CCN3: the-pain-killer inside me

Abstract

There is increasing evidence that metalloproteinases are involved in neuropathic pain [Dev et al., Expert Opin Investig Drugs 19:455-468 2010] Hence, the identification of molecules that can regulate MMP9 and MMP2 is warranted. In a recent publication, Kular et al. (2012) claim that CCN3 functions to decrease inflammatory pain via the regulation of two metalloproteinases, MMP2 and MMP9, in response to experimentally-induced inflammation. Their conclusion is based on the following observations : i) the expression of CCN3 was reduced following induction of pain by subcutaneous injection of complete Freund's adjuvent in rat's paw, ii) an inhibition of MMP9 decreased CFA-associated mechanical allodynia, iii) inhibition of CCN3 expression by siRNA led to an upregulation of MMP2 in the dorsal horn of the spinal cord (DHSC) and MMP9 in the dorsal root ganglia (DRG), iv) a partial effect of CCN3 on CFA-induced expression of MMP9 and MMP2 in DRG and DHSC following intrathecal injection of CCN3. Unfortunately, the conclusion of this study is weakened by the lack of experimental evidence showing a direct relationship between the expression of CCN3 and MMPs. Furthermore, several results contained in this manuscript only confirm data that were previously established by others. Owing to the wide range of activities which have been attributed to CCN3 (Perbal, Mol Pathol 54:57-79 2001, Brigstock, J Endocrinol 178:169-175 2003, Perbal, Lancet 363(9402):62-64 2004, Perbal, Cell Commun Signal 4:6 2006, Holbourn et al. Trends Biochem Sci. 33:461-473 2008, Leask and Abraham, J Cell Sci 119:4803-4810 2006, Jun and Lau, Nat Rev Drug Discov 10:945-963 2011, Rachfal and Brigstock, Vitam Horm 70:69-103 2005), the mechanisms underlying the potential role of CCN3 in the expression of these MMPs in the context of inflammatory pain must be thoroughly studied before a meaningful conclusion can be reached. Indeed, Kular et al. description of variations in CCN3, MMP9 and MMP2 levels occurring simultaneously is not sufficient to draw a functional relationship between these three proteins. It should be noted that the expression of CCN3 was already reported to repress MMP9 (Benini et al., Oncogene 24:4349-4361 2005, Fukunaga-Kalabis et al., Oncogene 27:2552-2560 2008) and the roles of CCN3 in inflammatory processes has been extensively documented in the past few years (Bleau et al., Front Biosci 10:998-1009 2005, Lin et al., J Biol Chem 280:8229-8237 2005, Perbal, Cell Commun Signal 4:6 2006, Hughes et al., Diabetologia 50:1089-1098 2007, Lin et al., J Cell Commun Signal 4:141-153 2010, Pasmant et al., J Neuropathol Exp Neurol 69:60-69 2010, Shimoyama et al., Thromb Vasc Biol 30:675-682 2010, Lemaire et al., J Invest Dermatol 130:2517 2010, Chen and Lau, J Cell Commun Signal 4:63-69 2010, Le Dréau et al., Glia 58:1510-1521 2010, Rittié et al. J Cell Commun Signal 5:69-80 2011, Janune et al., J Cell Commun Signal 5:167-171 2011). In addition, the expression of CCN3 in the neurons of dorsal root ganglia and dorsal horn of the spinal horn in rat and human has also been documented (Su et al., C R Acad Sci III 321:883-892 1998, Mol Pathol 54:184-191 2001, Kocialkowski et al., Anat Embryol (Berl) 203:417-427 2001). Implication of CCN3 in cognitive functions (Su et al., Sheng Li Xue Bao 52:290-294 2000) and the possible involvement of CCN3 in the regulation of pain was already suggested almost a decade ago (Perbal, Expert Rev Mol Diagn 3:597-604 2003, Perbal et al., Mol Pathol 56:80-85 2003) with the demonstration of cell-specific effects of CCN3 on intracellular calcium stores and inhibition of anionic channels by CCN3 (Li et al., Mol Pathol 55:250-261 2002, Lombet et al., Cell Commun Signal 1:1 2003, Perbal, Expert Rev Mol Diagn 3:597-604 2003, Perbal et al., Mol Pathol 56:80-85 2003). Aside from these general aspects, and in the light of the potential participation of CCN3 in the whole process of pain sensing, the reader would have appreciated the discussion in this manuscript not being essentially a flat summary of the data presented, but a more thorough discussion of the possible role for CCN3 in the regulation of MMPs and its significance in the context of the wide biological functions of CCN3.