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MMP9 is protective against lethal inflammatory mass lesions in the mouse colon.

Hald A, Rønø B, Melander MC, Ding M, Holck S, Lund LR - Dis Model Mech (2010)

Bottom Line: 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.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.These data demonstrate a non-appreciated vital protective role for MMP9 in the absence of Plg.

View Article: PubMed Central - PubMed

Affiliation: Department 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.

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Epithelial cell proliferation in the healthy mucosa does not differ between WT, MMP9−/−, Plg−/− and MMP9−/−:Plg−/−mice. The fraction and localization of dividing cells in both normal mucosal tissue and inflamed areas were determined using BrdU-incorporation analyses (red is BrdU, blue is nuclear visualization by Hoechst). (A–D) Tangential sections of healthy colon mucosa of WT, MMP9−/−, Plg−/− and MMP9−/−:Plg−/− mice showed a normal fraction and localization of proliferating cells, which were mainly localized in the bottom of the crypts. (E,F) Sections of inflamed and/or tumorous areas in Plg−/− and MMP9−/−:Plg−/− mice revealed that, despite the deranged mucosa of these mice, distinct areas in the mucosa still display unrestrained epithelial proliferation along with increased numbers of dividing cells in the lamina propria. (G) The percentage of BrdU-incorporated cells remained constant over large areas, although localized variations were observed. For all groups, n≥5.
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f4-0040212: Epithelial cell proliferation in the healthy mucosa does not differ between WT, MMP9−/−, Plg−/− and MMP9−/−:Plg−/−mice. The fraction and localization of dividing cells in both normal mucosal tissue and inflamed areas were determined using BrdU-incorporation analyses (red is BrdU, blue is nuclear visualization by Hoechst). (A–D) Tangential sections of healthy colon mucosa of WT, MMP9−/−, Plg−/− and MMP9−/−:Plg−/− mice showed a normal fraction and localization of proliferating cells, which were mainly localized in the bottom of the crypts. (E,F) Sections of inflamed and/or tumorous areas in Plg−/− and MMP9−/−:Plg−/− mice revealed that, despite the deranged mucosa of these mice, distinct areas in the mucosa still display unrestrained epithelial proliferation along with increased numbers of dividing cells in the lamina propria. (G) The percentage of BrdU-incorporated cells remained constant over large areas, although localized variations were observed. For all groups, n≥5.

Mentions: Because an elevated cell-turnover rate in the colon epithelium could in part explain the formation of the mass lesions, a bromodeoxyuracil (BrdU)-incorporation study was conducted. In normal colon epithelium no difference in cell division frequency was found between WT, MMP9−/−, Plg−/− and MMP9−/−:Plg−/− mice, in which proliferating cells were found to be localized in the bottom of the crypts as expected (Fig. 4A,D). By contrast, the mass lesions in MMP9−/−:Plg−/− mice, as well as the inflamed areas of colon mucosa observed in Plg−/− mice, displayed an increased number of dividing cells in the lamina propria and a disordered staining pattern in the distended crypts when compared with normal colon mucosa (Fig. 4E,F). However, the fraction of all dividing cells did not differ in the inflamed tissue in comparison with the fraction in normal epithelium (Fig. 4G).


MMP9 is protective against lethal inflammatory mass lesions in the mouse colon.

Hald A, Rønø B, Melander MC, Ding M, Holck S, Lund LR - Dis Model Mech (2010)

Epithelial cell proliferation in the healthy mucosa does not differ between WT, MMP9−/−, Plg−/− and MMP9−/−:Plg−/−mice. The fraction and localization of dividing cells in both normal mucosal tissue and inflamed areas were determined using BrdU-incorporation analyses (red is BrdU, blue is nuclear visualization by Hoechst). (A–D) Tangential sections of healthy colon mucosa of WT, MMP9−/−, Plg−/− and MMP9−/−:Plg−/− mice showed a normal fraction and localization of proliferating cells, which were mainly localized in the bottom of the crypts. (E,F) Sections of inflamed and/or tumorous areas in Plg−/− and MMP9−/−:Plg−/− mice revealed that, despite the deranged mucosa of these mice, distinct areas in the mucosa still display unrestrained epithelial proliferation along with increased numbers of dividing cells in the lamina propria. (G) The percentage of BrdU-incorporated cells remained constant over large areas, although localized variations were observed. For all groups, n≥5.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3046095&req=5

f4-0040212: Epithelial cell proliferation in the healthy mucosa does not differ between WT, MMP9−/−, Plg−/− and MMP9−/−:Plg−/−mice. The fraction and localization of dividing cells in both normal mucosal tissue and inflamed areas were determined using BrdU-incorporation analyses (red is BrdU, blue is nuclear visualization by Hoechst). (A–D) Tangential sections of healthy colon mucosa of WT, MMP9−/−, Plg−/− and MMP9−/−:Plg−/− mice showed a normal fraction and localization of proliferating cells, which were mainly localized in the bottom of the crypts. (E,F) Sections of inflamed and/or tumorous areas in Plg−/− and MMP9−/−:Plg−/− mice revealed that, despite the deranged mucosa of these mice, distinct areas in the mucosa still display unrestrained epithelial proliferation along with increased numbers of dividing cells in the lamina propria. (G) The percentage of BrdU-incorporated cells remained constant over large areas, although localized variations were observed. For all groups, n≥5.
Mentions: Because an elevated cell-turnover rate in the colon epithelium could in part explain the formation of the mass lesions, a bromodeoxyuracil (BrdU)-incorporation study was conducted. In normal colon epithelium no difference in cell division frequency was found between WT, MMP9−/−, Plg−/− and MMP9−/−:Plg−/− mice, in which proliferating cells were found to be localized in the bottom of the crypts as expected (Fig. 4A,D). By contrast, the mass lesions in MMP9−/−:Plg−/− mice, as well as the inflamed areas of colon mucosa observed in Plg−/− mice, displayed an increased number of dividing cells in the lamina propria and a disordered staining pattern in the distended crypts when compared with normal colon mucosa (Fig. 4E,F). However, the fraction of all dividing cells did not differ in the inflamed tissue in comparison with the fraction in normal epithelium (Fig. 4G).

Bottom Line: 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.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.These data demonstrate a non-appreciated vital protective role for MMP9 in the absence of Plg.

View Article: PubMed Central - PubMed

Affiliation: Department 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.

Show MeSH
Related in: MedlinePlus