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Inhibitors of Connective Tissue Growth Factor (CCN2)-Mediated Fibrogenesis: Underlying Mechanisms and Prospects for Anti-fibrotic Therapy

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CCN Proteins in Health and Disease

Abstract

Accumulating evidence from in vitro and in vivo studies has shown that connective tissue growth factor (CCN2) often drives fibrogenic pathways downstream of transforming growth factor beta (TGF-β)-mediated intracellular signaling. In recent years the role of CCN2 in fibrogenic pathways has been explored by experimentally attenuating its production or action through the use of pharmacological inhibitors, neutralizing antibodies, antisense oligonucleotides, or small interfering RNA (siRNA). These investigations, conducted in cell culture and animal models, have revealed important information about the mechanisms by which CCN2 production is regulated, have definitively established a role for CCN2 in contributing to fibrotic pathologies, and have provided proof of principle for targeting CCN2 as an anti-fibrotic strategy.

This chapter is dedicated to the memory of Dr Kenneth D. Brown who died in May 2009. Ken was the authors’ PhD mentor from 1984 to 1988 at The Babraham Institute/Cambridge University. In addition to being a skilled cell and molecular biologist, Ken was a terrific teacher and friend. His pioneering work on growth factor purification and cell signaling were central to the author’s subsequent characterization of bioactive forms of connective tissue growth factor. He will be missed.

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Abbreviations

αSMA:

alpha smooth muscle actin

CCl4 :

carbon tetrachloride

CCN2:

connective tissue growth factor

COX:

cyclo-oxygenase

CVIR:

Collagen Type VI receptor

ECM:

extracellular matrix

HSC:

hepatic stellate cell

PG:

prostaglandin

PSC:

pancreatic stellate cell

RT-PCR:

reverse-transcriptase polymerase chain reaction

siRNA:

small interfering RNA

TGF-β:

transforming growth factor beta

TIMP:

tissue inhibitor of metalloprotease

TNF-α:

tumor necrosis factor alpha

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Acknowledgements

DRB was supported by the Ben Bryer Trust and NIH grants 5R01AA016003 and 5R01AA015554.

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  1. The Research Institute at Nationwide Children’s Hospital, Room WA2022, Research Building II, 700 Children’s Drive, Columbus, OH, 43205, USA

    David R. Brigstock

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  1. David R. Brigstock
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  1. Med Sci-I 6447, Ann Arbor, 48109, USA

    Annick Perbal

  2. Shikata-Cho 2-5-1, Okayama, 700-8525, Japan

    Masaharu Takigawa

  3. Palais du Grand Large, International CCN Society, Saint-Malo, France

    Bernard Perbal

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Brigstock, D.R. (2010). Inhibitors of Connective Tissue Growth Factor (CCN2)-Mediated Fibrogenesis: Underlying Mechanisms and Prospects for Anti-fibrotic Therapy. In: Perbal, A., Takigawa, M., Perbal, B. (eds) CCN Proteins in Health and Disease. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-3779-4_14

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