Key Role for Matrix Metalloproteinases -19 and -28 in Maintenance of Intestinal Homeostasis
The present study investigates the role of two matrix metalloproteinases, MMP-19 and MMP-28, in intestinal homeostasis and inflammation by means of a mouse model for inflammatory bowel disease (IBD). MMP-19 and -28 are abundantly expressed in epithelial tissues. However, their functions in this compartment and their functional overlap have not been elucidated so far. MMP-19 contributes to IGF-signaling, cell proliferation, and migration and is able to cleave several soluble proteins and components of extracellular matrix. MMP-28 was shown to be important in wound healing. Comparison of wildtype and MMP-19-deficient mice revealed an increased susceptibility to acute and chronic DSS-induced colitis accompanied by impaired healing process compared to the wildtype animals. Survival rates during acute and chronic colitis were significantly reduced. In contrast, the MMP-28-deficient mice show only moderate signs of disease and behaved similarly to the DSS-treated wildtype group. Strikingly, the MMP-19/-28 double-deficient mice showed the most severe phenotype in acute colitis and during the recovery, which was reflected in very poor survival rates and impaired wound healing in the surviving animals. In conclusion, this study provides several lines of evidence for a pivotal role of MMP-19 and MMP-28 in maintenance of intestinal tissue homeostasis. The data suggest that loss-of-function of MMP-19 results in an increased susceptibility to colonic inflammation, mediated by an exacerbated innate immune response and inability of colonic tissue to heal.