Thrombospondin-1 Is a Major Activator of TGF-β1 In Vivo

Crawford, Susan E.; Stellmach, Veronica; Murphy-Ullrich, Joanne E.; Ribeiro, Solange M. F.; Lawler, Jack; Hynes, Richard O.; Boivin, Gregory P.; Bouck, Noël

doi:10.1016/s0092-8674(00)81460-9

Cited by 1,072 publications

(899 citation statements)

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“…23 TSP-1 gene expression is low in the native pancreas, but histological staining for TSP-1 in the normal pancreas is not well characterized. 22 Given its induction and role in wound repair, 21 we anticipated that TSP-1 expression would be regulated by PEDF in vivo.…”

Section: Tsp-1 Demonstrates Low Levels Of Expression In the Wild-typementioning

confidence: 99%

“…TSP-1 is a multifunctional matrix protein expressed at sites of wound repair 21,22 that acts as a profibrogenic cytokine by activating latent TGF-␤1 and regulating fibrillar collagen expression. [22][23][24] TSP-1 blockade has been shown to reduce TGF-␤1 signaling and tissue fibrosis. [25][26][27][28] TSP-1 expression also markedly increased after experimental acute pancreatitis.…”

mentioning

confidence: 99%

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Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1

Schmitz

Protiva

Gattu

et al. 2011

The American Journal of Pathology

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Pigment epithelium-derived factor (PEDF) is important for maintaining the normal extracellular matrix. We hypothesized that the initiation of pancreatic fibrosis is dependent on the loss of PEDF. Pancreatic PEDF expression was assessed in wild-type mice fed either a control or ethanol diet using an intragastric feeding model. Pancreatitis responses were elicited with either a single episode or a repetitive ceruleininduced (50 g/kg, 6 hourly i.p. injections) protocol in wild-type and PEDF-null mice. Quantitative realtime PCR and immunoblotting were performed to assess fibrogenic responses. In wild-type animals, PEDF expression increased with pancreatitis and was more pronounced in mice fed ethanol. Compared with wild-type mice, ␣-smooth muscle actin staining and expression levels of fibrogenic markers (eg, transforming growth factor-␤1, platelet-derived growth factor, collagen I, and thrombospondin-1) were higher in PEDF-null mice at baseline. Sirius red staining revealed more fibrosis in PEDF-null versus wildtype pancreas 1 week after pancreatitis. Differences in tissue fibrosis resolved with longer recovery periods. PEDF overexpression suppressed thrombospondin-1 levels in vitro. Ethanol feeding and experimental pancreatitis increased PEDF expression in wildtype mice. PEDF-null mice, however, demonstrated enhanced early fibrotic responses compared with wildtype mice with pancreatitis. These findings indicate that PEDF acts as a compensatory antifibrotic cytokine in

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Section: Tsp-1 Demonstrates Low Levels Of Expression In the Wild-typementioning

confidence: 99%

mentioning

confidence: 99%

Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1

Schmitz

Protiva

Gattu

et al. 2011

The American Journal of Pathology

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“…(Bornstein and Sage 2002) Thrombospondin 1 is thought to be a major activator of TGFβ, most isoforms of which are present in latent forms that need activation for function. (Crawford et al 1998) Since TGFβ is thought to be of significance in affecting the normal and glaucomatous ECMs of the outflow pathway and has been shown to modify outflow facility, this may be of considerable importance. (Tripathi, RC et al 1994;Welge-Lussen et al 1999;Li et al 2000;Welge-Lussen et al 2000;Lutjen-Drecoll and Rohen 2001;Gottanka et al 2004) Immunostaining for thrombospondin 1 is observed throughout the TM, with the greatest density in the JCT region.…”

