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Membrane-type MMPs enable extracellular matrix permissiveness and mesenchymal cell proliferation during embryogenesis.

ABSTRACT: Peri-cellular remodeling of mesenchymal extracellular matrices is considered a prerequisite for cell proliferation, motility and development. Here we demonstrate that membrane-type 3 MMP, MT3-MMP, is expressed in mesenchymal tissues of the skeleton and in peri-skeletal soft connective tissue. Consistent with this localization, MT3-MMP-deficient mice display growth inhibition tied to a decreased viability of mesenchymal cells in skeletal tissues. We document that MT3-MMP works as a major collagenolytic enzyme, enabling cartilage and bone cells to cleave high-density fibrillar collagen and modulate their resident matrix to make it permissive for proliferation and migration. Collectively, these data uncover a novel extracellular matrix remodeling mechanism required for proper function of mesenchymal cells. The physiological significance of MT3-MMP is highlighted in mice double deficient for MT1-MMP and MT3-MMP. Double deficiency transcends the combined effects of the individual single deficiencies and leads to severe embryonic defects in palatogenesis and bone formation incompatible with life. These defects are directly tied to loss of indispensable collagenolytic activities required in collagen-rich mesenchymal tissues for extracellular matrix remodeling and cell proliferation during embryogenesis.

SUBMITTER: Shi J

PROVIDER: S-EPMC2262846 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Membrane-type MMPs enable extracellular matrix permissiveness and mesenchymal cell proliferation during embryogenesis.

Shi Joanne J Son Mi-Young MY Yamada Susan S Szabova Ludmila L Kahan Stacie S Chrysovergis Kaliopi K Wolf Lauren L Surmak Andrew A Holmbeck Kenn K

Developmental biology 20071023 1

Peri-cellular remodeling of mesenchymal extracellular matrices is considered a prerequisite for cell proliferation, motility and development. Here we demonstrate that membrane-type 3 MMP, MT3-MMP, is expressed in mesenchymal tissues of the skeleton and in peri-skeletal soft connective tissue. Consistent with this localization, MT3-MMP-deficient mice display growth inhibition tied to a decreased viability of mesenchymal cells in skeletal tissues. We document that MT3-MMP works as a major collagen ...[more]

PMID: 18022611

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Project description:BACKGROUND:Chronic alcohol consumption has been shown in human and animal studies to result in collagen accumulation, myocardial fibrosis, and heart failure. Cardiac fibroblasts produce collagen and regulate extracellular matrix (ECM) homeostasis through the synthesis and activity of matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), with the balance of MMPs/TIMPs determining the rate of collagen turnover. Dynamic changes of MMP and TIMP expression were reported in alcohol-induced hepatic fibrosis; however, the effect of alcohol on MMP/TIMP balance in the heart and cardiac fibroblasts is unknown. We hypothesized that alcohol exposure alters cardiac fibroblast MMP and TIMP expression to promote collagen accumulation in the heart. METHODS:Cardiac fibroblasts isolated from adult rats were cultured in the presence of alcohol (12.5 to 200 mM) for 48 hours. MMP, TIMP, and collagen type I and III expression were assayed by Western blot analysis. Hydroxyproline (HPro) was used as a marker of collagen production. The in vivo cardiac effects of ethanol (EtOH) were determined using rats exposed to EtOH vapor for 2 weeks, resulting in blood alcohol levels of 150 to 200 mg/dl. Cardiac collagen volume fraction (CVF), as well as MMP, TIMP, and collagen expression, was assessed. RESULTS:EtOH-exposed rats exhibited up-regulation of TIMP-1, TIMP-3 and TIMP-4 in the heart, with no significant increases in MMPs. Cardiac fibroblasts exhibited transformation to a profibrotic phenotype following exposure to alcohol. These changes were reflected by increased ?-smooth muscle actin and collagen I and III expression, as well as increased collagen secretion. In vivo EtOH exposure also produced fibrosis, indicated by increased CVF and expression of collagens. CONCLUSIONS:Alcohol exposure modulates cardiac fibroblast MMP/TIMP expression favoring a profile associated with collagen accumulation. Our data suggest that this disrupted MMP/TIMP profile may contribute to the development of myocardial fibrosis and cardiac dysfunction resulting from chronic alcohol abuse.

