The Calreticulin-Binding Sequence of Thrombospondin 1 Regulates Collagen Expression and Organization During Tissue Remodeling

Sweetwyne, Mariya T.; Pallero, Manuel A.; Lu, Ailing; Graham, Lauren V.; Murphy-Ullrich, Joanne E.

doi:10.2353/ajpath.2010.090903

Cited by 30 publications

(42 citation statements)

References 65 publications

(91 reference statements)

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“…[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. 22 Thus, it would be expected that PEDF and TSP-1 would be reciprocally regulated if PEDF functions to inhibit fibrosis in the pancreas.…”

mentioning

confidence: 91%

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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mentioning

confidence: 91%

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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“…TSP1 binding to cell surface CRT does not appear to be important for cellular responsiveness to TGF-␤, as CRTϪ/Ϫ MEFs stably expressing CRT lacking the TSP1 binding site were able to respond to TGF-␤ (Fig. 3B) (44,47).…”

Section: Calreticulin Is Required For Tgf-␤-mediated Stimulation Of Cmentioning

confidence: 99%

“…Deoxycholate Extraction of the Extracellular Matrix FractionDeoxycholate (DOC) extractions of detergent-soluble and -insoluble fractions were performed similarly to previous reports (47). Briefly, wild type and CRTϪ/Ϫ MEFs were plated in full serum (10%) DMEM for 24 h, switched to low serum (0.5%) DMEM with 20 M ascorbic acid, and treated with 100 pM TGF-␤ for 24 h. After 24 h, wells were rinsed with PBS and harvested by scraping with 300 l of 4% DOC (4% DOC in 20 mM Tris-HCL, pH 8.8, with 1ϫ protease inhibitor).…”

Section: Methodsmentioning

confidence: 99%

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Calreticulin Regulates Transforming Growth Factor-β-stimulated Extracellular Matrix Production

Zimmerman

Graham²,

Pallero

et al. 2013

Journal of Biological Chemistry

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Background: Endoplasmic reticulum (ER) stress is associated with fibrotic diseases, although the mechanisms are not completely understood. Results: The ER stress protein calreticulin regulates TGF-␤ stimulated extracellular matrix through control of intracellular calcium and NFAT signaling. Conclusion: Calreticulin is necessary for TGF-␤ stimulated extracellular matrix production. Significance: These findings identify calreticulin as a mechanistic link between ER stress and fibrosis.

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“…Expression of trimeric TSP-2 was consistently elevated in COMP-deficient versus wild-type fibroblasts, but this trend failed to reach statistical significance. Expression of thrombospondin-1 (TSP-1) in COMP-deficient cells, which has also been implicated in impacting collagen expression as well as fibril organization (Sweetwyne et al, 2010;Sweetwyne and Murphy-Ullrich, 2012) did not differ from controls. Interestingly, the other pentameric thrombospondin, thrombospondin-4 (TSP-4), which is also stimulated by mechanical load (Cingolani et al, 2011), implicated in cardiac fibrosis (Frolova et al, 2012) and in an adaptive endoplasmic reticulum (ER) stress response (Lynch et al, 2012) might be a candidate for functional compensation because its expression was significantly up-regulated in COMP-deficient fibroblasts.…”

Section: Comp-deficient Skin Exhibits Inconspicuous Histology But Incmentioning

confidence: 99%

COMP-assisted collagen secretion - a novel intracellular function required for fibrosis

Schulz

Nüchel

Niehoff

et al. 2016

Journal of Cell Science

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Cartilage oligomeric matrix protein (COMP) is an abundant component in the extracellular matrix (ECM) of load-bearing tissues such as tendons and cartilage. It provides adaptor functions by bridging different ECM structures. We have previously shown that COMP is also a constitutive component of healthy human skin and is strongly induced in fibrosis. It binds directly and with high affinity to collagen I and to collagen XII that decorates the surface of collagen I fibrils. We demonstrate here that lack of COMP-collagen interaction in the extracellular space leads to changes in collagen fibril morphology and density, resulting in altered skin biomechanical properties. Surprisingly, COMP also fulfills an important intracellular function in assisting efficient secretion of collagens, which were retained in the endoplasmic reticulum of COMP-null fibroblasts. Accordingly, COMPnull mice showed severely attenuated fibrotic responses in skin. Collagen secretion was fully restored by introducing wild-type COMP. Hence, our work unravels a new, non-structural and intracellular function of the ECM protein COMP in controlling collagen secretion.

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The Calreticulin-Binding Sequence of Thrombospondin 1 Regulates Collagen Expression and Organization During Tissue Remodeling

Cited by 30 publications

References 65 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

Calreticulin Regulates Transforming Growth Factor-β-stimulated Extracellular Matrix Production

COMP-assisted collagen secretion - a novel intracellular function required for fibrosis

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