CCN3/NOV encoded by the Nephroblastoma overexpressed gene represents a matricellular
protein of the CCN family. These proteins comprise six different secreted proteins
associating specifically with the extracellular matrix [1]. CCN proteins lack specific high-affinity receptors but signal through integrins
and proteoglycans and regulate crucial biological processes in liver including fibrosis
[2]. Previously we have demonstrated that CCN3 expression increases dramatically during
activation of hepatic stellate cells (HSC) and in models of experimental liver fibrosis
[3]. Notably, suppression of CCN3 enhanced expression of profibrotic marker proteins
including Connective tissue growth factor (CCN2/CTGF) in primary HSC and in the immortalized
stellate cell line CFSC. Vice versa, the overexpression of CCN2 reduced CCN3 expression. Surprisingly, the adenoviral
transfer of CCN3 enhanced CCN2 expression suggesting that the CCN protein network
is highly complex and extends well beyond the classic Yin and Yang interaction. In
the present study, we analysed the effects of CCN3 overexpression in a model of ongoing
fibrogenesis induced by ligature of the common bile duct and in primary cultured hepatocytes.
Contrasting to the findings in HSC, transfer of CCN3 resulted in marked reduced levels
of CCN2 in primary hepatocytes. In addition, CCN3 prevented TGF-β-induced expression
of Snail1, vimentin. fibronectin and matrix metalloproteinase 9 that are associated
in vitro with EMT. We further found that Ad5-CMV-NOV significantly induce hepatocyte apoptosis
as demonstrated in positive TUNEL staining and Western blot analysis of cleaved caspase–3.
The infection of hepatocytes with Ad5-CMV-NOV further resulted in strong activation
of the JNK and p38 MAPKs. However, the adenoviral gene transfer of CCN3 was not sufficient
to attenuate ongoing fibrogenesis indicating that CCN3 treatment alone is not sufficient
to inhibit the fibrotic pathway in the bile duct ligation model.
Literatur: [1] Bork P: The modular architecture of a new family of growth regulators related
to connective tissue growth factor. FEBS Lett 1993, 327:125-130. [2] Weiskirchen R.
CCN proteins in normal and injured liver. Front Biosci 2011;16:1939-1961. [3] Borkham-Kamphorst
E, van Roeyen CR, Van de Leur E, Floege J, Weiskirchen R. CCN3/NOV small interfering
RNA enhances fibrogenic gene expression in primary hepatic stellate cells and cirrhotic
fat storing cell line CFSC. J Cell Commun Signal 2011, in press.
BDL - CCN2 - CCN3 - EMT - adenovirus gene transfer - animal models. - apoptosis -
hepatic stellate cells - hepatocytes - inflammation - liver fibrosis
