NOV/CCN3 attenuates inflammatory pain through regulation of matrix metalloproteinases-2 and -9

Journal of Neuroinflammation

Cécile Martinerie³  Stéphane Melik-Parsadaniantz³  Patrick Kitabgi³  Michel Pohl³  Maryvonne Laurent³  Claire Calmel³  Brigitte Lelongt³  Cyril Rivat²  Lara Kular¹ 

[1] INSERM UMR_S 975; CNRS UMR 7225, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, Hôpital Pitié-Salpêtrière, Paris F-75013, France;Department of Anesthesiology and Pain Medicine, Health Sciences RR415, 1959 NE Pacific Street, Seattle, WA, USA;Université Pierre et Marie Curie 6, Paris, France

关键词: Allodynia;    MMP-9;    MMP-2;    CCL2;    TNF-alpha;    IL-1beta;    Neuroinflammation;    Inflammatory pain;    NOV/CCN3;   

Others  :  1212786
DOI  :  10.1186/1742-2094-9-36

 received in 2011-09-20, accepted in 2012-02-21,  发布年份 2012

【 摘 要 】

Background

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.

Methods

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.

Results

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.

Conclusions

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.

【 授权许可】

   
2012 Kular et al; BioMed Central Ltd.

【 图 表 】

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