NOV, located on human chromosome 8q24.1, was originally cloned following discovery of its avian homolog as a consequence of over-expression
in virally induced nephroblastoma. The gene product is a secreted, modular, protein and a member of the CCN gene family. Evidence
to date indicates that the expression of the wild type protein is associated with cellular quiescence in normal embryonic
fibroblasts yet produces growth stimulatory effects on established murine NIH 3T3 cells. Here we report the expression of
NOV in the first trimester of human embryogenesis, between 5 and 10 weeks. In situ hybridisation and immunohistochemistry reveal
widespread expression in derivatives of all three germ layers. The most abundant sites of expression are in the motor neurons
and floor plate of the spinal cord, adrenal cortex, fusing skeletal, and smooth muscle, the urogenital system and the developing
heart. Additionally, expression is seen in the cranial ganglia, differentiating chondrocytes, gonads, and lung. The sites
of expression suggest strongly that autocrine or paracrine expression of NOV is associated with the process of cell differentiation.
"Here, we show for the first time that in the adult mouse pancreas, CCN3 expression is restricted to ducts and β-cells. The previous detection of CCN3 in pancreatic ducts during embryonic development  raises the possibility that CCN3 could play a role in duct and/or islet cell differentiation. CCN3 has been previously shown to inhibit myoblast ,  as well as osteoblast differentiation . "
[Show abstract][Hide abstract] ABSTRACT: Type 2 diabetes is characterized by both insulin resistance and progressive deterioration of β-cell function. The forkhead transcription factor FoxO1 is a prominent mediator of insulin signaling in β-cells. We reasoned that identification of FoxO1 target genes in β-cells could reveal mechanisms linking β-cell dysfunction to insulin resistance. In this study, we report the characterization of Nov/Ccn3 as a novel transcriptional target of FoxO1 in pancreatic β-cells. FoxO1 binds to an evolutionarily conserved response element in the Ccn3 promoter to regulate its expression. Accordingly, CCN3 levels are elevated in pancreatic islets of mice with overexpression of a constitutively active form of FoxO1 or insulin resistance. Our functional studies reveal that CCN3 impairs β-cell proliferation concomitantly with a reduction in cAMP levels. Moreover, CCN3 decreases glucose oxidation, which translates into inhibition of glucose-stimulated Ca(2+) entry and insulin secretion. Our results identify CCN3, a novel transcriptional target of FoxO1 in pancreatic β-cells, as a potential target for therapeutic intervention in the treatment of diabetes.
PLoS ONE 05/2013; 8(5):e64957. DOI:10.1371/journal.pone.0064957 · 3.23 Impact Factor
"The nephroblastoma overexpressed gene (NOV)  encodes a secreted cysteine-enriched multimodular protein that acts as a localized multivalent signal integrator, primarily mediating its activities through interactions with specific dimers of integrins . Previous findings have shown that NOV is highly expressed in the nervous system, especially in the spinal cord and in the dorsal root ganglion (DRG) during human and murine development [14-16]. This protein is also detected in the cerebrospinal fluid  and plays a role in the maturation of granular neuron precursors . "
[Show abstract][Hide abstract] ABSTRACT: Sustained neuroinflammation strongly contributes to the pathogenesis of pain. The clinical challenge of chronic pain relief led to the identification of molecules such as cytokines, chemokines and more recently matrix metalloproteinases (MMPs) as putative therapeutic targets. Evidence points to a founder member of the matricial CCN family, NOV/CCN3, as a modulator of these inflammatory mediators. We thus investigated the possible involvement of NOV in a preclinical model of persistent inflammatory pain.
We used the complete Freund's adjuvant (CFA)-induced model of persistent inflammatory pain and cultured primary sensory neurons for in vitro experiments. The mRNA expression of NOV and pro-inflammatory factors were measured with real-time quantitative PCR, CCL2 protein expression was assessed using ELISA, MMP-2 and -9 activities using zymography. The effect of drugs on tactile allodynia was evaluated by the von Frey test.
