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.
Bibliographical noteFunding Information:
We are especially thankful to Dr Mark Frey of the University of Southern California for paraffin sections from IL-10-null mice, to Dr Lynn Matrisian for the MMP10 in situ hybridization probe, and to the Vanderbilt Tissue Acquisition Core for the archival de-identified human IBD specimens. Additionally, we gratefully acknowledge Dr MK Washington for helpful discussions regarding histology scoring, and Dr JT Roland and the Epithelial Biology Center Shared Imaging Resource for Ariol scanning of slides. FLK was supported by training Grant T32CA106183. This work was also supported by the Vanderbilt-Ingram Cancer Center support Grant P30CA068485, by pilot funding from the Vanderbilt Digestive Disease Research Center P30DK058404, and by HL089455 and HL098067 (WCP).
All Science Journal Classification (ASJC) codes
- Pathology and Forensic Medicine
- Molecular Biology
- Cell Biology