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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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Offspring of MMP9−/+:Plg−/+ mice express a mixed phenotype and additional traits. (A) The offspring of MMP9−/+:Plg−/+ mice were genotyped at weaning. A total of 1217 pups were tested for the mutant alleles. Genotypes are presented as follows (MMP9:Plg): + indicates a WT allele and – indicates the dysfunctional mutant allele. Highlighted areas indicate a decreased fraction of pups compared with the expected fraction on the basis of a theoretical mendelian distribution. MMP9−/− pups were observed at a decreased frequency, which was further decreased by the lack of one or two functional Plg alleles down to 69% and 57% of the expected number for females and males, respectively. P<0.001 for both males and females. (B) From time of weaning, mice were weighed weekly until the age of 26 weeks. MMP9−/− and MMP9−/−:Plg−/− mice were generally smaller than WT and Plg−/− mice (P<0.05). Male Plg−/− mice showed a sudden steep decline in weight around week 22, by which time point they had also developed severe rectal prolapses. In contrast to male Plg−/− mice, male MMP9−/−:Plg−/− mice stopped gaining weight around 12 weeks of age (P<0.05). A similar development of weight over time was not evident in female mice. (C) Plg−/− and MMP9−/−:Plg−/− mice were examined weekly for the presence of rectal lesions. The time of onset of rectal prolapse development took place from 10 to 24 weeks of age. The Kaplan-Meier analysis showed that Plg−/− (7 males and 8 females) and MMP9−/−:Plg−/− (8 males and 5 females) mice both followed the same time course of rectal prolapse development, and furthermore, no significant effect of gender was observed. (D) Spontaneous deaths of unknown cause were monitored in male and female MMP9−/−:Plg−/− mice and compared with controls. Among the included MMP9−/−:Plg−/− mice (7 males and 7 females), three male mice died from unknown causes. The tendency for a decreased survival rate of MMP9−/−:Plg−/− mice did not reach statistical significance (P=0.22). (E) Bone-length measurements showed that the short-bone phenotype observed in MMP9−/− mice is unaffected by the lack of functional Plg. The graph shows the length of femoral bones isolated from adult mice. The number of mice in each group is shown above the columns. ***P<0.0001 compared with respective controls. (F) Reconstruction of cancellous bone from distal femurs of WT and MMP9−/− mice, in which significant differences in the microarchitecture can be observed. WT and Plg−/− mice had a more plate-like structure with thicker trabeculae compared with MMP9−/− and MMP9−/−:Plg−/− mice, which had a combination of plate- and rod-like structure with relatively thin trabeculae. Data are presented as means ± s.e.m. and analyzed by ANOVA with a Newman-Keuls post-test.
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f1-0040212: Offspring of MMP9−/+:Plg−/+ mice express a mixed phenotype and additional traits. (A) The offspring of MMP9−/+:Plg−/+ mice were genotyped at weaning. A total of 1217 pups were tested for the mutant alleles. Genotypes are presented as follows (MMP9:Plg): + indicates a WT allele and – indicates the dysfunctional mutant allele. Highlighted areas indicate a decreased fraction of pups compared with the expected fraction on the basis of a theoretical mendelian distribution. MMP9−/− pups were observed at a decreased frequency, which was further decreased by the lack of one or two functional Plg alleles down to 69% and 57% of the expected number for females and males, respectively. P<0.001 for both males and females. (B) From time of weaning, mice were weighed weekly until the age of 26 weeks. MMP9−/− and MMP9−/−:Plg−/− mice were generally smaller than WT and Plg−/− mice (P<0.05). Male Plg−/− mice showed a sudden steep decline in weight around week 22, by which time point they had also developed severe rectal prolapses. In contrast to male Plg−/− mice, male MMP9−/−:Plg−/− mice stopped gaining weight around 12 weeks of age (P<0.05). A similar development