Project description:BackgroundTissue remodeling caused by increased MMPs is involved in the pathogenesis of chronic rhinosinusitis with nasal polyposis (CRSwNP). We previously found higher levels of periostin and tenascin C in CRSwNPs, but whether they are associated with the dysregulation of MMPs is unknown. Therefore, the present study aimed to investigate the regulatory roles of these two ECM proteins in the expression of MMPs in nasal polyps.MethodsThe concentrations of MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12, MMP-13, TIMP-1, TIMP-2, TIMP-3, TIMP-4, periostin, and tenascin C in tissue homogenates of 51 patients with chronic rhinosinusitis with and without nasal polyps and 15 control subjects were measured and were analyzed by adjusted logistic regression and spearman correlation test. Primary human nasal polyp fibroblasts and epithelial cells were stimulated ex vivo with periostin and tenascin C and the gene expression of MMPs and TIMPs was determined by means of real-time PCR.ResultsThe protein levels of MMP-3, MMP-7, MMP-8, MMP-9, TIMP-1, TIMP-2, periostin, and tenascin C were significantly higher in patients with CRSwNPs than in healthy control subjects. The adjusted logistic regression analyses showed that MMP-3, MMP-7, MMP-8, MMP-9, TIMP-2, periostin, and tenascin C were related to the occurrence of CRSwNP. Spearman correlation test showed periostin was positively correlated with MMP-3 and TIMP-2, and tenascin C was positively correlated with MMP-3, MMP-7, MMP-8, MMP-9, and TIMP-2. Periostin stimulated the gene expression of MMP-3, MMP-7, MMP-8, and MMP-9 in fibroblasts and MMP-9 in epithelial cells ex vivo. Tenascin C stimulated the expression of MMP-3, MMP-7, MMP-8, and MMP-9 in epithelial cells. The expression of TIMPs in fibroblasts and epithelial cells was affected by neither periostin nor tenascin C.ConclusionsPeriostin and tenascin C might be involved in the remodeling of nasal polyps by regulating the expression of different MMPs in epithelial cells and fibroblasts. Our findings have the potential to identify key factors of tissue remodeling in CRSwNPs.

Project description:Extracellular matrix (ECM) is comprised of different types of proteins, which change in composition and ratios during morphogenesis and disease progression. ECM proteins provide cell adhesion and impart mechanical cues to the cells. Increasing substrate stiffness has been shown to induce Yes-associated protein (YAP) translocation from the cytoplasm to the nucleus, yet these mechanistic studies used fibronectin only as the biochemical cue. How varying the types of ECM modulates mechanotransduction of stem cells remains largely unknown. Using polyacrylamide hydrogels with tunable stiffness as substrates, here we conjugated four major ECM proteins commonly used for cell adhesion: fibronectin, collagen I, collagen IV and laminin, and assessed the effects of varying ECM type and density on YAP translocation in human mesenchymal stem cells (hMSCs). For all four ECM types, increasing ECM ligand density alone can induce YAP nuclear translocation without changing substrate stiffness. The ligand threshold for such biochemical ligand-induced YAP translocation differs across ECM types. While stiffness-dependent YAP translocation can be induced by all four ECM types, each ECM requires a different optimized ligand density for this to occur. Using antibody blocking, we further identified integrin subunits specifically involved in mechanotransduction of different ECM types. Finally, we demonstrated that altering ECM type further modulates hMSC osteogenesis without changing substrate stiffness. These findings highlight the important role of ECM type in modulating mechanotransduction and differentiation of stem cells, and call for future mechanistic studies to further elucidate the role of changes in ECM compositions in mediating mechanotransduction during morphogenesis and disease progression. STATEMENT OF SIGNIFICANCE: Our study addresses a critical gap of knowledge in mechanobiology. Increasing substrate stiffness has been shown to induce nuclear YAP translocation, yet only on fibronectin-coated substrates. However, extracellular matrix (ECM) is comprised of different protein types. How varying the type of ECM modulates stem cell mechanotransduction remains largely unknown. We here reveal that the choice of ECM type can directly modulate stem cell mechanotransduction, filling this critical gap. This work has broad impacts in mechanobiology and biomaterials, as it provides the first evidence that varying ECM type can impact YAP translocation independent of substrate stiffness, opening doors for a more rational biomaterials design tuning ECM properties to control cell fate for promoting normal development and for preventing disease progression.

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Membrane-type MMPs enable extracellular matrix permissiveness and mesenchymal cell proliferation during embryogenesis.

Publications

Membrane-type MMPs enable extracellular matrix permissiveness and mesenchymal cell proliferation during embryogenesis.

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