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

Hald, Andreas; Rønø, Birgitte; Melander, Maria C.; Ding, Ming; Holck, Susanne; Lund, Leif R.

doi:10.1242/dmm.005801

Cited by 15 publications

(25 citation statements)

References 62 publications

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“…Tissue libraries were derived from FVB/n mice [4]. The thioglycollate (TG) induced peritonitis experiments were performed in C57Bl/6 mice.…”

Section: Methodsmentioning

confidence: 99%

“…The progressive deformation of these organs results in organ dysfunction and wasting of the animals, which rarely live for more than 30 weeks. In addition to these syndromes, fibrin depositions, which are associated with infiltration of inflammatory cells, accumulate in the liver throughout the lifespan of Plg −/− mice [3], [4]. Moreover, wound healing in humans with plasmin deficiency and in Plg −/− mice is severely retarded and associated with accumulation of fibrin in the provisional matrix [5], [6].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Gender Affects Skin Wound Healing in Plasminogen Deficient Mice

Rønø

Engelholm²,

Lund³

et al. 2013

PLoS ONE

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The fibrinolytic activity of plasmin plays a fundamental role in resolution of blood clots and clearance of extravascular deposited fibrin in damaged tissues. These vital functions of plasmin are exploited by malignant cells to accelerate tumor growth and facilitate metastases. Mice lacking functional plasmin thus display decreased tumor growth in a variety of cancer models. Interestingly, this role of plasmin has, in regard to skin cancer, been shown to be restricted to male mice. It remains to be clarified whether gender also affects other phenotypic characteristics of plasmin deficiency or if this gender effect is restricted to skin cancer. To investigate this, we tested the effect of gender on plasmin dependent immune cell migration, accumulation of hepatic fibrin depositions, skin composition, and skin wound healing. Gender did not affect immune cell migration or hepatic fibrin accumulation in neither wildtype nor plasmin deficient mice, and the existing differences in skin composition between males and females were unaffected by plasmin deficiency. In contrast, gender had a marked effect on the ability of plasmin deficient mice to heal skin wounds, which was seen as an accelerated wound closure in female versus male plasmin deficient mice. Further studies showed that this gender effect could not be reversed by ovariectomy, suggesting that female sex-hormones did not mediate the accelerated skin wound healing in plasmin deficient female mice. Histological examination of healed wounds revealed larger amounts of fibrotic scars in the provisional matrix of plasmin deficient male mice compared to female mice. These fibrotic scars correlated to an obstruction of cell infiltration of the granulation tissue, which is a prerequisite for wound healing. In conclusion, the presented data show that the gender dependent effect of plasmin deficiency is tissue specific and may be secondary to already established differences between genders, such as skin thickness and composition.

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“…Tissue libraries were derived from FVB/n mice [4]. The thioglycollate (TG) induced peritonitis experiments were performed in C57Bl/6 mice.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gender Affects Skin Wound Healing in Plasminogen Deficient Mice

Rønø

Engelholm²,

Lund³

et al. 2013

PLoS ONE

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“…This resulted in a genotypic distribution in accordance with the expected Mendelian distribution for Mmp2;Plg offspring whereas a non-Mendelian distributuion was observed for Mmp9 ; Plg offspring [42], [43]. Furthermore, we were not able to demonstrate any phenotypic overlap between MMP-2 and Plg or MMP-9 and Plg during wound healing [42], [43]. Thus, it still remains to be clarified which MMP, or which combinations of MMPs, are responsible for the phenotypic overlap with plasmin during wound healing.…”

Section: Introductionmentioning

confidence: 66%

Phenotypic Overlap between MMP-13 and the Plasminogen Activation System during Wound Healing in Mice

