Connective tissue growth factor (CTGF) from basics to clinics

Ramazani, Yasaman; Knops, Noël; Elmonem, Mohamed A.; Nguyen, Tri Q.; Arcolino, Fanny Oliveira; Heuvel, Lambert van den; Levtchenko, Elena; Kuypers, Dirk; Goldschmeding, Roel

doi:10.1016/j.matbio.2018.03.007

Cited by 256 publications

(229 citation statements)

References 243 publications

(232 reference statements)

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“…Data from previous studies have found tissue CTGF expression is upregulated in people with fibrotic diseases, including cirrhosis , cardiac fibrosis , crescentic glomerulonephritis , idiopathic pulmonary fibrosis , and systemic sclerosis . In addition, pharmacological blockade or genetic deletion of CTGF ameliorates the progression of fibrosis in various mouse organs . Together, these findings support the concept that adipose tissue fibrosis is involved in the pathogenesis of insulin resistance associated with obesity in humans, which has previously been demonstrated in rodent models .…”

Section: Discussionsupporting

confidence: 83%

“…Connective tissue growth factor (CTGF) (also known as cellular communication network factor 2, CCN2) is a matricellular protein that is involved in regulating many biological processes, including fibrogenesis in multiple organs . Overexpression of CTGF increases ECM production, decreases ECM degradation, can cause fibrosis or enhance the susceptibility to fibrosis in lung, kidney, liver, and skin in mice .…”

Section: Introductionmentioning

confidence: 99%

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Adipose Tissue CTGF Expression is Associated with Adiposity and Insulin Resistance in Humans

Yoshino

Patterson

Klein

2019

Obesity

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Objective Connective tissue growth factor (CTGF) is an important regulator of fibrogenesis in many organs. This study evaluated the interrelationship among adipose tissue CTGF expression, fat mass, and insulin resistance in humans. Methods This study examined (1) CTGF gene expression in human subcutaneous preadipocytes before and after inducing adipogenesis; (2) relationships among abdominal subcutaneous adipose tissue CTGF gene expression, body fat mass, and indices of insulin sensitivity, including the hepatic insulin sensitivity index and the hyperinsulinemic‐euglycemic clamp procedure in conjunction with stable isotope glucose tracer infusion, in 72 people who had marked differences in adiposity and insulin sensitivity; (3) localization of CTGF protein in subcutaneous adipose tissue; and (4) effect of progressive (5%, 11%, and 16%) weight loss on adipose tissue CTGF gene expression. Results CTGF was highly expressed in preadipocytes, not adipocytes. Adipose tissue CTGF expression was strongly correlated with body fat mass and both skeletal muscle and liver insulin sensitivity, and CTGF‐positive cells were predominantly found in areas of fibrosis. Progressive weight loss caused a stepwise decrease in adipose tissue CTGF expression. Conclusions It was concluded that increased CTGF expression is associated with adipose tissue expansion, adipose tissue fibrosis, and multi‐organ insulin resistance in people with obesity.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Adipose Tissue CTGF Expression is Associated with Adiposity and Insulin Resistance in Humans

Yoshino

Patterson

Klein

2019

Obesity

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“…CTGF is just the promoter of extracellular matrix. 21 VEGF can promote the growth of capillaries which could provide nutrition to extracellular matrix, thus, this cytokine is also the promoter of the extracellular matrix. 22 As VEGF is also a promoter of cancer 23 and β-elemene is an anticancer drug, whether there are other mechanisms for this drug to inhibit the expression of VEGF, needs to be further explored.…”

Section: Discussionmentioning

confidence: 99%

β‐Elemene suppresses the proliferation of human airway granulation fibroblasts via attenuation of TGF‐β/Smad signaling pathway

Xue

Lin

Zhang

et al. 2019

J of Cellular Biochemistry

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Background Benign airway stenosis is easily to recur as a result of hyperplastic airway granulation tissues. Our previous study proved that a Chinese drug, β‐elemene, could inhibit the proliferation of fibroblasts cultured from these tissues, which could decrease the recurrence rate of this disease. Methods To find out the mechanism for this effect, we first cultured normal human airway fibroblasts and human airway granulation fibroblasts with different concentrations of β‐elemene for the same time or the same dose of β‐elemene for different times to explore the dose/time‐effect relationship between the drug and these cells. Then we used gene microarray to screen out the most important pathway by which the drug influenced human airway granulation fibroblasts. At last, we assessed the condition of this pathway in human airway granulation fibroblasts and verified the effect of this drug on this pathway. Results β‐Elemene inhibited the proliferation of human airway granulation fibroblasts in a dose but no time‐dependent manner and did not affect normal human airway fibroblasts. Affecting the expression of transforming growth factor β (TGF‐β)/Smad pathway may be the key mechanism for this effect. This pathway was activated in human airway granulation fibroblasts and β‐elemene inhibited it in a dose‐dependent manner. This effect was similar to the pathway inhibitor, SB431542, and exogenous TGF‐β could attenuate this effect. Conclusion These results indicated that suppressing TGF‐β/Smad pathway was possibly the key mechanism by which β‐elemene inhibits the proliferation of human airway granulation fibroblasts. This pathway may be a promising target to treat benign airway stenosis.

