CCN2: a Bona Fide Target for Anti-fibrotic Drug Intervention

Overview

Journal J Cell Commun Signal

Date 2011 Apr 13

PMID 21484186

Citations 6

Authors

Andrew Leask

Affiliations

Soon will be listed here.

Abstract

CCN2 (formerly known as connective tissue growth factor) was identified by several different laboratories approximately 20 years ago. Almost since its identification as a factor induced in normal fibroblasts by transforming growth factor β and overexpressed in fibrotic disease, CCN2 has been hypothesized to be not only a marker but also a central mediator of fibrosis in vivo. Finally, in vivo data are emerging to validate this key hypothesis. For example, a neutralizing anti-CCN2 antibody was found to attenuate fibrogenesis in three separate animal models (Wang et al. in Fibrogenesis Tissue Repair 4:1-4, 2011). This commentary addresses recent data indicating that CCN2 appears to represent a key central mediator of fibrosis and a good target for anti-fibrotic drug intervention.

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References

Liu S, Shi-Wen X, Abraham D, Leask A . CCN2 is required for bleomycin-induced skin fibrosis in mice. Arthritis Rheum. 2010; 63(1):239-46. DOI: 10.1002/art.30074. View

Chen C, Lau L . Deadly liaisons: fatal attraction between CCN matricellular proteins and the tumor necrosis factor family of cytokines. J Cell Commun Signal. 2009; 4(1):63-9. PMC: 2821476. DOI: 10.1007/s12079-009-0080-4. View

Pinzani M . Welcome to fibrogenesis & tissue repair. Fibrogenesis Tissue Repair. 2008; 1(1):1. PMC: 2577043. DOI: 10.1186/1755-1536-1-1. View

He Z, Way K, Arikawa E, Chou E, Opland D, Clermont A . Differential regulation of angiotensin II-induced expression of connective tissue growth factor by protein kinase C isoforms in the myocardium. J Biol Chem. 2005; 280(16):15719-26. DOI: 10.1074/jbc.M413493200. View

Yoon P, Lee M, Cha H, Jeong M, Kim J, Jang S . The opposing effects of CCN2 and CCN5 on the development of cardiac hypertrophy and fibrosis. J Mol Cell Cardiol. 2010; 49(2):294-303. DOI: 10.1016/j.yjmcc.2010.04.010. View

Grotendorst G, Okochi H, Hayashi N . A novel transforming growth factor beta response element controls the expression of the connective tissue growth factor gene. Cell Growth Differ. 1996; 7(4):469-80. View

Abraham D, Shiwen X, Black C, Sa S, Xu Y, Leask A . Tumor necrosis factor alpha suppresses the induction of connective tissue growth factor by transforming growth factor-beta in normal and scleroderma fibroblasts. J Biol Chem. 2000; 275(20):15220-5. DOI: 10.1074/jbc.275.20.15220. View

Takigawa M, Tajima K, Pan H, Enomoto M, Kinoshita A, Suzuki F . Establishment of a clonal human chondrosarcoma cell line with cartilage phenotypes. Cancer Res. 1989; 49(14):3996-4002. View

Phanish M, Winn S, Dockrell M . Connective tissue growth factor-(CTGF, CCN2)--a marker, mediator and therapeutic target for renal fibrosis. Nephron Exp Nephrol. 2009; 114(3):e83-92. DOI: 10.1159/000262316. View

10.

Xu S, Liu S, Eastwood M, Sonnylal S, Denton C, Abraham D . Rac inhibition reverses the phenotype of fibrotic fibroblasts. PLoS One. 2009; 4(10):e7438. PMC: 2757676. DOI: 10.1371/journal.pone.0007438. View

11.

Liu S, Taghavi R, Leask A . Connective tissue growth factor is induced in bleomycin-induced skin scleroderma. J Cell Commun Signal. 2009; 4(1):25-30. PMC: 2821481. DOI: 10.1007/s12079-009-0081-3. View

12.

Twigg S . Mastering a mediator: blockade of CCN-2 shows early promise in human diabetic kidney disease. J Cell Commun Signal. 2011; 4(4):189-96. PMC: 2995133. DOI: 10.1007/s12079-010-0102-2. View

13.

Frazier K, Williams S, Kothapalli D, Klapper H, Grotendorst G . Stimulation of fibroblast cell growth, matrix production, and granulation tissue formation by connective tissue growth factor. J Invest Dermatol. 1996; 107(3):404-11. DOI: 10.1111/1523-1747.ep12363389. View

14.

Brigstock D . Connective tissue growth factor (CCN2, CTGF) and organ fibrosis: lessons from transgenic animals. J Cell Commun Signal. 2009; 4(1):1-4. PMC: 2821473. DOI: 10.1007/s12079-009-0071-5. View

15.

Brigstock D, Steffen C, Kim G, Vegunta R, Diehl J, Harding P . Purification and characterization of novel heparin-binding growth factors in uterine secretory fluids. Identification as heparin-regulated Mr 10,000 forms of connective tissue growth factor. J Biol Chem. 1997; 272(32):20275-82. DOI: 10.1074/jbc.272.32.20275. View

16.

Brigstock D . Strategies for blocking the fibrogenic actions of connective tissue growth factor (CCN2): From pharmacological inhibition in vitro to targeted siRNA therapy in vivo. J Cell Commun Signal. 2009; 3(1):5-18. PMC: 2686750. DOI: 10.1007/s12079-009-0043-9. View

17.

Igarashi A, Nashiro K, Kikuchi K, Sato S, Ihn H, Fujimoto M . Connective tissue growth factor gene expression in tissue sections from localized scleroderma, keloid, and other fibrotic skin disorders. J Invest Dermatol. 1996; 106(4):729-33. DOI: 10.1111/1523-1747.ep12345771. View

18.

Bradham D, Igarashi A, Potter R, Grotendorst G . Connective tissue growth factor: a cysteine-rich mitogen secreted by human vascular endothelial cells is related to the SRC-induced immediate early gene product CEF-10. J Cell Biol. 1991; 114(6):1285-94. PMC: 2289134. DOI: 10.1083/jcb.114.6.1285. View

19.

Hinz B . Tissue stiffness, latent TGF-beta1 activation, and mechanical signal transduction: implications for the pathogenesis and treatment of fibrosis. Curr Rheumatol Rep. 2009; 11(2):120-6. DOI: 10.1007/s11926-009-0017-1. View

20.

Leask A, Parapuram S, Shi-Wen X, Abraham D . Connective tissue growth factor (CTGF, CCN2) gene regulation: a potent clinical bio-marker of fibroproliferative disease?. J Cell Commun Signal. 2009; 3(2):89-94. PMC: 2721078. DOI: 10.1007/s12079-009-0037-7. View