs) have been implicated in numerous tissue-remodeling processes. The finding that mice deficient in collagenase-2 (MMP-8) are more susceptible to develop skin cancer, prompted us to investigate the role of this protease in cutaneous wound healing. We have observed a significant delay in wound closure in MMP8-/- mice and an altered inflammatory response in their wounds, with a delay of neutrophil infiltration during the first days and a persistent inflammation at later time points. These changes were accompanied by alterations in the TGF-beta1 signaling pathway and by an apoptosis defect in MMP8-/- mice. The delay in wound healing observed in MMP8-/- mice was rescued by bone marrow transplantation from wild-type mice. Analysis of other MMPs showed that MMP8-/- mice had a significant increase in the expression of MMP-9, suggesting that both proteases might act coordinately in this process. This possibility was further supported by the novel finding that MMP-8 and MMP-9 form specific complexes in vivo. Taken together, these data indicate that MMP-8 participates in wound repair by contributing to the resolution of inflammation and open the possibility to develop new strategies for treating wound healing defects.

Disciplines :

Biochemistry, biophysics & molecular biology

Author, co-author :

Gutierrez-Fernandez, A.

Inada, M.

Balbin, M.

Fueyo, A.

Pitiot, A. S.

Astudillo, A.

Hirose, K.

Hirata, M.

Shapiro, S. D.

Noël, Agnès ; Université de Liège - ULiège > Département des sciences biomédicales et précliniques > Biologie cellulaire et moléculaire appliquée à l'homme

More authors (4 more)

Language :

English

Title :

Increased Inflammation Delays Wound Healing in Mice Deficient in Collagenase-2 (MMP-8)

Publication date :

2007

Journal title :

FASEB Journal

ISSN :

0892-6638

eISSN :

1530-6860

Publisher :

Federation of American Society for Experimental Biology, Bethesda, United States - Maryland

Volume :

Issue :

Pages :

