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Lack of MMP10 exacerbates experimental colitis and promotes development of inflammation-associated colonic dysplasia

 Felicitas L. Koller  ;  E. Ashley Dozier  ;  Ki Taek Nam  ;  Mei Swee  ;  Timothy P. Birkland  ;  William C. Parks  ;  Barbara Fingleton 
 LABORATORY INVESTIGATION, Vol.92(12) : 1749-1759, 2012 
Journal Title
Issue Date
Animals ; Bone Marrow/enzymology ; Bone Marrow Transplantation ; Cell Line ; Colitis, Ulcerative/chemically induced ; Colitis, Ulcerative/enzymology* ; Colitis, Ulcerative/immunology ; Colitis, Ulcerative/pathology ; Colon/chemistry ; Colon/enzymology* ; Colon/pathology* ; Cytokines/metabolism ; Dextran Sulfate ; Disease Models, Animal ; Female ; Histocytochemistry ; Humans ; Inflammatory Bowel Diseases/enzymology ; Inflammatory Bowel Diseases/immunology ; Leukocytes/metabolism ; Male ; Matrix Metalloproteinase 10/deficiency* ; Matrix Metalloproteinase 10/genetics ; Matrix Metalloproteinase 10/immunology ; Matrix Metalloproteinase 10/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Real-Time Polymerase Chain Reaction
bone marrow-derived cells ; cancer ; colitis ; protease ; resolution
Inflammatory bowel diseases such as ulcerative colitis represent serious health burdens, both because of the tissue-damaging disease itself, and because of an elevated risk of colon cancer. The increased expression of many members of the matrix metalloproteinase (MMP) family of enzymes that occurs in colitis, has long been associated with the destructive nature of the disease. Recent findings in cancer and other MMP-associated diseases, however, led us to question whether MMPs are indeed detrimental in the setting of colitis. Here, we focus on a single MMP family member, MMP10, and assess its role in a murine model of colonic tissue damage induced by dextran sulphate sodium (DSS) treatment. Using mice genetically deficient for MMP10, we find that absence of this enzyme leads to significantly worse disease scores and failure to resolve inflammation even after extended recovery periods. We show that MMP10 is produced predominantly by infiltrating myeloid cells in both murine and human colitis. Through bone marrow transplant experiments, we confirm that bone marrow-derived MMP10 contributes to colitis severity. Mice lacking MMP10 have a significantly higher propensity for development of dysplastic lesions in the colon after two rounds of DSS exposure. Thus, we conclude that MMP10 is required for resolution of DSS-induced colonic damage, and in its absence, chronic inflammation and ultimately dysplasia occurs.
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Yonsei Authors
Nam, Ki Taek(남기택)
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