Functional genetic mouse models: promising tools for investigation of the proteolytic internet

Krüger, Achim

doi:10.1515/bc.2009.015

Cited by 27 publications

(23 citation statements)

References 29 publications

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“…Inhibition of MMP-9 is currently tested as therapeutic approach in clinical trials (11), despite the seminal failure of MMP inhibitors in the past (5), because increased selectivity of inhibitors for target MMPs is thought to be key to the expected antitumorigenic and antimetastatic therapeutic potential of MMP inhibition (8,9). However, functions of specific MMPs can be context dependent (28). Thus, critical assessment of potential target MMPs in relevant disease contexts is imperative to their evaluation as therapeutic targets (12).…”

Section: Discussionmentioning

confidence: 99%

“…We thus hypothesized that systemic alterations in the MMP-9-deficient hosts promoted the invasive growth of PDAC. Previously, we have shown that MMP-9 knockout can result in specific induction of IL6 in the bone marrow (28). Noteworthy, elevated systemic and tumoral IL6 levels derived from the bone marrow were recently shown to be central to PDAC initiation and progression (29) by acting on various tumorpromoting processes including tumor cell proliferation, survival, migration, invasion (i.e., invasive growth) as well as angiogenesis, activation of stromal fibroblasts, and immune invasion (30).…”

Section: G12d -Lsl-trp53mentioning

confidence: 99%

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Systemic Ablation of MMP-9 Triggers Invasive Growth and Metastasis of Pancreatic Cancer via Deregulation of IL6 Expression in the Bone Marrow

Grünwald

Vandooren

Gerg

et al. 2016

Molecular Cancer Research

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Matrix metalloproteinase 9 (MMP-9/Gelatinase B) is overexpressed in pancreatic ductal adenocarcinoma (PDAC) and plays a central role in tumor cell invasion and metastasis. Here we complemented mechanistic insights in the cancer biology of MMP-9 and investigated the effects of specific long-term lossof-function, by genetic ablation, of MMP-9 on PDAC initiation and progression in the well-established KPC mouse model of spontaneous PDAC. Tumor growth and progression were analyzed by histopathology and IHC. Invasive growth of PDAC cells was analyzed by both in vitro (proliferation, survival, migration, invasion assays) and in vivo (experimental metastasis assays) methods. Retroviral shRNAi was used to knockdown target genes (MMP-9, IL6R). Gene expression was analyzed by qRT-PCR, immunoblot, ELISA, in situ hybridization, and zymography. PDAC tumors from MMP-9-deficient mice were dramatically larger, more invasive, and contained more stroma.Yet, ablation of MMP-9 in PDAC cells did not directly promote invasive growth. Interestingly, systemic ablation of MMP-9 led to increased IL6 levels resulting from abrogation of MMP-9-dependent SCF signaling in the bone marrow. IL6 levels in MMP-9 À/À mice were sufficient to induce invasive growth and STAT3 activation in PDAC cells via IL6 receptor (IL6R). Interference with IL6R blocked the increased invasion and metastasis of PDAC cells in MMP-9-deficient hosts. In conclusion, ablation of systemic MMP-9 initiated fatal communication between maintenance of physiological functions of MMP-9 in the bone marrow and invasive growth of PDAC via the IL6/ IL6R/STAT3 axis.Implications: Thus, the beneficial effects of host MMP-9 on PDAC are an important caveat for the use of systemic MMP-9 inhibitors in cancer.

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Section: Discussionmentioning

confidence: 99%

Section: G12d -Lsl-trp53mentioning

confidence: 99%

Systemic Ablation of MMP-9 Triggers Invasive Growth and Metastasis of Pancreatic Cancer via Deregulation of IL6 Expression in the Bone Marrow

Grünwald

Vandooren

Gerg

et al. 2016

Molecular Cancer Research

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“…However the utility of MMP knockout models is questionable due to compensatory upregulation of other MMPs [47,48] , and because of conflicting results in cancer studies [49] , where MMPs were highly involved in cancer progression.…”

Section: Targeting Mmp-9mentioning

confidence: 99%

Matrix metalloproteinases contribute to kidney fibrosis in chronic kidney diseases

Zhao

Dong²,

Tian³

et al. 2013

WJN

120

104

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Matrix metalloproteinases (MMPs) are members of the neutral proteinase family. They were previously thought to be anti-fibrotic because of their ability to degrade and remodel of extracellular matrix. However, recent studies have shown that MMPs are implicated in initiation and progression of kidney fibrosis through tubular cell epithelial-mesenchymal transition (EMT) as well as activation of resident fibroblasts, endothelial-mesenchymal transition (EndoMT) and pericyte-myofibroblast transdifferentiation.