2580-91

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 27 August 2009

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213

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Bibliography

Puente, X. S., Sánchez, L. M., Overall, C. M., and López-Otín, C. (2003) Human and mouse proteases: a comparative genomic approach. Nat. Rev. Genet. 4, 544-558
Coussens, L. M., and Werb, Z. (2002) Inflammation and cancer. Nature 420, 860-867
Parks, W. C., Wilson, C. L., and Lopez-Boado, Y. S. (2004) Matrix metalloproteinases as modulators of inflammation and innate immunity. Nat. Rev. Immunol. 4, 617-629
Overall, C. M., and López-Otín, C. (2002) Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat. Rev. Cancer. 2, 657-672
Folgueras, A. R., Pendás, A. M., Sánchez, L. M., and López-Otín, C. (2004) Matrix metalloproteinases in cancer: from new functions to improved inhibition strategies. Int. J. Dev. Biol. 48, 411-424
Lund, L. R., Green, K. A., Stoop, A. A., Ploug, M., Almholt, K., Lilla, J., Nielsen, B. S., Christensen, I. J., Craik, C. S., Werb, Z., Dano, K., and Romer, J. (2006) Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice. EMBO J. 25, 2686-2697
Lund, L. R., Romer, J., Bugge, T. H., Nielsen, B. S., Frandsen, T. L., Degen, J. L., Stephens, R. W., and Dano, K. (1999) Functional overlap between two classes of matrix-degrading proteases in wound healing. EMBO J. 18, 4645-4656
Mirastschijski, U., Haaksma, C. J., Tomasek, J. J., and Agren, M. S. (2004) Matrix metalloproteinase inhibitor GM 6001 attenuates keratinocyte migration, contraction and myofibroblast formation in skin wounds. Exp. Cell Res. 299, 465-475
Salonurmi, T., Parikka, M., Kontusaari, S., Pirila, E., Munaut, C., Salo, T., and Tryggvason, K. (2004) Overexpression of TIMP-1 under the MMP-9 promoter interferes with wound healing in transgenic mice. Cell Tissue Res. 315, 27-37
Beare, A. H., O'Kane, S., Krane, S. M., and Ferguson, M. W. (2003) Severely impaired wound healing in the collagenase-resistant mouse. J. Invest. Dermatol. 120, 153-163
Mirastschijski, U., Zhou, Z., Rollman, O., Tryggvason, K., and Agren, M. S. (2004) Wound healing in membrane-type-1 matrix metalloproteinase-deficient mice. J. Invest. Dermatol. 123, 600-602
Sato, H., Takino, T., Okada, Y., Cao, J., Shinagawa, A., Yamamoto, E., and Seiki, M. (1994) A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 370, 61-65
Sabeh, F., Ota, I., Holmbeck, K., Birkedal-Hansen, H., Soloway, P., Balbin, M., Lopez-Otin, C., Shapiro, S., Inada, M., Krane, S., Allen, E., Chung, D., and Weiss, S. J. (2004) Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP. J. Cell Biol. 167, 769-781
Hartenstein, B., Dittrich, B. T., Stickens, D., Heyer, B., Vu, T. H., Teurich, S., Schorpp-Kistner, M., Werb, Z., and Angel, P. (2006) Epidermal development and wound healing in matrix metalloproteinase 13-deficient mice. J. Invest. Dermatol. 126, 486-496
Balbín, M., Fueyo, A., Knäuper, V., Pendás, A. M., López, J. M., Jiménez, M. G., Murphy, G., and López- Otín, C. (1998) Collagenase 2 (MMP-8) expression in murine tissue-remodeling processes. Analysis of its potential role in postpartum involution of the uterus. J. Biol. Chem. 273, 23959-23968
Herman, M. P., Sukhova, G. K., Libby, P., Gerdes, N., Tang, N., Horton, D. B., Kilbride, M., Breitbart, R. E., Chun, M., and Schonbeck, U. (2001) Expression of neutrophil collagenase (matrix metalloproteinase-8) in human atheroma: a novel collagenolytic pathway suggested by transcriptional profiling. Circulation 104, 1899-1904
Kiili, M., Cox, S. W., Chen, H. Y., Wahlgren, J., Maisi, P., Eley, B. M., Salo, T., and Sorsa, T. (2002) Collagenase-2 (MMP-8) and collagenase-3 (MMP-13) in adult periodontitis: molecular forms and levels in gingival crevicular fluid and immunolocalisation in gingival tissue. J. Clin. Periodontol. 29, 224-232
