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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 knock-down with shRNA inhibits TGFb-dependent cell proliferation of cardiac fibroblasts. Primary cardiac fibroblasts (P) were infected with lentiviruses encoding CTGF shRNAs (h2 or h5) or with a lentivirus expressing a scrambled shRNA as control. Cells were serum starved for 24 hrs and replated in medium containing growth supplements and the indicated concentrations of TGFb (TGFb). Panel A: CTGF protein expression was measured after 7 days. Panel B: Cell proliferation was measured by Cyquant at the indicated timepoints.
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Figure 5: CTGF knock-down with shRNA inhibits TGFb-dependent cell proliferation of cardiac fibroblasts. Primary cardiac fibroblasts (P) were infected with lentiviruses encoding CTGF shRNAs (h2 or h5) or with a lentivirus expressing a scrambled shRNA as control. Cells were serum starved for 24 hrs and replated in medium containing growth supplements and the indicated concentrations of TGFb (TGFb). Panel A: CTGF protein expression was measured after 7 days. Panel B: Cell proliferation was measured by Cyquant at the indicated timepoints.

Mentions: To evaluate the importance of CTGF for TGFβ-induced proliferation of these fibroblasts, cells were infected with lentiviruses expressing CTGF shRNAs or a scrambled negative control shRNA (Figure 5). In serum-starved cells infected with the scrambled shRNA, TGFβ induced expression of more CTGF than in unstimulated fibroblasts. The CTGF shRNA suppressed CTGF expression in cells in control medium or medium supplemented with TGFβ (Figure 5, Panel A). TGFβ stimulation of fibroblasts infected with the lentivirus expressing the scrambled shRNA strongly increased the number of cells after 7 days in culture. In contrast, TGFβ stimulation of fibroblasts infected with the lentiviruses expressing the CTGF shRNAs exhibited no response to TGFβ, and the number of cells after 7 days in culture was lower than the number of cells in unstimulated fibroblasts containing the scrambled shRNA (Figure 5, Panel B). These data suggest that CTGF expression is essential for fibroblast proliferation, and in the absence of CTGF, fibroblasts are unresponsive to stimuli like TGFβ that would normally strongly enhance their proliferation.


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 knock-down with shRNA inhibits TGFb-dependent cell proliferation of cardiac fibroblasts. Primary cardiac fibroblasts (P) were infected with lentiviruses encoding CTGF shRNAs (h2 or h5) or with a lentivirus expressing a scrambled shRNA as control. Cells were serum starved for 24 hrs and replated in medium containing growth supplements and the indicated concentrations of TGFb (TGFb). Panel A: CTGF protein expression was measured after 7 days. Panel B: Cell proliferation was measured by Cyquant at the indicated timepoints.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: CTGF knock-down with shRNA inhibits TGFb-dependent cell proliferation of cardiac fibroblasts. Primary cardiac fibroblasts (P) were infected with lentiviruses encoding CTGF shRNAs (h2 or h5) or with a lentivirus expressing a scrambled shRNA as control. Cells were serum starved for 24 hrs and replated in medium containing growth supplements and the indicated concentrations of TGFb (TGFb). Panel A: CTGF protein expression was measured after 7 days. Panel B: Cell proliferation was measured by Cyquant at the indicated timepoints.
Mentions: To evaluate the importance of CTGF for TGFβ-induced proliferation of these fibroblasts, cells were infected with lentiviruses expressing CTGF shRNAs or a scrambled negative control shRNA (Figure 5). In serum-starved cells infected with the scrambled shRNA, TGFβ induced expression of more CTGF than in unstimulated fibroblasts. The CTGF shRNA suppressed CTGF expression in cells in control medium or medium supplemented with TGFβ (Figure 5, Panel A). TGFβ stimulation of fibroblasts infected with the lentivirus expressing the scrambled shRNA strongly increased the number of cells after 7 days in culture. In contrast, TGFβ stimulation of fibroblasts infected with the lentiviruses expressing the CTGF shRNAs exhibited no response to TGFβ, and the number of cells after 7 days in culture was lower than the number of cells in unstimulated fibroblasts containing the scrambled shRNA (Figure 5, Panel B). These data suggest that CTGF expression is essential for fibroblast proliferation, and in the absence of CTGF, fibroblasts are unresponsive to stimuli like TGFβ that would normally strongly enhance their proliferation.

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