CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis (original) (raw)
Related papers
Connective tissue growth factor (CTGF) from basics to clinics
Matrix Biology, 2018
Connective tissue growth factor, also known as CCN2, is a cysteine-rich matricellular protein involved in the control of biological processes, such as cell proliferation, differentiation, adhesion and angiogenesis, as well as multiple pathologies, such as tumor development and tissue fibrosis. Here, we describe the molecular and biological characteristics of CTGF, its regulation and various functions in the spectrum of development and regeneration to fibrosis. We further outline the preclinical and clinical studies concerning compounds targeting CTGF in various pathologies with the focus on heart, lung, liver, kidney and solid organ transplantation. Finally, we address the advances and pitfalls of translational fibrosis research and provide suggestions to move towards a better management of fibrosis.
Cooperative interaction of CTGF and TGF-β in animal models of fibrotic disease
Fibrogenesis & Tissue Repair, 2011
BACKGROUND: Connective tissue growth factor (CTGF) is widely thought to promote the development of fibrosis in collaboration with transforming growth factor (TGF)-β; however, most of the evidence for its involvement comes from correlative and culture-based studies. In this study, the importance of CTGF in tissue fibrosis was directly examined in three murine models of fibrotic disease: a novel model of
American journal of physiology. Cell physiology, 2017
Fibrosis is a common feature of several chronic diseases, and is characterized by exacerbated accumulation of extracellular matrix (ECM). Understanding the cellular and molecular mechanisms involved in the development of this condition is crucial for designing efficient treatments for those pathologies. Connective tissue growth factor (CTGF/CCN2) is a pleiotropic protein with strong pro-fibrotic activity. In this report, we present experimental evidence showing that ECM stimulates the synthesis of CTGF in response to lysophosphatidic acid (LPA). This effect is mediated by the integrin/FAK signaling pathway, since CTGF expression is abolished by the use of the RGDS peptide and also by an inhibitor of FAK auto-phosphorylation at tyrosine 397. Cilengitide, a specific inhibitor of αv integrins, inhibits the expression of CTGF mediated by LPA or TGF-β1. We show that ECM obtained from decellularized myofibroblasts cultures or derived from activated fibroblasts from muscles of the Duchenne...
Arthritis & Rheumatism, 2010
Objective. Connective tissue growth factor (CTGF) is a cysteine-rich secreted matricellular protein involved in wound healing and tissue repair. Enhanced and prolonged expression of CTGF has been associated with tissue fibrosis in humans. However, questions remain as to whether CTGF expression alone is sufficient to drive fibrosis. This study was undertaken to investigate whether CTGF alone is sufficient to cause fibrosis in intact animals and whether its effects are mediated through activation of transforming growth factor  (TGF) signaling or through distinct signal transduction pathways.
Mechanism of Fibrosis and Their Role in TGF-Β
2020
Fibrosis is an excessive accumulation of fibrous connective tissue. It is a pathological feature of most chronic inflammatory diseases. Every tissue in the body can be affected by fibrosis. If the fibrosis is highly progressive, it leads to organ failure and death. The alternate of regular structural elements of the tissue with extreme growth of scar tissue comprised of distorted collagens. Cellular and immunological changes occur along with age related tissue remodelling. In mechanical properties of ECM (Extra cellular matrix), the Mechanotransduction pathways impact such critical cellular functions as proliferation, differentiation, and migration. Those ECM properties were sensed by integrins. Preclinical studies with the mechanotransduction inhibitors in TGF Pathway have shown a variety of different tumor models. TGFβ pathways is upregulated and activated in fibrotic diseases and modulate the phenotype of fibroblast and its function. While promoting the matrix preservation induce...