Pirila, E., Ramamurthy, N. S., Sorsa, T., Salo, T., Hietanen, J., and Maisi, P. (2003) Gelatinase A (MMP-2), collagenase-2 (MMP-8), and laminin-5 gamma2-chain expression in murine inflammatory bowel disease (ulcerative colitis). Dig. Dis. Sci. 48, 93-98
Pirila, E., Ramamurthy, N., Maisi, P., McClain, S., Kucine, A., Wahlgren, J., Golub, L., Salo, T., and Sorsa, T. (2001) Wound healing in ovariectomized rats: effects of chemically modified tetracycline (CMT-8) and estrogen on matrix metalloproteinases -8, -13 and type I collagen expression. Curr. Med. Chem. 8, 281-294
Nwomeh, B. C., Liang, H. X., Cohen, I. K., and Yager, D. R. (1999) MMP-8 is the predominant collagenase in healing wounds and nonhealing ulcers. J. Surg. Res. 81, 189-195
Balbín, M., Fueyo, A., Tester, A. M., Pendás, A. M., Pitiot, A. S., Astudillo, A., Overall, C. M., Shapiro, S. D., and López-Otín, C. (2003) Loss of collagenase-2 confers increased skin tumor susceptibility to male mice. Nat. Genet. 35, 252-257
Vu, T. H., Shipley, J. M., Bergers, G., Berger, J. E., Helms, J. A., Hanahan, D., Shapiro, S. D., Senior, R. M., and Werb, Z. (1998) MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell 93, 411-422
Peters, T., Sindrilaru, A., Hinz, B., Hinrichs, R., Menke, A., Al-Azzeh, E. A., Holzwarth, K., Oreshkova, T., Wang, H., Kess, D., Walzog, B., Sulyok, S., Sunderkotter, C., Friedrich, W., Wlaschek, M., Krieg, T., and Scharffetter-Kochanek, K. (2005) Wound-healing defect of CD18(-/-) mice due to a decrease in TGF-beta1 and myofibroblast differentiation. EMBO J. 24, 3400-3410
Westerhof, G. R., Ploemacher, R. E., Boudewijn, A., Blokland, I., Dillingh, J. H., McGown, A. T., Hadfield, J. A., Dawson, M. J., and Down, J. D. (2000) Comparison of different busulfan analogues for depletion of hematopoietic stem cells and promotion of donor-type chimerism in murine bone marrow transplant recipients. Cancer Res. 60, 5470-5478
Inada, M., Wang, Y., Byrne, M. H., Rahman, M. U., Miyaura, C., Lopez-Otin, C., and Krane, S. M. (2004) Critical roles for collagenase-3 (MMP13) in development of growth plate cartilage and in endochondral ossification. Proc. Natl. Acad. Sci. U. S. A. 101, 17192-17197
Low, Q. E., Drugea, I. A., Duffner, L. A., Quinn, D. G., Cook, D. N., Rollins, B. J., Kovacs, E. J., and DiPietro, L. A. (2001) Wound healing in MIP-1alpha(-/-) and MCP-1(-/-) mice. Am. J. Pathol. 159, 457-463
Beare, A. H., Krane, S. M., and Ferguson, M. W. (2005) Variable impairment of wound healing in the heterozygous collagenase-resistant mouse. Wound. Repair. Regen. 13, 27-40
Martin, P. (1997) Wound healing-aiming for perfect skin regeneration. Science 276, 75-81
Singer, A. J., and Clark, R. A. (1999) Cutaneous wound healing. N. Engl. J. Med. 341, 738-746
Werner, S., and Grose, R. (2003) Regulation of wound healing by growth factors and cytokines. Physiol. Rev. 83, 835-870
Savill, J., Dransfield, I., Gregory, C., and Haslett, C. (2002) A blast from the past: clearance of apoptotic cells regulates immune responses. Nat. Rev. Immunol. 2, 965-975
Gueders, M. M., Balbín, M., Rocks, N., Foidart, J. M., Gosset, P., Louis, R., Shapiro, S., López-Otín, C., Noël, A., and Cataldo, D. D. (2005) Matrix metalloproteinase-8 deficiency promotes granulocytic allergen-induced airway inflammation. J. Immunol. 175, 2589-2597
Ashcroft, G. S., Yang, X., Glick, A. B., Weinstein, M., Letterio, J. L., Mizel, D. E., Anzano, M., Greenwell-Wild, T., Wahl, S. M., Deng, C., and Roberts, A. B. (1999) Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat. Cell Biol. 1, 260-266
Hosokawa, R., Urata, M. M., Ito, Y., Bringas, P., Jr., and Chai, Y. (2005) Functional significance of Smad2 in regulating basal keratinocyte migration during wound healing. J Invest Dermatol 125, 1302-1309
