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Updated: Jun 6, 2026
Non-invasive Assessment of the Efficacy of New Therapeutics for Intestinal Pathologies Using Serial Endoscopic Imaging of Live Mice
Published on: March 10, 2015
MMP9 is protective against lethal inflammatory mass lesions in the mouse colon
Andreas Hald1, Birgitte Rønø, Maria C Melander
1Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. ahald@sund.ku.dk
Abstract:
The 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.
Insights
Matrix metalloproteinase-9 (MMP9) plays a vital protective role, especially when plasmin is absent. Simultaneous loss of MMP9 and plasmin leads to lethal colon lesions and systemic inflammation in mice.
Area of Science:
- Biochemistry
- Immunology
- Molecular Biology
Background:
- Matrix metalloproteinases (MMPs) are crucial for tissue remodeling.
- Previous studies showed limited effects of ablating single MMPs, suggesting functional redundancy.
- Functional overlap between MMPs and other protease systems is hypothesized.
Purpose of the Study:
- To investigate the functional overlap between MMP9 and plasmin.
- To elucidate the consequences of combined MMP9 and plasmin deficiency.
- To identify novel protective roles of MMP9.
Main Methods:
- Genetic ablation of MMP9 and plasmin in mice.
- Histological analysis of colon lesions and associated organs.
- Time-course studies to observe lesion development and systemic effects.
- Analysis of immune cell populations.
Main Results:
- Concomitant ablation of MMP9 and plasmin resulted in lethal inflammatory mass lesions in the colon.
- Lesions exhibited characteristics of human mucosal prolapse.
- Associated findings included splenomegaly, lymphadenopathy, thymic atrophy, and altered immune cell profiles.
- Mice deficient only in plasminogen (Plg) developed fibrinous lesions, indicating secondary lymphoid hyperplasia.
Conclusions:
- MMP9 has a critical, previously unappreciated protective function in the absence of plasmin.
- The combined deficiency of MMP9 and plasmin leads to severe, life-threatening inflammatory conditions.
- These findings highlight the importance of protease interactions in maintaining tissue homeostasis and preventing inflammatory diseases.