Journal of Molecular and Cellular Cardiology, 2000
Connective tissue growth factor (CTGF) is a cysteine-rich protein induced by transforming growth factor beta (TGF-) in connective tissue cells. CTGF can trigger many of the cellular processes underlying fibrosis, such as cell proliferation, adhesion, migration and the synthesis of extracellular matrix; however, its role in acute and chronic cardiac injury is not fully understood. Here, we show that TGF-is a specific inducer of CTGF expression in both cardiac fibroblasts and cardiac myocytes. The activity of a CTGF promoter-based reporter construct correlated with endogenous CTGF expression, suggesting that TGF-induces CTGF expression most likely by activating its promoter. Upregulation of CTGF coincided with an increase in fibronectin, collagen type I and plasminogen activator inhibitor-1 production. Forskolin, a stimulator of cyclic AMP, blocked TGF-induced CTGF expression and reduced the basal level of CTGF, whereas an inhibitor that blocks the MAP kinase signaling pathway (PD 98059) significantly enhanced TGF-induced CTGF expression. Furthermore, we found that both TGF-and CTGF mRNAs were significantly elevated in the left ventricles and septa of rat hearts 2-16 weeks following myocardial infarction. This correlated well with concomitant increases in fibronectin, and type I and type III collagen mRNA levels in these animal hearts. Significant upregulation of CTGF was also detected in human heart samples derived from patients diagnosed with cardiac ischemia. Based on these findings, we propose that CTGF is an important mediator of TGF-signaling in the heart and abnormal expression of this gene could be used as a diagnostic marker for cardiac fibrosis.
Inhibition of PDGF, VEGF and FGF signalling attenuates fibrosis
European Respiratory Journal, 2007
BIBF 1000 is a small molecule inhibitor targeting the receptor kinases of plateletderived growth factor (PDGF), basic fibroblast growth factor and vascular endothelial growth factor, which have known roles in the pathogenesis of pulmonary fibrosis.
Connective Tissue Growth Factor: What's in a Name?
Molecular Genetics and Metabolism, 2000
Connective tissue growth factor (CTGF) is a member of the recently described CCN gene family which contains CTGF itself, cyr61, nov, elm1, Cop1, and WISP-3. CTGF is transcriptionally activated by several factors although its stimulation by transforming growth factor  (TGF-) has attracted considerable attention. CTGF acts to promote fibroblast proliferation, migration, adhesion, and extracellular matrix formation, and its overproduction is proposed to play a major role in pathways that lead to fibrosis, especially those that are TGF--dependent. This includes fibrosis of major organs, fibroproliferative diseases, and scarring. CTGF also appears to play a role in the extracellular matrix remodeling that occurs in normal physiological processes such as embryogenesis, implantation, and wound healing. However, recent advances have shown that CTGF is involved in diverse autocrine or paracrine actions in several other cell types such as vascular endothelial cells, epithelial cells, neuronal cells, vascular smooth muscle cells, and cells of supportive skeletal tissues. Moreover, in some circumstances CTGF has negative effects on cell growth in that it can be antimitotic and apoptotic. In light of these discoveries, CTGF has been implicated in a diverse variety of processes that include neovascularization, transdifferentiation, neuronal scarring, atherosclerosis, cartilage differentiation, and endochondral ossification. CTGF has thus emerged as a potential important effector molecule in both physiological and pathological processes and has provided a new target for therapeutic intervention in fibrotic diseases.
Regulation of pro-inflammatory and pro-fibrotic factors by CCN2/CTGF in H9c2 cardiomyocytes
Journal of cell communication and signaling, 2010
Connective tissue growth factor (CTGF), also known as CCN2, is implicated in fibrosis through both extracellular matrix (ECM) induction and inhibition of ECM degradation. The role of CTGF in inflammation in cardiomyocytes is unknown. In some mesenchymal cell systems, CTGF mediates effects through TGF-beta or tyrosine kinase cell surface receptor, TrkA, signalling. In this study, cellular mechanisms by which CTGF regulates pathways involved in fibrosis and inflammation were explored. Murine H9c2 cardiomyocytes were treated with recombinant human (rh)CTGF and ECM formation gene expression: fibronectin, collagen type -I and -III and ECM degradation genes: TIMP-1, TIMP-2 and PAI-1 were found to be induced. CTGF treatment also increased pro-inflammatory cytokines TNF-alpha, IL-6, MCP-1 and IL-8. CTGF upregulated TGF-beta1 mRNA and rapidly induced phosphorylation of TrkA. The CTGF-induced pro-fibrotic and pro-inflammatory effects were blocked by anti-TGF-beta neutralizing antibody and Alk...