Activated human platelets release connective tissue growth factor

2004 ◽  
Vol 91 (04) ◽  
pp. 755-760 ◽  
Author(s):  
Iwona Cicha ◽  
Christoph Garlichs ◽  
Werner Daniel ◽  
Margarete Goppelt-Struebe
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Bone Marrow Cells ◽  
Plaque Rupture ◽  
Tissue Injury ◽  
Human Platelets ◽  
Tissue Growth ◽  
Biologically Active

SummaryConnective tissue growth factor (CTGF) is overexpressed in wound healing, fibrosis and advanced atherosclerotic lesions. Platelets adhere to CTGF, suggesting that this protein may be involved in the formation of platelet-rich thrombi at the sites of tissue injury or atherosclerotic plaque rupture. Since platelets contain a wide array of biologically active proteins, we investigated the presence, localization and release of CTGF from these cells. For this purpose, human platelets from healthy donors were washed and stimulated with thrombin or ADP. Following incubation, proteins from unstimulated and stimulated cell lysates and the supernatants were analysed by Western blotting. The experiments showed that unstimulated platelets contain considerable amounts of CTGF, whereas no CTGF was detectable in platelet-poor plasma. To elucidate the origin of CTGF in platelets, we performed immunohistochemical analysis of human bone marrow sections. The analysis showed that although CTGF protein is widely expressed in bone marrow cells, it is not expressed by platelet-producing megakaryocytes, suggesting that CTGF presence in platelets is a result of endocytosis from extracellular environment in bone marrow. Agonist-stimulation of platelets resulted in a significant release of CTGF from the storage granules, with thrombin at 0.1 U/mL being a more potent activator than ADP at 20 µmol/L. The agonist-dependent CTGF secretion was significantly inhibited by aspirin. In conclusion, CTGF is stored in normal human platelets, and can be released upon platelet activation. Aspirin treatment prevents CTGF release, suggesting that clinical benefits of this drug may involve the inhibition of CTGF secretion.

scholarly journals Connective tissue growth factor regulates adipocyte differentiation of mesenchymal stromal cells and facilitates leukemia bone marrow engraftment

Blood ◽  
2013 ◽  
Vol 122 (3) ◽  
pp. 357-366 ◽  
Author(s):  
V. Lokesh Battula ◽  
Ye Chen ◽  
Maria da Graca Cabreira ◽  
Vivian Ruvolo ◽  
Zhiqiang Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Stromal Cells ◽  
Adipocyte Differentiation ◽  
Adipogenic Differentiation ◽  
Tissue Growth ◽  
Key Points ◽  
Bone Marrow Engraftment

Key Points Connective tissue growth factor regulates adipogenic differentiation of MSCs. Connective tissue growth factor regulates leukemia engraftment.

scholarly journals Connective tissue growth factor (CCN2) is a matricellular preproprotein controlled by proteolytic activation

2018 ◽  
Vol 293 (46) ◽  
pp. 17953-17970 ◽  
Author(s):  
Ole Jørgen Kaasbøll ◽  
Ashish K. Gadicherla ◽  
Jian-Hua Wang ◽  
Vivi Talstad Monsen ◽  
Else Marie Valbjørn Hagelin ◽  
...  
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Osteoclast Differentiation ◽  
Tissue Growth ◽  
Proteolytic Processing ◽  
Biologically Active ◽  
Proteolytic Fragment ◽  
Proteolytic Activation ◽  
Fibroblast Migration

Connective tissue growth factor (CTGF; now often referred to as CCN2) is a secreted protein predominantly expressed during development, in various pathological conditions that involve enhanced fibrogenesis and tissue fibrosis, and in several cancers and is currently an emerging target in several early-phase clinical trials. Tissues containing high CCN2 activities often display smaller degradation products of full-length CCN2 (FL-CCN2). Interpretation of these observations is complicated by the fact that a uniform protein structure that defines biologically active CCN2 has not yet been resolved. Here, using DG44 CHO cells engineered to produce and secrete FL-CCN2 and cell signaling and cell physiological activity assays, we demonstrate that FL-CCN2 is itself an inactive precursor and that a proteolytic fragment comprising domains III (thrombospondin type 1 repeat) and IV (cystine knot) appears to convey all biologically relevant activities of CCN2. In congruence with these findings, purified FL-CCN2 could be cleaved and activated following incubation with matrix metalloproteinase activities. Furthermore, the C-terminal fragment of CCN2 (domains III and IV) also formed homodimers that were ∼20-fold more potent than the monomeric form in activating intracellular phosphokinase cascades. The homodimer elicited activation of fibroblast migration, stimulated assembly of focal adhesion complexes, enhanced RANKL-induced osteoclast differentiation of RAW264.7 cells, and promoted mammosphere formation of MCF-7 mammary cancer cells. In conclusion, CCN2 is synthesized and secreted as a preproprotein that is autoinhibited by its two N-terminal domains and requires proteolytic processing and homodimerization to become fully biologically active.