NOV was expressed in neurons of both dorsal root ganglia (DRG) and dorsal horn of the spinal cord (DHSC). After intraplantar CFA injection, NOV levels were transiently and persistently down-regulated in the DRG and DHSC, respectively, occurring at the maintenance phase of pain (15 days). NOV-reduced expression was restored after treatment of CFA rats with dexamethasone. In vitro, results based on cultured DRG neurons showed that siRNA-mediated inhibition of NOV enhanced IL-1β- and TNF-α-induced MMP-2, MMP-9 and CCL2 expression whereas NOV addition inhibited TNF-α-induced MMP-9 expression through β1 integrin engagement. In vivo, the intrathecal delivery of MMP-9 inhibitor attenuated mechanical allodynia of CFA rats. Importantly, intrathecal administration of NOV siRNA specifically led to an up-regulation of MMP-9 in the DRG and MMP-2 in the DHSC concomitant with increased mechanical allodynia. Finally, NOV intrathecal treatment specifically abolished the induction of MMP-9 in the DRG and, MMP-9 and MMP-2 in the DHSC of CFA rats. This inhibitory effect on MMP is associated with reduced mechanical allodynia.
This study identifies NOV as a new actor against inflammatory pain through regulation of MMPs thus uncovering NOV as an attractive candidate for therapeutic improvement in pain relief.
Journal of Neuroinflammation 02/2012; 9(1):36. DOI:10.1186/1742-2094-9-36 · 5.41 Impact Factor
"The expression of CCN3 was also observed in medium-sized vessels such as coronary arteries and small pulmonary veins (Fig. 1a). In addition, and correlating with previously reported analyses (Kocialkowski et al. 2001), CCN3 was also found to be present in the heart as evidenced by the positive staining in intramyocardial vessels and the endocardium (illustrated in the cardiac valve leaflet panel). Finally, ECs from the small vessels (bronchial vein) also stained positive for CCN3 (Fig. 1a). "
[Show abstract][Hide abstract] ABSTRACT: The vascular endothelium plays a fundamental role in the health and disease of the cardiovascular system. The molecular mechanisms regulating endothelial homeostasis, however, remain incompletely understood. CCN3, a member of the CCN (Cyr61, Ctgf, Nov) family of cell growth and differentiation regulators, has been shown to play an important role in numerous cell types. The function of CCN3 in endothelial cells has yet to be elucidated. Immunohistochemical analysis of CCN3 expression in mouse tissues revealed robust immunoreactivity in the endothelium of large arteries, small resistance vessels, and veins. We found that CCN3 expression in human umbilical vein endothelial cells (HUVECs) is transcriptionally induced by laminar shear stress (LSS) and HMG CoA-reductase inhibitors (statins). Promoter analyses identified the transcription factor Kruppel-like factor 2 (KLF2) as a direct regulator of CCN3 expression. In contrast to LSS, proinflammatory cytokines reduced CCN3 expression. Adenoviral overexpression of CCN3 in HUVEC markedly inhibited the cytokine-mediated induction of vascular adhesion molecule-1 (VCAM-1). Consistent with this observation, CCN3 significantly reduced monocyte adhesion. Conversely, CCN3 knockdown in HUVECs resulted in enhancement of cytokine-induced VCAM-1 expression. Concordant effects were observed on monocyte adhesion. Gain and loss-of-function mechanistic studies demonstrated that CCN3 negatively regulates nuclear factor kappaB (NF-κB) activity by reducing its translocation into the nucleus and subsequent binding to the VCAM-1 promoter, suggesting that CCN3's anti-inflammatory effects occur secondary to inhibition of NF-κB nuclear accumulation. This study identifies CCN3 as a novel regulator of endothelial proinflammatory activation.
Journal of Cell Communication and Signaling 10/2010; 4(3):141-53. DOI:10.1007/s12079-010-0095-x
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