Full Text:   <2183>

Summary:  <1498>

CLC number: R34

On-line Access: 2017-11-06

Received: 2017-01-25

Revision Accepted: 2017-05-07

Crosschecked: 2017-10-20

Cited: 0

Clicked: 4272

Citations:  Bibtex RefMan EndNote GB/T7714


Hai-tao Ren


-   Go to

Article info.
Open peer comments

Journal of Zhejiang University SCIENCE B 2017 Vol.18 No.11 P.994-1001


Endostatin inhibits fibrosis by modulating the PDGFR/ERK signal pathway: an in vitro study

Author(s):  Yuan Li, Hai-tao Ren

Affiliation(s):  Department of Ultrasound, Womens Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China; more

Corresponding email(s):   docliyuan@zju.edu.cn, rht@zju.edu.cn

Key Words:  Endostatin, Hypertrophic scar, Phosphorylated platelet-derived growth factor receptor (p-PDGFR), Extracellular signal-regulated kinase (ERK), Signal pathway

Yuan Li, Hai-tao Ren. Endostatin inhibits fibrosis by modulating the PDGFR/ERK signal pathway: an in vitro study[J]. Journal of Zhejiang University Science B, 2017, 18(11): 994-1001.

@article{title="Endostatin inhibits fibrosis by modulating the PDGFR/ERK signal pathway: an in vitro study",
author="Yuan Li, Hai-tao Ren",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Endostatin inhibits fibrosis by modulating the PDGFR/ERK signal pathway: an in vitro study
%A Yuan Li
%A Hai-tao Ren
%J Journal of Zhejiang University SCIENCE B
%V 18
%N 11
%P 994-1001
%@ 1673-1581
%D 2017
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1700052

T1 - Endostatin inhibits fibrosis by modulating the PDGFR/ERK signal pathway: an in vitro study
A1 - Yuan Li
A1 - Hai-tao Ren
J0 - Journal of Zhejiang University Science B
VL - 18
IS - 11
SP - 994
EP - 1001
%@ 1673-1581
Y1 - 2017
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1700052

Accumulating evidence indicates that endostatin inhibits fibrosis. However, the mechanism is yet to be clarified. The aim of this study is to evaluate the effect of endostatin on platelet-derived growth factor-BB (PDGF-BB)- or transforming growth factor β1 (TGF-β1)-induced fibrosis in cultured human skin fibroblasts, and to further examine the molecular mechanisms involved. Human dermal fibroblasts were cultured in Dulbecco’s modified Eagle’s medium (DMEM) and serum-starved for 48 h before treatment. Cells were grouped as follows: “PDGF-BB”, “PDGF-BB+ endostatin”, “TGF-β1”, “TGF-β1+endostatin”, “endostatin”, and “blank control”. The fibroblasts were stimulated with either TGF-β1 or PDGF-BB for 72 h in order to set up the fibrosis model in vitro. The cells were co-cultured with either TGF-β1 or PDGF-BB and endostatin and were used to check the inhibiting effect of endostatin. A blank control group and an endostatin group were used as negative control groups. The biomarkers of fibrosis, including the expression of collagen I, hydroxyproline, and α-smooth muscle actin (α-SMA), were evaluated using an enzyme-linked immunosorbent assay (ELISA) and Western blot. The expression of phosphorylated PDGF receptor β (p-PDGFRβ), PDGFRβ, phosphorylated extracellular signal-regulated kinase (p-ERK), and ERK was detected using Western blot and immunofluorescent staining was used to explore the mechanisms. Both PDGF-BB and TGF-β1 significantly up-regulated the expression of collagen I, hydroxyproline, and α-SMA. endostatin significantly attenuated both the PDGF-BB- and TGF-β1-induced over-expression of collagen I, hydroxyproline, and α-SMA. PDGF-BB and TGF-β1 both promoted the expression of PDGFR, ERK, and p-ERK. endostatin inhibited the expression of PDGFR and p-ERK but did not affect the expression of total ERK. endostatin inhibited hypertrophic scar by modulating the PDGFRβ/ERK pathway. endostatin could be a promising multi-target drug in future fibrosis therapy.




Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Andrae, J., Gallini, R., Betsholtz, C., 2008. Role of platelet-derived growth factors in physiology and medicine. Gene Dev., 22(10):1276-1312.

[2]Bochaton-Piallat, M.L., Gabbiani, G., Hinz, B., 2016. The myofibroblast in wound healing and fibrosis: answered and unanswered questions. F1000Research, 5:752.

[3]Bonner, J.C., 2004. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth F. R., 15(4):255-273.

[4]Borkham-Kamphorst, E., Weiskirchen, R., 2015. The PDGF system and its antagonists in liver fibrosis. Cytokine Growth Factor Rev., 28:53-61.

[5]Cho, J.S., Fang, T.C., Reynolds, T.L., et al., 2016. PDGF-BB promotes type I IFN-dependent vascular alterations and monocyte recruitment in a model of dermal fibrosis. PLoS ONE, 11(9):e0162758.

[6]Choi, H.I., Ma, S.K., Bae, E.H., et al., 2016. Peroxiredoxin 5 protects TGF-β induced fibrosis by inhibiting Stat3 activation in rat kidney interstitial fibroblast cells. PLoS ONE, 11(2):e0149266.

[7]Erawan, B.K., Evgenia, K., Roeyen, C.R.C., et al., 2008. Platelet-derived growth factor isoform expression in carbon tetrachloride-induced chronic liver injury. Lab. Invest., 88(10):1090-1100.

[8]Fang, L., Zhan, S., Huang, C., et al., 2013. TRPM7 channel regulates PDGF-BB-induced proliferation of hepatic stellate cells via PI3K and ERK pathways. Toxicol. Appl. Pharmacol., 272(3):713-725.

