TISSUE INHIBITOR OF METALLOPROTEINASE-3 IS UP-REGULATED BY TRANSFORMING GROWTH FACTOR-<i>β</i>1 IN VITRO AND EXPRESSED IN FIBROBLASTIC FOCI IN VIVO IN IDIOPATHIC PULMONARY FIBROSIS

García, Jorge A.; Ramı́rez, Remedios; Checa, Marco; Nuttall, Robert K.; Sampieri, Clara Luz; Edwards, Dylan R.; Selman, Moisés; Pardo, Annie

doi:10.1080/01902140600817481

Cited by 45 publications

(34 citation statements)

References 35 publications

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“…Interestingly, tissue inhibitor of metalloproteinase (TIMP)-3, an inhibitor of MMPs, was upregulated by 3.6-to 8.8-fold. TIMP3 is believed to be an inhibitor of tumor progression; however, it has also been shown to be a key factor in pathologic fibrosis (42). Several extracellular matrix structural components related to myofibroblast differentiation were also up-regulated by TGFh such as collagens, elastin, fibronectin, and matrix Gla protein (MGP).…”

Section: Cancer Researchmentioning

confidence: 99%

Transforming Growth Factor-β Signaling in Prostate Stromal Cells Supports Prostate Carcinoma Growth by Up-regulating Stromal Genes Related to Tissue Remodeling

Verona¹,

Elkahloun

Yang³

et al. 2007

Cancer Research

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Increasing evidence points to an active stromal involvement in cancer initiation and progression. Cytokines derived from tumor cells are believed to modulate stromal cells to produce growth and angiogenic factors, which in turn provide the tumor with the necessary microenvironment for expansion and invasion. Transforming growth factor B (TGFB) has been implicated as a candidate cytokine to mediate this communication. However, how its signaling in stromal cells regulates tumorigenesis and tumor progression remains unresolved. We show that normal, presenescent fibroblasts or prostate stromal cells cotransplanted with prostate carcinoma cells s.c. into nude mice reduced tumor latency and accelerated tumor growth. When their TGFB signaling was blocked, the fibroblasts and stromal cells still stimulated tumor initiation but no longer supported tumor growth as control cells did. The loss of the tumor growth-promoting activity of the stromal cells with attenuated TGFB signaling was not associated with altered cellular senescence or tumor angiogenicity. TGFB and the medium conditioned by the prostate carcinoma cells stimulated myofibroblast differentiation of the intact stromal cells, but not the stromal cells with attenuated TGFB signaling. Gene microarray and quantitative reverse transcription-PCR analyses showed that TGFB upregulated a host of genes in stromal cells that are involved in tissue remodeling and wound healing. Thus, our study provides evidence for TGFB as a supporting agent in tumor progression through the induction of a perpetual wound healing process in the tumor microenvironment. [Cancer Res 2007;67(12):5737-46]

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Section: Cancer Researchmentioning

confidence: 99%

Transforming Growth Factor-β Signaling in Prostate Stromal Cells Supports Prostate Carcinoma Growth by Up-regulating Stromal Genes Related to Tissue Remodeling

Verona¹,

Elkahloun

Yang³

et al. 2007

Cancer Research

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“…It is believed that TIMP/MMP imbalance is a determinant of fibrogenesis [134][135][136][137]. For example, TIMP1 was upregulated in a mouse model of bleomycin-induced pulmonary fibrosis [138] and TIMP3 was upregulated in patients with IPF [139]. Upregulation of TIMP1 or TIMP3 generates a ''noncollagenolytic microenvironment'' and leads to excessive deposition of extracellular matrix [137].…”

Section: Dysregulation Of Mmps In Different Lung Disorders and Its Thmentioning

confidence: 99%

A therapeutic role for matrix metalloproteinase inhibitors in lung diseases?

Vandenbroucke¹,

Dejonckheere²,

Libert³

2011

Eur Respir J

112

105

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Disruption of the balance between matrix metalloproteinases (MMPs) and their endogenous inhibitors is considered a key event in the development of pulmonary diseases such as chronic obstructive pulmonary disease, asthma, interstitial lung diseases and lung cancer. This imbalance often results in elevated net MMP activity, making MMP inhibition an attractive therapeutic strategy. Although promising results have been obtained, the lack of selective MMP inhibitors, together with limited knowledge regarding the exact functions of a particular MMP, hampers clinical application. This review discusses the involvement of different MMPs in lung disorders and future opportunities and limitations of therapeutic MMP inhibition.

