CCN2 Suppresses Catabolic Effects of Interleukin-1 {beta}(IL-1{beta}) through {alpha}5{beta}1 and {alpha}V{beta}3 Integrins in Nucleus Pulposus Cells: Implications in Intervertebral Disc Degeneration [Cell Biology]

January 24th, 2014 by Tran, C. M., Schoepflin, Z. R., Markova, D. Z., Kepler, C. K., Anderson, D. G., Shapiro, I. M., Risbud, M. V.

The objective of the study was to examine the regulation of CCN2 by inflammatory cytokines, IL-1β and TNF-α and to determine if CCN2 modulates IL-1β-dependent catabolic gene expression in nucleus pulposus (NP) cells. IL-1β and TNF-α suppress CCN2 mRNA and protein expression in an NF-κB dependent but MAPK independent manner. The conserved κB sites located at -93/-86 and -546/-537 bp in the CCN2 promoter mediated this suppression. On the other hand, treatment of NP cells with IL-1β in combination with CCN2 suppressed the inductive effect of IL-1β on catabolic genes, including MMP-3, ADAMTS-5, syndecan 4 (SDC4) and prolyl hydroxylase 3 (PHD3). Likewise, silencing of CCN2 in human NP cells resulted in elevated basal expression of several catabolic genes and inflammatory cytokines like IL-6, IL-4 and IL-12 as measured by gene expression and cytokine protein array respectively. Interestingly, the suppressive effect of CCN2 on IL-1β was independent of modulation of NF-κB signaling. Using disintegrins, echistatin (ECH) and VLO4, peptide inhibitors to αvβ3 and α5β1 integrins, we showed that CCN2 binding to both integrins was required for the inhibition of IL-1β-induced catabolic gene expression. Noteworthy, analysis of human tissues showed a trend of altered expression of these integrins during degeneration. Taken together, these results suggest that CCN2 and inflammatory cytokines form a functional negative feedback loop in NP cells that may be important in the pathogenesis of disc disease.
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