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“…Moreover, the use of MMP-KO model has yielded conflicting results in various disease models. 20 Recent studies from our group have demonstrated that MMP-9 itself is capable of inducing the entire course of tubular cell EMT via the disruption of E-cadherin/b-cateninmediated cell-to-cell adhesion complex, independent of epithelial cell-basement membrane disruption. 6,21 Moreover, results from our in vitro study has highlighted a prominent role and potentially an important source of MMP-9 from macrophages and TEC in tubular cell EMT induction, which has not previously been addressed in renal fibrosis.…”

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confidence: 99%

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

Tan

Zheng

Hsu

et al. 2013

Laboratory Investigation

132

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A pro-fibrotic role of matrix metalloproteinase-9 (MMP-9) in tubular cell epithelial-mesenchymal transition (EMT) is well established in renal fibrosis; however studies from our group and others have demonstrated some previously unrecognized complexity of MMP-9 that has been overlooked in renal fibrosis. Therefore, the aim of this study was to determine the expression pattern, origin and the exact mechanism underlying the contribution of MMP-9 to unilateral ureteral obstruction (UUO), a well-established model of renal fibrosis via MMP-9 inhibition. Renal MMP-9 expression in BALB/c mice with UUO was examined on day 1, 3, 5, 7, 9, 11 and 14. To inhibit MMP-9 activity, MMP-2/9 inhibitor or MMP-9-neutralizing antibody was administered daily for 4 consecutive days from day 0-3, 6-9 or 10-13 and tissues harvested at day 14. In UUO, there was a bi-phasic early-and late-stage upregulation of MMP-9 activity. Interestingly, tubular epithelial cells (TECs) were the predominant source of MMP-9 during early stage, whereas TECs, macrophages and myofibroblasts produced MMP-9 during late-stage UUO. Early-and late-stage inhibition of MMP-9 in UUO mice significantly reduced tubular cell EMT and renal fibrosis. Moreover, MMP-9 inhibition caused a significant reduction in MMP-9-cleaved osteopontin and macrophage infiltration in UUO kidney. Our in vitro study showed MMP-9-cleaved osteopontin enhanced macrophage transwell migration and MMP-9 of both primary TEC and macrophage induced tubular cell EMT. In summary, our result suggests that MMP-9 of both TEC and macrophage origin may directly or indirectly contribute to the pathogenesis of renal fibrosis via osteopontin cleavage, which, in turn further recruit macrophage and induce tubular cell EMT. Our study also highlights the time dependency of its expression and the potential of stage-specific inhibition strategy against renal fibrosis. KEYWORDS: Epithelial-mesenchymal transition; macrophage; matrix metalloproteinase-9; osteopontin; renal fibrosis; tubular epithelial cell Matrix metalloproteinase-9 (MMP-9), also known as gelatinase B, belongs to a large family of zinc-dependent matrixdegrading enzymes called matrix metalloproteinases (MMPs) that have an important role in both physiological and pathological conditions in vivo. 1 MMPs are well known for their anti-fibrotic effect due to their ability to degrade and remodel extracellular matrix (ECM) proteins, however it has been recognized that MMPs can also exert pro-fibrotic effect under various pathological conditions.Myofibroblasts are the effector cells responsible for the production and secretion of ECM in renal fibrosis. It has been reported that myofibroblasts can derive from the activation of renal interstitial fibroblasts, perivascular fibroblasts and pericytes, from bone marrow-derived stem cells and

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Functional genetic mouse models: promising tools for investigation of the proteolytic internet

Cited by 27 publications

References 29 publications

Systemic Ablation of MMP-9 Triggers Invasive Growth and Metastasis of Pancreatic Cancer via Deregulation of IL6 Expression in the Bone Marrow

Systemic Ablation of MMP-9 Triggers Invasive Growth and Metastasis of Pancreatic Cancer via Deregulation of IL6 Expression in the Bone Marrow

Matrix metalloproteinases contribute to kidney fibrosis in chronic kidney diseases

Matrix metalloproteinase-9 of tubular and macrophage origin contributes to the pathogenesis of renal fibrosis via macrophage recruitment through osteopontin cleavage

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