of weight over time was not evident in female mice. (C) Plg−/− and MMP9−/−:Plg−/− mice were examined weekly for the presence of rectal lesions. The time of onset of rectal prolapse development took place from 10 to 24 weeks of age. The Kaplan-Meier analysis showed that Plg−/− (7 males and 8 females) and MMP9−/−:Plg−/− (8 males and 5 females) mice both followed the same time course of rectal prolapse development, and furthermore, no significant effect of gender was observed. (D) Spontaneous deaths of unknown cause were monitored in male and female MMP9−/−:Plg−/− mice and compared with controls. Among the included MMP9−/−:Plg−/− mice (7 males and 7 females), three male mice died from unknown causes. The tendency for a decreased survival rate of MMP9−/−:Plg−/− mice did not reach statistical significance (P=0.22). (E) Bone-length measurements showed that the short-bone phenotype observed in MMP9−/− mice is unaffected by the lack of functional Plg. The graph shows the length of femoral bones isolated from adult mice. The number of mice in each group is shown above the columns. ***P<0.0001 compared with respective controls. (F) Reconstruction of cancellous bone from distal femurs of WT and MMP9−/− mice, in which significant differences in the microarchitecture can be observed. WT and Plg−/− mice had a more plate-like structure with thicker trabeculae compared with MMP9−/− and MMP9−/−:Plg−/− mice, which had a combination of plate- and rod-like structure with relatively thin trabeculae. Data are presented as means ± s.e.m. and analyzed by ANOVA with a Newman-Keuls post-test.

Mentions: 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. Surprisingly, MMP9−/−:Plg−/− pups were found to be viable and resembled WT littermates at gross inspection. However, at time of weaning, MMP9−/−:Plg−/− pups were obtained at a lower frequency than expected based on a normal mendelian distribution pattern. Moreover, a decreased proportion of MMP9−/− and MMP9−/−:Plg−/+ pups was observed, whereas the other genotypes were obtained in an expected ratio (Fig. 1A).


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)

Offspring of MMP9−/+:Plg−/+ mice express a mixed phenotype and additional traits. (A) The offspring of MMP9−/+:Plg−/+ mice were genotyped at weaning. A total of 1217 pups were tested for the mutant alleles. Genotypes are presented as follows (MMP9:Plg): + indicates a WT allele and – indicates the dysfunctional mutant allele. Highlighted areas indicate a decreased fraction of pups compared with the expected fraction on the basis of a theoretical mendelian distribution. MMP9−/− pups were observed at a decreased frequency, which was further decreased by the lack of one or two functional Plg alleles down to 69% and 57% of the expected number for females and males, respectively. P<0.001 for both males and females. (B) From time of weaning, mice were weighed weekly until the age of 26 weeks. MMP9−/− and MMP9−/−:Plg−/− mice were generally smaller than WT and Plg−/− mice (P<0.05). Male Plg−/− mice showed a sudden steep decline in weight around week 22, by which time point they had also developed severe rectal prolapses. In contrast to male Plg−/− mice, male MMP9−/−:Plg−/− mice stopped gaining weight around 12 weeks of age (P<0.05). A similar development of weight over time was not evident in female mice. (C) Plg−/− and MMP9−/−:Plg−/− mice were examined weekly for the presence of rectal lesions. The time of onset of rectal prolapse development took place from 10 to 24 weeks of age. The Kaplan-Meier analysis showed that Plg−/− (7 males and 8 females) and MMP9−/−:Plg−/− (8 males and 5 females) mice both followed the same time course of rectal prolapse development, and furthermore, no significant effect of gender was observed. (D) Spontaneous deaths of unknown cause were monitored in male and female MMP9−/−:Plg−/− mice and compared with controls. Among the included MMP9−/−:Plg−/− mice (7 males and 7 females), three male mice died from unknown causes. The tendency for a decreased survival rate of MMP9−/−:Plg−/− mice did not reach statistical significance (P=0.22). (E) Bone-length measurements