Section: Matricellular Proteinsmentioning

confidence: 99%

Extracellular matrix in the trabecular meshwork

Acott

Kelley

2008

Experimental Eye Research

408

443

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The extracellular matrix (ECM) of the trabecular meshwork (TM) is thought to be important in regulating intraocular pressure (IOP) in both normal and glaucomatous eyes. IOP is regulated primarily by a fluid resistance to aqueous humor outflow. However, neither the exact site nor the identity of the normal resistance to aqueous humor outflow has been established. Whether the site and nature of the increased outflow resistance, which is associated with open-angle glaucoma, is the same or different from the normal resistance is also unclear.The ECMs of the TM beams, juxtacanalicular region (JCT) and Schlemm's canal (SC) inner wall are comprised of fibrillar and non-fibrillar collagens, elastin-containing microfibrils, matricellular and structural organizing proteins, glycosaminoglycans (GAGs) and proteoglycans. Both basement membranes and stromal ECM are present in the TM beams and JCT region. Cell adhesion proteins, cell surface ECM receptors and associated binding proteins are also present in the beams, JCT and SC inner wall region.The outflow pathway ECM is relatively dynamic, undergoing constant turnover and remodeling. Regulated changes in enzymes responsible for ECM degradation and biosynthetic replacement are observed. IOP homeostasis, triggered by pressure changes or mechanical stretching of the TM, appears to involve ECM turnover. Several cytokines, growth factors and drugs, which affect the outflow resistance, change ECM component expression, mRNA alternative splicing, cellular cytoskeletal organization or all of these. Changes in ECM associated with open-angle glaucoma have been identified.

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“…Furthermore, it has been reported as an important factor in the adipocyte-and macrophage-driven inflammation in the adipose tissue, and that could mediate the elevation of PAI-1, promoting a prothrombotic state [41]. Also, TSP-1 has been described as a major regulator of the transforming growth factor (TGF)-β activity [11,31], which, together with the increased 3 PAI-1 levels, are correlated with different features of obesity, insulin-resistance, and metabolic syndrome [1,29,37]. Finally, it has been described higher TSP-1 gene expression in visceral respect to subcutaneous adipose tissue in obese subjects [35].…”

Section: Introductionmentioning

confidence: 99%

Glucose and insulin modify thrombospondin 1 expression and secretion in primary adipocytes from diet-induced obese rats

et al. 2011

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Thrombospondin 1 (TSP-1), an anti-angiogenic factor and TGF-β activity regulator, has been recently recognized as an adipokine that correlates with obesity, inflammation and insulin-resistance processes. In the present study, epididymal adipocytes of rats that were fed a chow (C) or a high fat diet (HFD) for 50 days, were isolated and incubated (24-72 h) in low (LG; 5.6 mM) or high (HG; 25 mM) glucose, in presence or absence of 1.6 nM insulin. Rats fed the HF diet showed an established obesity state. Serum TSP-1 levels and TSP-1 mRNA basal expression of adipocytes from HFD rats were higher than those from controls. Adipocytes from HFD animals presented an insulin-resistance state, as suggested by the lower insulin-stimulated glucose uptake as compared to controls. TSP-1 expression in culture was higher in adipocytes from obese animals at 24 h, but when the adipocytes were treated with HG, these expression levels dropped dramatically. Later at 72 h, TSP-1 expression was lower in adipocytes from HFD rats, and no effects of the other treatments were observed. Surprisingly, the secretion levels of this protein at 72 h were increased significantly by the HG treatment in both types of adipocytes, although they were even higher in adipocytes from obese animals. Finally, cell viability was significantly reduced by HG treatment in both types of adipocytes. In summary, TSP-1 expression/secretion was modulated in an in vitro model of insulinresistant adipocytes. The difference between expression and secretion patterns suggests a post-transcriptional regulation. The present study confirms that TPS-1 is closely associated with obesity-related mechanisms.

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Thrombospondin-1 Is a Major Activator of TGF-β1 In Vivo

Cited by 1,072 publications

References 64 publications

Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1

Pigment Epithelium-Derived Factor Regulates Early Pancreatic Fibrotic Responses and Suppresses the Profibrotic Cytokine Thrombospondin-1

Extracellular matrix in the trabecular meshwork

Glucose and insulin modify thrombospondin 1 expression and secretion in primary adipocytes from diet-induced obese rats

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