Abstract
SUMMARYThe family of matrix metalloproteinases (MMPs) is responsible for extracellular matrix degradation during physiological and pathophysiological tissue remodeling processes such as embryogenesis, tissue repair and cancer progression. Despite these important roles of MMPs, inhibition or ablation of individual members of the MMP family in animal models have been shown to have little effect. It has been speculated that this results from a functional overlap between individual MMPs and (as-yet-unclassified) functional overlaps between MMPs and other protease systems. We here present genetic data showing that concomitant ablation of MMP9 (gelatinase B) and the serine protease plasmin results in lethal inflammatory mass lesions in the colon. These lesions possessed several histological attributes that are characteristic of mucosal prolapse seen in humans, and they were found to be associated with splenomegaly, enlarged mesenteric lymph nodes, decreased thymus size and altered populations of circulating immune cells. A time-course study provided evidence that the massive lymphoid hyperplasia and reactive changes were secondary to discrete fibrinous lesions also observed in mice only deficient for plasminogen (Plg), the zymogen for plasmin. These data demonstrate a non-appreciated vital protective role for MMP9 in the absence of Plg.
Highlights
Increased expression of several different matrix metalloproteinases (MMPs), the main role of which is to degrade extracellular matrix (ECM) proteins, has been associated with a poor prognosis in various diseases, including cancer, arthritis and cardiovascular pathologies, as well as in cerebral infarction (Fingleton, 2008)
Skewed genetic distribution of MMP9 and Plg alleles in the offspring of MMP9–/+:Plg–/+ mice To test the existence of a putative embryonic lethal phenotype of MMP9 and Plg double deficiency, MMP9–/+:Plg–/+ mice were mated and their offspring were genotyped at weaning
MMP9 and Plg deficiency have additive effects on development To investigate the effect of concurrent ablation of MMP9 and Plg on mouse development and during adulthood, we set up a cohort study including MMP9–/–:Plg–/– mice and their WT, MMP9–/– and Plg–/– littermate controls
Summary
Increased expression of several different matrix metalloproteinases (MMPs), the main role of which is to degrade extracellular matrix (ECM) proteins, has been associated with a poor prognosis in various diseases, including cancer, arthritis and cardiovascular pathologies, as well as in cerebral infarction (Fingleton, 2008). In contrast to their well-documented involvement in pathological events, their role during normal physiological processes still remains poorly understood. This notion is supported by the synergistic effects of broad-spectrum
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