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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 serum-dependent cell proliferation of cardiac fibroblasts. Primary cardiac fibroblasts (P) were infected with lentiviruses encoding 2 different CTGF shRNAs (h2 and h5 from OpenBiosystems) or with a lentivirus generated from an empty vector (V) as control. Panel A: CTGF protein expression was measured by ELISA in culture supernatants. Panel B: 96 hrs after infection, cells were re-plated in quadruplicate wells of a 96-well plate in medium containing serum and defined growth supplements and incubated for up to 10 days. Cell proliferation was measured by Cyquant Fluorescense Intensity at the indicated timepoints. Panel C: Parallel cultures of cells were stained with crystal violet at day 10 and doubling time (DT) was determined by linear regression analysis on the data shown in B. * p < 0.001 vs. vector by ANOVA.
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Figure 4: CTGF knock-down with shRNA inhibits serum-dependent cell proliferation of cardiac fibroblasts. Primary cardiac fibroblasts (P) were infected with lentiviruses encoding 2 different CTGF shRNAs (h2 and h5 from OpenBiosystems) or with a lentivirus generated from an empty vector (V) as control. Panel A: CTGF protein expression was measured by ELISA in culture supernatants. Panel B: 96 hrs after infection, cells were re-plated in quadruplicate wells of a 96-well plate in medium containing serum and defined growth supplements and incubated for up to 10 days. Cell proliferation was measured by Cyquant Fluorescense Intensity at the indicated timepoints. Panel C: Parallel cultures of cells were stained with crystal violet at day 10 and doubling time (DT) was determined by linear regression analysis on the data shown in B. * p < 0.001 vs. vector by ANOVA.

Mentions: The mechanism by which CTGF enables persistent fibrosis upon stimulation by TGFβ has never been elucidated, due at least in part to the very complex mechanism of action (MOA) of CTGF. In order to address one aspect of the possible MOA, the role of CTGF in fibroblast proliferation was explored. Primary human cardiac fibroblasts (ScienCell Research Laboratories) were examined for serum-dependent production of CTGF and shown to produce measurable amounts (Figure 4). The amount of CTGF produced in these cells could be decreased by infecting them with lentiviruses expressing CTGF shRNAs (Open Biosystems). Knock down of CTGF expression in these primary human cardiac fibroblasts suppressed their ability to grow in medium containing serum and added supplements, and after 9 days in culture, the number of cells correlated to the amount of CTGF produced (Figure 4, Panel B). Assessment of the doubling time of these cells showed that cells with lower CTGF expression levels proliferated more slowly than cells with normal expression levels, and the doubling time appeared to correlate to the amount of CTGF expressed (Figure 4, Panel C). These data indicate that autocrine CTGF expression is critical for the ability of these fibroblasts to proliferate in response to serum and growth supplements.


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 serum-dependent cell proliferation of cardiac fibroblasts. Primary cardiac fibroblasts (P) were infected with lentiviruses encoding 2 different CTGF shRNAs (h2 and h5 from OpenBiosystems) or with a lentivirus generated from an empty vector (V) as control. Panel A: CTGF protein expression was measured by ELISA in culture supernatants. Panel B: 96 hrs after infection, cells were re-plated in quadruplicate wells of a 96-well plate in medium containing serum and defined growth supplements and incubated for up to 10 days. Cell proliferation was measured by Cyquant Fluorescense Intensity at the indicated timepoints. Panel C: Parallel cultures of cells were stained with crystal violet at day 10 and doubling time (DT) was determined by linear regression analysis on the data shown in B. * p < 0.001 vs. vector by ANOVA.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: CTGF knock-down with shRNA inhibits serum-dependent cell proliferation of cardiac fibroblasts. Primary cardiac fibroblasts (P) were infected with lentiviruses encoding 2 different CTGF shRNAs (h2 and h5 from OpenBiosystems) or with a lentivirus generated from an empty vector (V) as control. Panel A: CTGF protein expression was measured by ELISA in culture supernatants. Panel B: 96 hrs after infection, cells were re-plated in quadruplicate wells of a 96-well plate in medium containing serum and defined growth supplements and incubated for up to 10 days. Cell proliferation was measured by Cyquant Fluorescense Intensity at the indicated timepoints. Panel C: Parallel cultures of cells were stained with crystal violet at day 10 and doubling time (DT) was determined by linear regression analysis on the data shown in B. * p < 0.001 vs. vector by ANOVA.
Mentions: The mechanism by which CTGF enables persistent fibrosis upon stimulation by TGFβ has never been elucidated, due at least in part to the very complex mechanism of action (MOA) of CTGF. In order to address one aspect of the possible MOA, the role of CTGF in fibroblast proliferation was explored. Primary human cardiac fibroblasts (ScienCell Research Laboratories) were examined for serum-dependent production of CTGF and shown to produce measurable amounts (Figure 4). The amount of CTGF produced in these cells could be decreased by infecting them with lentiviruses expressing CTGF shRNAs (Open Biosystems). Knock down of CTGF expression in these primary human cardiac fibroblasts suppressed their ability to grow in medium containing serum and added supplements, and after 9 days in culture, the number of cells correlated to the amount of CTGF produced (Figure 4, Panel B). Assessment of the doubling time of these cells showed that cells with lower CTGF expression levels proliferated more slowly than cells with normal expression levels, and the doubling time appeared to correlate to the amount of CTGF expressed (Figure 4, Panel C). These data indicate that autocrine CTGF expression is critical for the ability of these fibroblasts to proliferate in response to serum and growth supplements.

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