Making sense of latent TGFβ activation

Annes, Justin P.; Munger, John S.; Rifkin, Daniel B.

doi:10.1242/jcs.00229

Cited by 1,467 publications

(1,354 citation statements)

References 72 publications

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“…The extracellular concentration of TGF-β activity is primarily regulated by conversion of latent TGF-β to active TGF-β. Most tissues contain significant amounts of latent TGF-β; activation of only a small fraction of this latent TGF-β generates maximal cellular response [295]. Mature TGF-β is secreted as a homodimer of two 12.5 kD polypeptides joined by a disulfide bond.…”

Section: Tgf-β: a Key Regulator In Cardiac Repair The Biology Of Tgf-βmentioning

confidence: 99%

“…Proteases including plasmin, MMP-2 and MMP-9 are capable of activating TGF-β, coupling matrix degradation with activation of a molecule that has a primary role in maintaining matrix integrity and stability [295], [298], [299]. The matricellular protein Thrombospondin (TSP)-1 is a key TGF-β activator which acts by disrupting the non-covalent interactions between LAP and the TGF-β molecule [300].…”

Section: Tgf-β: a Key Regulator In Cardiac Repair The Biology Of Tgf-βmentioning

confidence: 99%

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The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

561

487

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Myocardial infarction is the most common cause of cardiac injury and results in acute loss of a large number of myocardial cells. Because the heart has negligible regenerative capacity, cardiomyocyte death triggers a reparative response that ultimately results in formation of a scar and is associated with dilative remodeling of the ventricle. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Toll Like Receptor-mediated pathways, the complement cascade and reactive oxygen generation induce Nuclear Factor (NF)-κB activation and upregulate chemokine and cytokine synthesis in the infarcted heart. Chemokines stimulate the chemotactic recruitment of inflammatory leukocytes into the infarct, while cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. Monocyte subsets play distinct roles in phagocytosis of dead cardiomyocytes and in granulation tissue formation through the release of growth factors. Clearance of dead cells and matrix debris may be essential for resolution of inflammation and transition into the reparative phase. Transforming Growth Factor (TGF)-β plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. Myofibroblast proliferation and angiogenesis result in formation of highly vascularized granulation tissue. As the healing infarct matures, fibroblasts become apoptotic and a collagen-based matrix is formed, while many infarct neovessels acquire a muscular coat and uncoated vessels regress. Timely resolution of the inflammatory infiltrate and spatial containment of the inflammatory and reparative response into the infarcted area are essential for optimal infarct healing. Targeting inflammatory pathways following infarction may reduce cardiomyocyte injury and attenuate adverse remodeling. In addition, understanding the role of the immune system in cardiac repair is necessary in order to design optimal strategies for cardiac regeneration.

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Section: Tgf-β: a Key Regulator In Cardiac Repair The Biology Of Tgf-βmentioning

confidence: 99%

Section: Tgf-β: a Key Regulator In Cardiac Repair The Biology Of Tgf-βmentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

561

487

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“…The binding of TGF-b-bound large latency complex to fibrillins has two roles; it renders TGF-b inactive, facilitating fine control of TGF-b activity. It also concentrates TGF-b to specific locations, thus regulating the biological response to TGF-b (Annes et al, 2003). FBN1 mutations in Marfan's syndrome result in the excess activation of TGF-b (Chaudhry et al, 2007).…”

Section: Ct Bstu1mentioning

confidence: 99%

Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma

et al. 2010

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The detection of promoter region hypermethylation and transcriptional silencing has facilitated the identification of candidate renal cell carcinoma (RCC) tumour suppressor genes (TSGs). We have used a genome-wide strategy (methylated DNA immunoprecipitation (MeDIP) and whole-genome array analysis in combination with highdensity expression array analysis) to identify genes that are frequently methylated and silenced in RCC. MeDIP analysis on 9 RCC tumours and 3 non-malignant normal kidney tissue samples was performed, and an initial shortlist of 56 candidate genes that were methylated by array analysis was further investigated; 9 genes were confirmed to show frequent promoter region methylation in primary RCC tumour samples (KLHL35 (39%), QPCT (19%), SCUBE3 (19%), ZSCAN18 (32%), CCDC8 (35%), FBN2 (34%), ATP5G2 (36%), PCDH8 (58%) and CORO6 (22%)). RNAi knockdown for KLHL35, QPCT, SCUBE3, ZSCAN18, CCDC8 and FBN2 resulted in an anchorage-independent growth advantage. Tumour methylation of SCUBE3 was associated with a significantly increased risk of cancer death or relapse (P ¼ 0.0046). The identification of candidate epigenetically inactivated RCC TSGs provides new insights into renal tumourigenesis.

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“…To measure the concentrations of IGF-1 and TGF-β1 in pellet supernatants, each growth factor was quantified using a commercial enzymelinked immunosorbent assay kit (ELISA; R&D Systems, Minneapolis, MN, USA) following the manufacturer's protocol. The TGF-β1 production was determined either after activation with 0.2 M HCl or without prior activation to determine the active TGF-β1 present in the medium [41]. The mean value concentration of active and inactive TGF-β1 was compared by Student's t-test (n = 4), and p values equal to or less than 0.05 were considered significant.…”

Section: Elisa For Tgf-β1 and Igf-1 Productionmentioning

confidence: 99%

Adenoviral-mediated transfer of TGF-β1 but not IGF-1 induces chondrogenic differentiation of human mesenchymal stem cells in pellet cultures

Kawamura¹,

Chu²,

Sobajima³

et al. 2005

Experimental Hematology

102

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Objective. The objective of the present study was to investigate the potential of application of growth factor genes to induce chondrogenic differentiation of human-derived mesenchymal stem cells (MSCs). The growth factor genes evaluated in the present study were transforming growth factor 1 (TGF-β1) and insulin-like growth factor 1 (IGF-1).Methods. Human MSCs were transduced with the adenoviral vectors carrying either TGF-β1 or IGF-1 (AdTGF-β1 and AdIGF-1 respectively) or a combination of both growth factor genes at different multiplicities of infection (MOI) and were then made into pellets. Pellets were also made from nontransduced cells and maintained in culture medium supplemented with 10 ng/mL of TGF-β1. At specified time points, histological analysis, cartilage matrix gene expression, and immunofluorescence were performed to determine the extent of chondrogenic differentiation.Results. MSCs transduced with the AdTGF-β1 demonstrated robust chondrogenic differentiation, while those made from AdIGF-1 did not. AdTGF-β1 pellets demonstrated aggrecan gene expression as early as day 3 of pellet culture, while type II collagen gene expression was detected by day 10 of culture. The AdIGF-1, alone or in combination with TGF-β1 pellets, did not show any type II collagen gene expression at any time point. By immunofluoresecence, type X collagen was distributed throughout the matrix in TGF-β1 protein pellets while the growth factor gene pellets displayed scant staining. Conclusion.The results suggest that sustained administration of TGF-β1 may be more effective in suppressing terminal differentiation than intermittent dosing and thus effective for cartilage repair.

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Making sense of latent TGFβ activation

Cited by 1,467 publications

References 72 publications

The immune system and cardiac repair

The immune system and cardiac repair

Genome-wide methylation analysis identifies epigenetically inactivated candidate tumour suppressor genes in renal cell carcinoma

Adenoviral-mediated transfer of TGF-β1 but not IGF-1 induces chondrogenic differentiation of human mesenchymal stem cells in pellet cultures

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