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CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis.

Lipson KE, Wong C, Teng Y, Spong S - Fibrogenesis Tissue Repair (2012)

Bottom Line: A monoclonal antibody to CTGF that is currently in clinical development (FG-3019) has demonstrated the ability to reverse vascular stiffening and improve cardiac function in a rat model of diabetic complications.FG-3019 has also exhibited activity in a murine radiation-induced pulmonary fibrosis model.When FG-3019 was administered to mice after a significant radiation-induced increase in lung density could be observed by CT imaging, the density of the lungs was observed to decrease over the period during which the antibody was administered and to remain stable after therapy had ceased.

View Article: PubMed Central - HTML - PubMed

Affiliation: FibroGen, Inc., 409 Illinois St., San Francisco, CA 94158, USA.

ABSTRACT
CTGF is a secreted matricellular protein with very complex biology. It has been shown to modulate many signaling pathways leading to cell adhesion and migration, angiogenesis, myofibroblast activation, and extracellular matrix deposition and remodeling, which together lead to tissue remodeling and fibrosis. It has been reported in the literature that inhibition of CTGF expression by siRNA prevents CCl4-induced liver fibrosis and can reverse fibrosis when administered after significant collagen deposition is observed. A monoclonal antibody to CTGF that is currently in clinical development (FG-3019) has demonstrated the ability to reverse vascular stiffening and improve cardiac function in a rat model of diabetic complications. FG-3019 has also exhibited activity in a murine radiation-induced pulmonary fibrosis model. When FG-3019 was administered to mice after a significant radiation-induced increase in lung density could be observed by CT imaging, the density of the lungs was observed to decrease over the period during which the antibody was administered and to remain stable after therapy had ceased. When considered together, these data indicate that inhibition of CTGF can prevent and reverse the process of fibrosis.

No MeSH data available.


Related in: MedlinePlus

CTGF is a central mediator of tissue remodeling and fibrosis. Many different stimuli can induce expression of CTGF, which then promotes formation of myofibroblasts by modulating differentiation of other cells, including epithelial cells (EMT, epithelial to mesenchymal transition), resident fibroblasts or recruited fibrocytes (bone-marrow-derived, circulating mesenchymal stem cells). CTGF also promotes activation of the myofibroblasts and stimulates extracellular matrix (ECM) deposition and tissue remodeling. Remodeling in the vasculature can produce local hypertension that induces the expression of more CTGF, resulting in a positive feedback loop. Other positive feedback loops result from cytokines whose expression may be stimulated by CTGF, that in turn induce the expression of CTGF.
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Figure 2: CTGF is a central mediator of tissue remodeling and fibrosis. Many different stimuli can induce expression of CTGF, which then promotes formation of myofibroblasts by modulating differentiation of other cells, including epithelial cells (EMT, epithelial to mesenchymal transition), resident fibroblasts or recruited fibrocytes (bone-marrow-derived, circulating mesenchymal stem cells). CTGF also promotes activation of the myofibroblasts and stimulates extracellular matrix (ECM) deposition and tissue remodeling. Remodeling in the vasculature can produce local hypertension that induces the expression of more CTGF, resulting in a positive feedback loop. Other positive feedback loops result from cytokines whose expression may be stimulated by CTGF, that in turn induce the expression of CTGF.

Mentions: Regardless of the complexity of the mechanism of action by which CTGF modulates cell biology, it is very clear that CTGF plays a central role in diseases in which tissue remodeling occurs (Figure 2). CTGF expression is induced by many cytokines and conditions associated with pathophysiology [20]. Its presence induces formation of myofibroblasts through transdifferentiation of other cells, including epithelial cells (via EMT, epithelial to mesenchymal transition) [21], stellate cells [22], resident fibroblasts [23] or fibrocytes (bone-marrow-derived, circulating mesenchymal stem cells) that have been recruited to an organ through chemokines [24]. CTGF also activates the myofibroblasts and stimulates their deposition and remodeling of ECM (extracellular matrix) proteins. This leads to tissue remodeling and fibrosis. When the tissue remodeling occurs in the vasculature, it can create local hypertension that can induce CTGF expression [25-27], thereby setting up a positive feedback loop leading to more tissue remodeling. CTGF also induces the expression of a variety of cytokines such as TGFβ [28] and VEGF [29], which induce more expression of CTGF. Thus, there are multiple positive feedback loops involving CTGF expression that can contribute to the progressive nature of fibrosis. By inhibiting CTGF, these positive feedback loops can be broken, which should enable organs to restore their normal wound healing response and their normal structure and function.


CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis.

Lipson KE, Wong C, Teng Y, Spong S - Fibrogenesis Tissue Repair (2012)

CTGF is a central mediator of tissue remodeling and fibrosis. Many different stimuli can induce expression of CTGF, which then promotes formation of myofibroblasts by modulating differentiation of other cells, including epithelial cells (EMT, epithelial to mesenchymal transition), resident fibroblasts or recruited fibrocytes (bone-marrow-derived, circulating mesenchymal stem cells). CTGF also promotes activation of the myofibroblasts and stimulates extracellular matrix (ECM) deposition and tissue remodeling. Remodeling in the vasculature can produce local hypertension that induces the expression of more CTGF, resulting in a positive feedback loop. Other positive feedback loops result from cytokines whose expression may be stimulated by CTGF, that in turn induce the expression of CTGF.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3368796&req=5

Figure 2: CTGF is a central mediator of tissue remodeling and fibrosis. Many different stimuli can induce expression of CTGF, which then promotes formation of myofibroblasts by modulating differentiation of other cells, including epithelial cells (EMT, epithelial to mesenchymal transition), resident fibroblasts or recruited fibrocytes (bone-marrow-derived, circulating mesenchymal stem cells). CTGF also promotes activation of the myofibroblasts and stimulates extracellular matrix (ECM) deposition and tissue remodeling. Remodeling in the vasculature can produce local hypertension that induces the expression of more CTGF, resulting in a positive feedback loop. Other positive feedback loops result from cytokines whose expression may be stimulated by CTGF, that in turn induce the expression of CTGF.
Mentions: Regardless of the complexity of the mechanism of action by which CTGF modulates cell biology, it is very clear that CTGF plays a central role in diseases in which tissue remodeling occurs (Figure 2). CTGF expression is induced by many cytokines and conditions associated with pathophysiology [20]. Its presence induces formation of myofibroblasts through transdifferentiation of other cells, including epithelial cells (via EMT, epithelial to mesenchymal transition) [21], stellate cells [22], resident fibroblasts [23] or fibrocytes (bone-marrow-derived, circulating mesenchymal stem cells) that have been recruited to an organ through chemokines [24]. CTGF also activates the myofibroblasts and stimulates their deposition and remodeling of ECM (extracellular matrix) proteins. This leads to tissue remodeling and fibrosis. When the tissue remodeling occurs in the vasculature, it can create local hypertension that can induce CTGF expression [25-27], thereby setting up a positive feedback loop leading to more tissue remodeling. CTGF also induces the expression of a variety of cytokines such as TGFβ [28] and VEGF [29], which induce more expression of CTGF. Thus, there are multiple positive feedback loops involving CTGF expression that can contribute to the progressive nature of fibrosis. By inhibiting CTGF, these positive feedback loops can be broken, which should enable organs to restore their normal wound healing response and their normal structure and function.

Bottom Line: A monoclonal antibody to CTGF that is currently in clinical development (FG-3019) has demonstrated the ability to reverse vascular stiffening and improve cardiac function in a rat model of diabetic complications.FG-3019 has also exhibited activity in a murine radiation-induced pulmonary fibrosis model.When FG-3019 was administered to mice after a significant radiation-induced increase in lung density could be observed by CT imaging, the density of the lungs was observed to decrease over the period during which the antibody was administered and to remain stable after therapy had ceased.

View Article: PubMed Central - HTML - PubMed

Affiliation: FibroGen, Inc., 409 Illinois St., San Francisco, CA 94158, USA.

ABSTRACT
CTGF is a secreted matricellular protein with very complex biology. It has been shown to modulate many signaling pathways leading to cell adhesion and migration, angiogenesis, myofibroblast activation, and extracellular matrix deposition and remodeling, which together lead to tissue remodeling and fibrosis. It has been reported in the literature that inhibition of CTGF expression by siRNA prevents CCl4-induced liver fibrosis and can reverse fibrosis when administered after significant collagen deposition is observed. A monoclonal antibody to CTGF that is currently in clinical development (FG-3019) has demonstrated the ability to reverse vascular stiffening and improve cardiac function in a rat model of diabetic complications. FG-3019 has also exhibited activity in a murine radiation-induced pulmonary fibrosis model. When FG-3019 was administered to mice after a significant radiation-induced increase in lung density could be observed by CT imaging, the density of the lungs was observed to decrease over the period during which the antibody was administered and to remain stable after therapy had ceased. When considered together, these data indicate that inhibition of CTGF can prevent and reverse the process of fibrosis.

No MeSH data available.


Related in: MedlinePlus