title: Lack of MMP10 exacerbates experimental colitis and promotes development of inflammation-associated colonic dysplasia.
abstract: Inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) represent serious health burdens because of both the tissue-damaging disease itself and 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 sulfate 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.
authors.affiliation: Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Felicitas L
authors.initials: FL
authors.lastname: Koller
authors.forename: E Ashley
authors.initials: EA
authors.lastname: Dozier
authors.forename: Ki Taek
authors.initials: KT
authors.lastname: Nam
authors.forename: Mei
authors.initials: M
authors.lastname: Swee
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Birkland
authors.forename: William C
authors.initials: WC
authors.lastname: Parks
authors.forename: Barbara
authors.initials: B
authors.lastname: Fingleton
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000201:enzymology; D016026:Bone Marrow Transplantation; D002460:Cell Line; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D003106:Colon / Q000737:chemistry / Q000201:enzymology* / Q000473:pathology*; D016207:Cytokines / Q000378:metabolism; D016264:Dextran Sulfate; D004195:Disease Models, Animal; D005260:Female; D006651:Histocytochemistry; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000201:enzymology / Q000276:immunology; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D053506:Matrix Metalloproteinase 10 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D016207:Cytokines; D016264:Dextran Sulfate; D053506:Matrix Metalloproteinase 10