Biological significance of connective tissue growth factor and its potential as a novel therapeutic target in hepatic fibrosis
AASLD LiverLearning®. Makino Y. Nov 14, 2016; 144576
Label: Basic Fibrosis Research and Stellate Cell Biology
Yuki Makino
Yuki Makino
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TITLE: Biological significance of connective tissue growth factor and its potential as a novel therapeutic target in hepatic fibrosis

This study was not sponsored.

Background and aim: Connective tissue growth factor (CTGF) is one of secreted matricellular proteins related with several systemic diseases. We analyzed the biological significance of CTGF in hepatic fibrosis.
Methods/Results: We examined CTGF gene expression under approval of institutional ethics committee. In 97 liver biopsy samples, CTGF expression levels increases along with the progression of fibrosis score and positively correlated with those of other fibrosis-related genes such as α-SMA, TGF-β1, and Col1a1. In addition, CTGF expression showed positive correlation with several fibrosis markers including serum hyaluronate and type 4 collagen levels, FIB-4 index, and shear wave velocity of ultrasound elastography, and negative correlation with platelet count.
In mice experiments, CTGF was also up-regulated in the liver after bile duct ligation (BDL). CTGF was up-regulated both in primary liver parenchymal cells (PC) and non-parenchymal cells (NPC) isolated from mice underwent BDL compared with those isolated from sham-operated mice. In vitro experiments revealed that the treatment of TGF-β, an inducing factor of CTGF, increased CTGF production in hepatocyte cell lines and a hepatic stellate cell (HSC) cell line LX-2, but not in a macrophage cell line, suggesting that hepatocytes and HSC might mainly produce CTGF in the fibrotic liver. Recombinant CTGF treatment induced the activation and collagen production in LX-2. In turn, siRNA-mediated knockdown of CTGF decreased the viability of LX-2. In addition, CTGF treatment induced the production of pro-fibrotic cytokines such as PDGF, TGFb1, and TIMP-1 from hepatocyte cell line PLC/PRF/5. These results suggest a promoting effect of CTGF in liver fibrosis.
We subsequently evaluated the influence of CTGF deficiency after BDL in 3 strains of conditional CTGF knockout mice; HSC-specific CTGF deficient mice (GFAP-Cre+ CTGF flox/flox mice; CTGFΔHSC mice), hepatocyte-specific CTGF deficient mice (Alb-Cre+ CTGF flox/flox mice; CTGFΔHep mice), and poly IC-induced PC and NPC CTGF deficient mice (MX1-Cre+ CTGF flox/flox mice; CTGFΔPC+NPC mice). As a result, compared with Cre- littermates, CTGF expression levels in the liver significantly decreased in CTGFΔHep and ΔPC+NPC mice. Only in CTGFΔPC+NPC mice, fibrosis-related genes such as αSMA, PDGF, TGFb1, and TIMP-1 were also down-regulated and liver fibrosis was markedly attenuated, evidenced by reduced collagen expression and Sirius Red-stained area.
Conclusion: CTGF is produced both from PC and NPC in the fibrotic liver. CTGF acts on HSC and hepatocytes and promotes hepatic fibrosis. CTGF could be a promising therapeutic target against liver fibrosis.
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