showed that the short-bone phenotype observed in MMP9−/− mice is unaffected by the lack of functional Plg. The graph shows the length of femoral bones isolated from adult mice. The number of mice in each group is shown above the columns. ***P<0.0001 compared with respective controls. (F) Reconstruction of cancellous bone from distal femurs of WT and MMP9−/− mice, in which significant differences in the microarchitecture can be observed. WT and Plg−/− mice had a more plate-like structure with thicker trabeculae compared with MMP9−/− and MMP9−/−:Plg−/− mice, which had a combination of plate- and rod-like structure with relatively thin trabeculae. Data are presented as means ± s.e.m. and analyzed by ANOVA with a Newman-Keuls post-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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f1-0040212: Offspring of MMP9−/+:Plg−/+ mice express a mixed phenotype and additional traits. (A) The offspring of MMP9−/+:Plg−/+ mice were genotyped at weaning. A total of 1217 pups were tested for the mutant alleles. Genotypes are presented as follows (MMP9:Plg): + indicates a WT allele and – indicates the dysfunctional mutant allele. Highlighted areas indicate a decreased fraction of pups compared with the expected fraction on the basis of a theoretical mendelian distribution. MMP9−/− pups were observed at a decreased frequency, which was further decreased by the lack of one or two functional Plg alleles down to 69% and 57% of the expected number for females and males, respectively. P<0.001 for both males and females. (B) From time of weaning, mice were weighed weekly until the age of 26 weeks. MMP9−/− and MMP9−/−:Plg−/− mice were generally smaller than WT and Plg−/− mice (P<0.05). Male Plg−/− mice showed a sudden steep decline in weight around week 22, by which time point they had also developed severe rectal prolapses. In contrast to male Plg−/− mice, male MMP9−/−:Plg−/− mice stopped gaining weight around 12 weeks of age (P<0.05). A similar development of weight over time was not evident in female mice. (C) Plg−/− and MMP9−/−:Plg−/− mice were examined weekly for the presence of rectal lesions. The time of onset of rectal prolapse development took place from 10 to 24 weeks of age. The Kaplan-Meier analysis showed that Plg−/− (7 males and 8 females) and MMP9−/−:Plg−/− (8 males and 5 females) mice both followed the same time course of rectal prolapse development, and furthermore, no significant effect of gender was observed. (D) Spontaneous deaths of unknown cause were monitored in male and female MMP9−/−:Plg−/− mice and compared with controls. Among the included MMP9−/−:Plg−/− mice (7 males and 7 females), three male mice died from unknown causes. The tendency for a decreased survival rate of MMP9−/−:Plg−/− mice did not reach statistical significance (P=0.22). (E) Bone-length measurements showed that the short-bone phenotype observed in MMP9−/− mice is unaffected by the lack of functional Plg. The graph shows the length of femoral bones isolated from adult mice. The number of mice in each group is shown above the columns. ***P<0.0001 compared with respective controls. (F) Reconstruction of cancellous bone from distal femurs of WT and MMP9−/− mice, in which significant differences in the microarchitecture can be observed. WT and Plg−/− mice had a more plate-like structure with thicker trabeculae compared with MMP9−/− and MMP9−/−:Plg−/− mice, which had a combination of plate- and rod-like structure with relatively thin trabeculae. Data are presented as means ± s.e.m. and analyzed by ANOVA with a Newman-Keuls post-test.
Mentions: 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. Surprisingly, MMP9−/−:Plg−/− pups were found to be viable and resembled WT littermates at gross inspection. However, at time of weaning, MMP9−/−:Plg−/− pups were obtained at a lower frequency than expected based on a normal mendelian distribution pattern. Moreover, a decreased proportion of MMP9−/− and MMP9−/−:Plg−/+ pups was observed, whereas the other genotypes were obtained in an expected ratio (Fig. 1A).

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