Kjeldsen, L., Johnsen, A. H., Sengelov, H., and Borregaard, N. (1993) Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J. Biol. Chem. 268, 10425-10432
Nwomeh, B. C., Liang, H. X., Diegelmann, R. F., Cohen, I. K., and Yager, D. R. (1998) Dynamics of the matrix metalloproteinases MMP-1 and MMP-8 in acute open human dermal wounds. Wound. Repair. Regen. 6, 127-134
Ahokas, K., Skoog, T., Suomela, S., Jeskanen, L., Impola, U., Isaka, K., and Saarialho-Kere, U. (2005) Matrilysin-2 (matrix metalloproteinase-26) is upregulated in keratinocytes during wound repair and early skin carcinogenesis. J. Invest. Dermatol. 124, 849-856
Okada, A., Tomasetto, C., Lutz, Y., Bellocq, J. P., Rio, M. C., and Basset, P. (1997) 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. 137, 67-77
Hieta, N., Impola, U., Lopez-Otin, C., Saarialho-Kere, U., and Kahari, V. M. (2003) Matrix metalloproteinase-19 expression in dermal wounds and by fibroblasts in culture. J. Invest. Dermatol. 121, 997-1004
Ravanti, L., Toriseva, M., Penttinen, R., Crombleholme, T., Foschi, M., Han, J., and Kahari, V. M. (2001) Expression of human collagenase-3 (MMP-13) by fetal skin fibroblasts is induced by transforming growth factor beta via p38 mitogen-activated protein kinase. FASEB J. 15, 1098-1100
Mohan, R., Chintala, S. K., Jung, J. C., Villar, W. V., McCabe, F., Russo, L. A., Lee, Y., McCarthy, B. E., Wollenberg, K. R., Jester, J. V., Wang, M., Welgus, H. G., Shipley, J. M., Senior, R. M., and Fini, M. E. (2002) Matrix metalloproteinase gelatinase B (MMP-9) coordinates and effects epithelial regeneration. J. Biol. Chem. 277, 2065-2072
Bullard, K. M., Lund, L., Mudgett, J. S., Mellin, T. N., Hunt, T. K., Murphy, B., Ronan, J., Werb, Z., and Banda, M. J. (1999) Impaired wound contraction in stromelysin-1-deficient mice. Ann. Surg. 230, 260-265
Van Lint, P., Wielockx, B., Puimege, L., Noël, A., López-Otín, C., and Libert, C. (2005) Resistance of collagenase-2 (matrix metalloproteinase-8)-deficient mice to TNF-induced lethal hepatitis. J. Immunol. 175, 7642-7649
Van Lint, P., and Libert, C. (2006) Matrix metalloproteinase-8: cleavage can be decisive. Cytokine Growth Factor Rev. 17, 217-223
Lobmann, R., Ambrosch, A., Schultz, G., Waldmann, K., Schiweck, S., and Lehnert, H. (2002) Expression of matrix-metalloproteinases and their inhibitors in the wounds of diabetic and non-diabetic patients. Diabetologia 45, 1011-1016
Marini, S., Fasciglione, G. F., de Sanctis, G., D'Alessio, S., Politi, V., and Coletta, M. (2000) Cleavage of bovine collagen I by neutrophil collagenase MMP-8. Effect of pH on the catalytic properties as compared to synthetic substrates. J. Biol. Chem. 275, 18657-18663
Balbín, M., Fueyo, A., Knäuper, V., López, J. M., Alvarez, J., Sánchez, L. M., Quesada, V., Bordallo, J., Murphy, G., and López-Otín, C. (2001) Identification and enzymatic characterization of two diverging murine counterparts of human interstitial collagenase (MMP-1) expressed at sites of embryo implantation. J. Biol. Chem. 276, 10253-10262
Freije, J. M., Díez-Itza, I., Balbín, M., Sánchez, L. M., Blasco, R., Tolivia, J., and López-Otín, C. (1994) Molecular cloning and expression of collagenase-3, a novel human matrix metalloproteinase produced by breast carcinomas. J. Biol. Chem. 269, 16766-16773
Owen, C. A., Hu, Z., López-Otín, C., and Shapiro, S. D. (2004) Membrane-bound matrix metalloproteinase-8 on activated polymorphonuclear cells is a potent, tissue inhibitor of metalloproteinase-resistant collagenase and serpinase. J. Immunol. 172, 7791-7803
Yan, L., Borregaard, N., Kjeldsen, L., and Moses, M. A. (2001) The high molecular weight urinary matrix metalloproteinase (MMP) activity is a complex of gelatinase B/MMP-9 and neutrophil gelatinase-associated lipocalin (NGAL). Modulation of MMP-9 activity by NGAL. J. Biol. Chem. 276, 37258-37265