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“…Upregulation of CTGF has already been described in fibrotic diseases of 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 F o r P e e r R e v i e w lung, liver and kidney amongst others (38). CTGF, as a matricellular protein, exerts its fibrotic effects through several mechanisms: binding to cell surface receptors and initiating signal transductions, binding to cytokines and mediating their binding to specific receptors, remodelling the extracellular matrix turnover and regulating the activity of cytokines and growth factors through signalling cross talks (39). Our data suggests that YAP/TAZ nuclear translocation, at least partially, drives CTGF activation.…”

Section: Discussionmentioning

confidence: 99%

Simvastatin and the Rho-kinase inhibitor Y-27632 prevent myofibroblast transformation in Peyronie’s disease-derived fibroblasts via inhibition of YAP/TAZ nuclear translocation

Milenković

Ilg

Zuccato

et al. 2019

European Urology Supplements

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word count: 328 Text body word count: 3100 Abstract:Objectives: To uncover the anti-myofibroblast (MFB) properties of Rho-kinase inhibitor (compound Y-27632) and simvastatin in an in vitro model of Peyronie's disease (PD). PD is a sexual debilitating disease caused by an irreversible fibrotic plaque in the penile tunica albuginea (TA). Treatment is limited to surgically restoring anatomical shape. Evidence for effective medical treatment is lacking.Material and Methods: Primary human fibroblasts were isolated from surgically obtained TA tissue from PD patients. To induce MFB status, cells where stimulated with 3 ng/mL TGF-β1. Increasing doses of Y-27632 and simvastatin were added. RT-qPCR was used to assess mRNA expression of alpha-smooth muscle actin (α-SMA), collagen III, elastin and CTGF after 72 h. WB was used to quantify α-SMA protein contents and IF visualized MFB differentiation by staining for α-SMA after 72 h. Resazurin-based assay was performed to assess cell viability to ensure anti-MFB effect of the drugs. A mechanistic study was performed using IF staining for YAP/TAZ nuclear translocation.Results: After 72 h of stimulation with TGF-β1, a 6-to10-fold upregulation of α-SMA could be observed. When treated with Y-27632 or simvastatin, the α-SMA, collagen III, elastin and CTGF mRNA expression was impeded. Additionally, TGF-β1-stimulation showed a two-fold increase in α-SMA protein expression, which was reversed to non-stimulated levels after treatment with Y-27632 and simvastatin. Using IF, stimulated cells were identified as MFB (α-SMA+, Vim+) as opposed to the non-stimulated, Y-27632-and simvastatin-treated cells (α-SMA-, Vim+). The resazurin-based assay confirmed that the cell viability was not compromised by the administered drugs. Upon stimulation with TGF-β1, nuclear translocation of YAP/TAZ could be observed, which was prevented by adding the aforementioned compounds.Conclusion: Transformation of fibroblasts into the contractile and extracellular matrix-producing myofibroblasts occurs after TGF-β1 stimulation. In our experiments Rho-kinase inhibition and simvastatin treatment were shown to prevent this in TGF-β1 stimulated cells on an RNA and protein level through the inhibition of YAP/TAZ nuclear translocation. Y-27632 and simvastatin could become a novel treatment option in the early treatment of PD.

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Connective tissue growth factor (CTGF) from basics to clinics

Cited by 256 publications

References 243 publications

Adipose Tissue CTGF Expression is Associated with Adiposity and Insulin Resistance in Humans

Adipose Tissue CTGF Expression is Associated with Adiposity and Insulin Resistance in Humans

β‐Elemene suppresses the proliferation of human airway granulation fibroblasts via attenuation of TGF‐β/Smad signaling pathway

Simvastatin and the Rho-kinase inhibitor Y-27632 prevent myofibroblast transformation in Peyronie’s disease-derived fibroblasts via inhibition of YAP/TAZ nuclear translocation

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