scholarly journals Activation-dependent Adhesion of Human Platelets to Cyr61 and Fisp12/Mouse Connective Tissue Growth Factor Is Mediated through Integrin αIIbβ3

1999 ◽  
Vol 274 (34) ◽  
pp. 24321-24327 ◽  
Author(s):  
Arom Jedsadayanmata ◽  
Chih-Chiun Chen ◽  
Maria L. Kireeva ◽  
Lester F. Lau ◽  
Stephen C.-T. Lam
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Human Platelets ◽  
Tissue Growth ◽  
Integrin Αiibβ3

Abstract P224: Connective Tissue Growth Factor Plays a Key Role in Myocardial Fibrosis After Angiotensin II Exposure

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Nicole L Rosin ◽  
Jean-François Légaré ◽  
Timothy D Lee
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Primary Cultures ◽  
Tissue Growth ◽  
Mrna Levels

Background: AngiotensinII (AngII) exposure to rodents is a common model of fibrosis, characterized by hypertension, hypertrophy and eventual deposition of excess extracellular matrix (ECM) proteins resulting in organ dysfunction. We have previously shown that cellular infiltration of bone marrow derived progenitor cells (fibrocytes) occurs prior to ECM deposition and is associated with production of the connective tissue growth factor (CTGF) and transforming growth factor beta (TGF-β). The objective of this project was to characterize the role of CTGF in promoting fibrocyte recruitment and subsequent fibrosis after AngII exposure. Methods: Mice were treated with AngII or saline using an osmotic mini-pump at 2.8mg/kg/day. After 6hr to 7d hearts were excised and embedded in paraffin or prepared for mRNA isolation. Immunohistochemistry was used to determine extent and localization of CTGF protein. Quantitative RT-PCR was used to determine relative CTGF and TGF-β mRNA levels. Primary cardiomyocyte and fibrocyte cultures were isolated from neonatal or 3d AngII exposed animals respectively. Primary cultures were stimulated to determine the source (qRT-PCR) and function (proliferation, migration and differentiation) of CTGF. Results: In animals exposed to AngII, CTGF mRNA peaked the earliest at 6hr (21-fold; p<0.01) when compared to TGFbeta, which peaked at 3d (5-fold; p<0.05). Concurrent CTGF protein expression was evident by 3d of AngII exposure and appeared localized to the cardiomyocytes. Findings were confirmed using isolated cardiomyocytes, which significantly increased expression of CTGF in response to AngII (2-fold; p<0.05). While CTGF did not promote fibrocyte migration in transwell chamber assay it promoted significant fibrocyte proliferation in vitro (2-fold; p<0.05). Conclusion: We provide strong evidence that AngII exposure first results in the production of CTGF by cardiomyocytes. Furthermore, we have shown that CTGF does not promote migration as a chemokine but instead contributes to proliferation of fibrocytes once recruited from the bone marrow into the myocardium.

scholarly journals Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10.

1991 ◽  
Vol 114 (6) ◽  
pp. 1285-1294 ◽  
Author(s):  
D M Bradham ◽  
A Igarashi ◽  
R L Potter ◽  
G R Grotendorst
Keyword(s):  
Endothelial Cells ◽  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Culture Media ◽  
Vascular Endothelial Cells ◽  
Tissue Growth ◽  
Biologically Active ◽  
Early Gene ◽  
Vascular Endothelial

Human umbilical vein endothelial (HUVE) cells have been previously reported to express the genes for the A and B chains of PDGF and to secrete PDGF-related factors into culture media. Antihuman PDGF IgG affinity chromatography was used to purify PDGF-related activity from HUVE cell-conditioned media. Immunoblot analysis of the affinity-purified proteins with anti-PDGF IgG and antibodies specific for the A or B chain peptides of PDGF combined with chemotactic and mitogenic assays revealed that the major PDGF immunorelated molecule secreted by HUVE cells is a monomer of approximately 36-38 kD and that less than 10% of the purified biologically active molecules are PDGF A or B chain peptides. Screening of an HUVE cell cDNA library in the expression vector lambda gtl 1 with the anti-PDGF antibody resulted in the cloning and sequencing of a cDNA with an open reading frame encoding a 38-kD cysteine-rich secreted protein which we show to be the major PDGF-related mitogen secreted by human vascular endothelial cells. The protein has a 45% overall homology to the translation product of the v-src-induced CEF-10 mRNA from chick embryo fibroblasts. We have termed this new mitogen connective tissue growth factor.

Identification of connective tissue growth factor as a hepatic negative acute phase protein

Hepatology ◽  
2009 ◽  
pp. NA-NA
Author(s):  
Ieva Peredniene ◽  
Eddy van de Leur ◽  
Birgit Lahme ◽  
Monika Siluschek ◽  
Axel M. Gressner ◽  
...  
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Connective Tissue Growth Factor ◽  
Acute Phase ◽  
Acute Phase Protein ◽  
Tissue Growth ◽  
Phase Protein
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