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“…On the other hand, several pathologies involving fibrosis show an increase in MMP expression, including gelatinase A. Augmented expression of MMP-2 was found in submucous (29), skin (30), liver (31), and lung fibrosis (32,33) and dystrophic myotubes from fibrotic muscles of Duchenne muscular dystrophy (34). It has been shown that transforming growth factor type ␤ induces an increase in the amount of MMP-2 in fibroblasts (35) and that CTGF induces MMP-2 expression in cultured renal interstitial fibroblasts (36).…”

mentioning

confidence: 99%

Matrix Metalloproteinase-2-deficient Fibroblasts Exhibit an Alteration in the Fibrotic Response to Connective Tissue Growth Factor/CCN2 because of an Increase in the Levels of Endogenous Fibronectin

Droppelmann

Gutiérrez

Víal

et al. 2009

Journal of Biological Chemistry

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Matrix metalloproteinase-2 (MMP-2) is an important extracellular matrix remodeling enzyme, and it has been involved in different fibrotic disorders. The connective tissue growth factor (CTGF/CCN2), which is increased in these pathologies, induces the production of extracellular matrix proteins. To understand the fibrotic process observed in diverse pathologies, we analyzed the fibroblast response to CTGF when MMP-2 activity is inhibited. CTGF increased fibronectin (FN) amount, MMP-2 mRNA expression, and gelatinase activity in 3T3 cells. When MMP-2 activity was inhibited either by the metalloproteinase inhibitor GM-6001 or in MMP-2-deficient fibroblasts, an increase in the basal amount of FN together with a decrease of its levels in response to CTGF was observed. This paradoxical effect could be explained by the fact that the excess of FN could block the access to other ligands, such as CTGF, to integrins. This effect was emulated in fibroblasts by adding exogenous FN or RGDS peptides or using anti-integrin ␣ V subunit-blocking antibodies. Additionally, in MMP-2-deficient cells CTGF did not induce the formation of stress fibers, focal adhesion sites, and ERK phosphorylation. Anti-integrin ␣ V subunit-blocking antibodies inhibited ERK phosphorylation in control cells. Finally, in MMP-2-deficient cells, FN mRNA expression was not affected by CTGF, but degradation of 125 I-FN was increased. These results suggest that expression, regulation, and activity of MMP-2 can play an important role in the initial steps of fibrosis and shows that FN levels can regulate the cellular response to CTGF.Extracellular proteolysis is an essential physiological process that controls the immediate cellular environment and thus plays a key role in cellular behavior and survival (1). The members of the matrix metalloproteinase (MMP) 2 family of zinc-dependent endopeptidases are major mediators of extracellular proteolysis by promoting the degradation of extracellular matrix (ECM) components and cell surface-associated proteins (2, 3). Each one of these enzymes is negatively regulated by tissue inhibitors of metalloproteinases (TIMPs) (4) and is secreted as a zymogen (pro-MMPs) that is activated in the extracellular space (5-7). This mechanism is an important form of regulation of gelatinase activity and in consequence, highly significant for ECM homeostasis. Among the members of the MMP family, the metalloproteinase type 2 (MMP-2 or gelatinase A) is known to be a key player in many physiological and pathological processes, such as cell migration, inflammation, angiogenesis, and fibrosis (8 -11). Fibrotic disorders are typified by excessive connective tissue and ECM deposition that precludes normal healing of different tissues. ECM accumulation can be explained in two ways: increasing expression and deposition of connective tissue proteins and/or decreasing degradation of ECM proteins (12). Transforming growth factor type ␤, a multifunctional cytokine, is strongly overexpressed, and it is associated to the pathogenesis of these diseases (...

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TISSUE INHIBITOR OF METALLOPROTEINASE-3 IS UP-REGULATED BY TRANSFORMING GROWTH FACTOR-β1 IN VITRO AND EXPRESSED IN FIBROBLASTIC FOCI IN VIVO IN IDIOPATHIC PULMONARY FIBROSIS

Cited by 45 publications

References 35 publications

Transforming Growth Factor-β Signaling in Prostate Stromal Cells Supports Prostate Carcinoma Growth by Up-regulating Stromal Genes Related to Tissue Remodeling

Transforming Growth Factor-β Signaling in Prostate Stromal Cells Supports Prostate Carcinoma Growth by Up-regulating Stromal Genes Related to Tissue Remodeling

A therapeutic role for matrix metalloproteinase inhibitors in lung diseases?

Matrix Metalloproteinase-2-deficient Fibroblasts Exhibit an Alteration in the Fibrotic Response to Connective Tissue Growth Factor/CCN2 because of an Increase in the Levels of Endogenous Fibronectin

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