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Originally published online as doi:10.2353/ajpath.2009.080241 on April 9, 2009

Published online before print April 9, 2009
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(American Journal of Pathology. 2009;174:1725-1734.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080241

CCN3 (NOV) Is a Negative Regulator of CCN2 (CTGF) and a Novel Endogenous Inhibitor of the Fibrotic Pathway in an in Vitro Model of Renal Disease

Bruce L. Riser*{dagger}, Feridoon Najmabadi*, Bernard Perbal{ddagger}, Darryl R. Peterson*, Jo Ann Rambow*, Melisa L. Riser*, Ernest Sukowski*, Herman Yeger§ and Sarah C. Riser*

From the Department of Physiology and Biophysics,* Rosalind Franklin University of Medicine and Science, North Chicago, Illinois; the Renal Division,{dagger} Baxter Healthcare, McGaw Park, Illinois; the Labratoroire d’ Oncologie Virale et Moleculaire,{ddagger} University of Paris, 7, Paris, France; the Department of Laboratory Medicine and Pathobiology,§ University of Toronto, Toronto, Canada; and the Department of Pediatric Lab Medicine, The Hospital for Sick Children, Toronto, Canada

Fibrosis is a major cause of end-stage renal disease, and although initiation factors have been elucidated, uncertainty concerning the downstream pathways has hampered the development of anti-fibrotic therapies. CCN2 (CTGF) functions downstream of transforming growth factor (TGF)-β, driving increased extracellular matrix (ECM) accumulation and fibrosis. We examined the possibility that CCN3 (NOV), another CCN family member with reported biological activities that differ from CCN2, might act as an endogenous negative regulator of ECM and fibrosis. We show that cultured rat mesangial cells express CCN3 mRNA and protein, and that TGF-β treatment reduced CCN3 expression levels while increasing CCN2 and collagen type I activities. Conversely, either the addition of CCN3 or CCN3 overexpression produced a marked down-regulation of CCN2 followed by virtual blockade of both collagen type I transcription and its accumulation. This finding occurred in both growth-arrested and CCN3-transfected cells under normal growth conditions after TGF-β treatment. These effects were not attributable to altered cellular proliferation as determined by cell cycle analysis, nor were they attributable to interference of Smad signaling as shown by analysis of phosphorylated Smad3 levels. In conclusion, both CCN2 and CCN3 appear to act in a yin/yang manner to regulate ECM metabolism. CCN3, acting downstream of TGF-β to block CCN2 and the up-regulation of ECM, may therefore serve to naturally limit fibrosis in vivo and provide opportunities for novel, endogenous-based therapeutic treatments.






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Copyright © 2009 by the American Society for Investigative Pathology.