[9]Friedstat, J.S., Hultman, C.S., 2014. Hypertrophic burn scar management: what does the evidence show? A systematic review of randomized controlled trials. Ann. Plastic Surg., 72(6):S198-S201.

[10]Haisa, M., Okochi, H., Grotendorst, G.R., 1994. Elevated levels of PDGF α receptors in keloid fibroblasts contribute to an enhanced response to PDGF. J. Invest. Dermatol., 103(4):560-563.

[11]Heldin, C.H., Eriksson, U., Östman, A., 2002. New members of the platelet-derived growth factor family of mitogens. Arch. Biochem. Biophys., 398(2):284-290.

[12]Hu, J.G., Wu, X.J., Feng, Y.F., et al., 2012. PDGF-AA and bFGF mediate B104CM-induced proliferation of oligodendrocyte precursor cells. Int. J. Mol. Med., 30(5):1113-1118.

[13]Jechlinger, M., Sommer, A., Moriggl, R., et al., 2006. Autocrine PDGFR signaling promotes mammary cancer metastasis. J. Clin. Invest., 116(6):1561-1570.

[14]Kaltalioglu, K., Coskuncevher, S., 2015. A bioactive molecule in a complex wound healing process: platelet-derived growth factor. Int. J. Dermatol., 54(8):972-977.

[15]Lee, J.H., Isayeva, T., Larson, M.R., et al., 2015. Endostatin: a novel inhibitor of androgen receptor function in prostate cancer. Proc. Natl. Acad. Sci. USA, 112(5):1392-1397.

[16]Lehembre, F., Yilmaz, M., Wicki, A., et al., 2008. NCAM-induced focal adhesion assembly: a functional switch upon loss of E-cadherin. EMBO J., 27(19):2603-2615.

[17]Lin, X., Kong, L.N., Huang, C., et al., 2015. Hesperetin derivative-7 inhibits PDGF-BB-induced hepatic stellate cell activation and proliferation by targeting Wnt/β-catenin pathway. Int. Immunopharmacol., 25(2):311-320.

[18]Mårtensson, J., Jonsson, N., Glassford, N.J., et al., 2016. Plasma endostatin may improve acute kidney injury risk prediction in critically ill patients. Ann. Intens. Care, 6(1):1-9.

[19]Meng, X.M., Nikolic-Paterson, D.J., Lan, H.Y., 2016. TGF-β: the master regulator of fibrosis. Nat. Rev. Nephrol., 12(6):325-338.

[20]Mori, R., Shaw, T.J., Martin, P., 2008. Molecular mechanisms linking wound inflammation and fibrosis: knockdown of osteopontin leads to rapid repair and reduced scarring. J. Exp. Med., 205(1):43-51.

[21]Okada, M., Suzuki, A., Yamawaki, H., et al., 2013. Levosimendan inhibits interleukin-1β-induced cell migration and MMP-9 secretion in rat cardiac fibroblasts. Eur. J. Pharmacol., 718(1-3):332-339.

[22]Peng, Y., Gao, M., Jiang, Y., et al., 2015. Angiogenesis inhibitor endostatin protects mice with sepsis from multiple organ dysfunction syndrome. Shock, 44(4):357-364.

[23]Reif, S., Lang, A., Lindquist, J.N., et al., 2003. The role of focal adhesion kinase-phosphatidylinositol 3-kinase-Akt signaling in hepatic stellate cell proliferation and type I collagen expression. J. Biol. Chem., 278(10):8083-8090.

[24]Ren, H.T., Hu, H., Li, Y., et al., 2013. Endostatin inhibits hypertrophic scarring in a rabbit ear model. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 14(3):224-230.

[25]Richeldi, L., Cottin, V., du Bois, R.M., et al., 2016. Nintedanib in patients with idiopathic pulmonary fibrosis: combined evidence from the TOMORROW and INPULSIS® trials. Resp. Med., 113:74-79.

[26]Tan, E., Qin, H., Kennedy, S., et al., 1995. Platelet-derived growth factors-AA and -BB regulate collagen and collagenase gene expression differentially in human fibroblasts. Biochem. J., 310(2):585-588.

[27]Tanaka, K.I., Ishihara, T., Azuma, A., et al., 2010. Therapeutic effect of lecithinized superoxide dismutase on bleomycin-induced pulmonary fibrosis. Am. J. Physiol.-Lung C, 298(3):L348-L360.

[28]Tangkijvanich, P., Santiskulvong, C., Melton, A.C., et al., 2002. p38 MAP kinase mediates platelet-derived growth factor-stimulated migration of hepatic myofibroblasts. J. Cell. Physiol., 191(3):351-361.

[29]Tiede, S., Ernst, N., Bayat, A., et al., 2009. Basic fibroblast growth factor: a potential new therapeutic tool for the treatment of hypertrophic and keloid scars. Ann. Anat., 191(1):33-44.

[30]Wynn, T., 2008. Cellular and molecular mechanisms of fibrosis. J. Pathol., 214(2):199-210.

[31]Yamaguchi, Y., Takihara, T., Chambers, R.A., et al., 2012. A peptide derived from endostatin ameliorates organ fibrosis. Sci. Transl. Med., 4(136):136ra71.

Open peer comments: Debate/Discuss/Question/Opinion


Please provide your name, email address and a comment

Journal of Zhejiang University-SCIENCE, 38 Zheda Road, Hangzhou 310027, China
Tel: +86-571-87952783; E-mail: cjzhang@zju.edu.cn
Copyright © 2000 - 2024 Journal of Zhejiang University-SCIENCE