Juncker-Jensen

Lund

2011

PLoS ONE

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BackgroundProteolytic degradation of extracellular matrix is a crucial step in the healing of incisional skin wounds. Thus, healing of skin wounds is delayed by either plasminogen-deficiency or by treatment with the broad-spectrum metalloproteinase (MP) inhibitor Galardin alone, while the two perturbations combined completely prevent wound healing. Both urokinase-type plasminogen activator and several matrix metallo proteinases (MMPs), such as MMP-3, -9 and -13, are expressed in the leading-edge keratinocytes of skin wounds, which may account for this phenotypic overlap between these classes of proteases.MethodologyTo further test that hypothesis we generated Mmp13;Plau and Mmp13;Plg double-deficient mice in a cross between Mmp13- and Plau-deficient mice as well as Mmp13- and Plg-deficient mice. These mice were examined for normal physiology in a large cohort study and in a well-characterized skin wound healing model, in which we made incisional 20 mm-long full-thickness skin wounds.Principal FindingsWhile mice that are deficient in Mmp13 have a mean healing time indistinguishable to wild-type mice, wound healing in both Plau- and Plg-deficient mice is significantly delayed. Histological analysis of healed wounds revealed a significant increase in keratin 10/14 immunoreactive layers of kerationcytes in the skin surface in Mmp13;Plau double-deficient mice. Furthermore, we observe, by immunohistological analysis, an aberrant angiogenic pattern during wound healing induced by Plau-deficiency, which has not previously been described.ConclusionsWe demonstrate a phenotypic overlap, defined as an additional delay in wound healing in the double-deficient mice compared to the individual single-deficient mice, between MMP-13 and the plasminogen activation system in the process of wound healing, but not during gestation and in postnatal development. Thus, a dual targeting of uPA and MMP-13 might be a possible future strategy in designing therapies aimed at tissue repair or other pathological processes, such as cancer invasion, where proteolytic degradation is a hallmark.

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“…This is based on the fact that MMP-9 knockdown mouse model of multistage tumorigenesis demonstrated decreased carcinogenesis, whereas tumor formed in MMP-9-deficient mice were more aggressive [57]. One genetic data indicates that concomitant ablation of MMP-9 and the serine protease plasmin can result in lethal inflammatory mass lesions in the mouse colon model [58]. Evidence also suggests MMP-9 might function as a tumor suppressor in the process of colon cancer (CAC) [59].…”

Section: Gelatinases (Mmp-2 and -9)mentioning

confidence: 99%

An Updated Patent Therapeutic Agents Targeting MMPs

Shi¹,

Shi³

et al. 2012

PRA

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The traditional consensus that matrix metalloproteinases (MMPs) has correlation with various pathological and physiological processes led to the exploitation of a vast number of natural or synthetic broad-spectrum MMP inhibitors (MMPIs) for the prophylaxis or treatment of various MMP-related disorders, such as autoimmune, inflammatory, cardiovascular, neurodegenerative, respiratory diseases, and malignant cancer as well. Yet the unsatisfactory preclinical and/or clinical results motivated further investigation of the physiological roles of certain MMP subtypes. Despite the intricate and complicated MMP functions in normal physiology and disease pathology, the effort of designing specific inhibitors that can selectively target certain MMP family members for individualized therapy is ongoing and remains an arduous task. Success will rely on continued insight into the biological roles of these multifaced proteases. In our previous effort, we summarized various MMPIs that have entered preclinical or clinical trials as well as the patents in regard to MMPIs (Recent Pat Anticancer Drug Discov. 2010; 5(2): 109-41). In our on-going review, to illustrate the major challenges in MMP validation as druggable targets, we highlighted the physiological and pathological roles of representative MMPs, with an emphasis on description of the newly emerging MMPI-based patents, in particular, the inhibitors containing sulfonamide or sulfone motif. By analyzing the structural characteristics and selectivity profiles of these supplementary inhibitors, we hereby described their pharmaceutical application, and also expanded the strategies for potent MMPI design.

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

Cited by 15 publications

References 62 publications

Gender Affects Skin Wound Healing in Plasminogen Deficient Mice

Gender Affects Skin Wound Healing in Plasminogen Deficient Mice

Phenotypic Overlap between MMP-13 and the Plasminogen Activation System during Wound Healing in Mice

An Updated Patent Therapeutic Agents Targeting MMPs

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