A complex interaction between Wnt signaling and TNF-α in nucleus pulposus cells

Abstract

IntroductionIncreased expression of the proinflammatory cytokine TNF-α in intervertebral discs (IVDs) leads to inflammation, which results in progressive IVD degeneration. We have previously reported that activation of Wnt-β-catenin (hereafter called Wnt) signaling suppresses the proliferation of nucleus pulposus cells and induces cell senescence, suggesting that Wnt signaling triggers the process of degeneration of the IVD. However, it is not known whether cross talk between TNF-α and Wnt signaling plays a role in the regulation of nucleus pulposus cells. The goal of the present study was to examine the effect of the interaction between Wnt signaling and the proinflammatory cytokine TNF-α in nucleus pulposus cells.MethodsCells isolated from rat nucleus pulposus regions of IVDs were cultured in monolayers, and the expression and promoter activity of Wnt signaling and TNF-α were evaluated. We also examined whether the inhibition of Wnt signaling using cotransfection with Dickkopf (DKK) isoforms and Sclerostin (SOST) could block the effects of pathological TNF-α expression in nucleus pulposus cells.ResultsTNF-α stimulated the expression and promoter activity of Wnt signaling in nucleus pulposus cells. In addition, the activation of Wnt signaling by 6-bromoindirubin-3′-oxime (BIO), which is a selective inhibitor of glycogen synthase kinase 3 (GSK-3) activity that activates Wnt signaling, increased TNF-α expression and promoter activity. Conversely, the suppression of TNF-α promoter activity using a β-catenin small interfering RNA was evident. Moreover, transfection with DKK-3, DKK-4, or SOST, which are inhibitors of Wnt signaling, blocked Wnt signaling-mediated TNF-α activation; these effects were not observed for DKK-1 or DKK-2.ConclusionsHere, we have demonstrated that Wnt signaling regulates TNF-α and that Wnt signaling and TNF-α form a positive-feedback loop in nucleus pulposus cells. The results of the present study provide in vitro evidence that activation of Wnt signaling upregulates the TNF-α expression and might cause the degeneration of nucleus pulposus cells. We speculate that blocking this pathway might protect nucleus pulposus cells against degeneration.

Effect of TNF-α Inhibition on Bone Marrow-Derived Mesenchymal Stem Cells in Neurological Function Recovery after Spinal Cord Injury via the Wnt Signaling Pathway in a Rat Model

“…Previous studies have analyzed the Wnt signaling pathway in nuclear pulposus cells and reported that activation of the Wnt signaling pathway inhibits the proliferation of nuclear pulposus cells and induces cell senescence, revealing that the Wnt signaling pathway promotes the progression of degeneration of intervertebral discs [36-38]. Largely consistent with our study, Hiyama et al reported that the Wnt signaling pathway modulates TNF-α, and the Wnt signaling pathway and TNF-α form a positive-feedback loop in nuclear pulposus cells [14]. …”

“…TNF-α can activate the Wnt/β-catenin signaling pathway, which in turn inhibits adipocytic differentiation [13]. According to Akihiko Hiyama et al, activation of the Wnt signaling pathway increases TNF-α expression and may contribute to degeneration of nuclear pulposus cells, which suggests that blockade of Wnt signaling pathway has the potential to reduce the degeneration of nuclear pulposus cells [14]. However, the effect of the Wnt signaling pathway on the recovery of SCI still requires further investigation.…”

Molecular Therapy for Degenerative Disc Disease: Clues from Secretome Analysis of the Notochordal Cell-Rich Nucleus Pulposus

“…We also identified LRP1, LRP2 and VLDLR, which act as receptors for activation of Wnt-signaling. Hiyama et al 42,. reported that the activation of Wnt signaling upregulates the pro-inflammatory cytokine TNF-α leading to disc degeneration.…”

Effect of sclerostin removal <i>in vivo</i> on experimental periodontitis in mice

“…Recent studies suggest that it might be associated with a number of factors, such as higher levels of pro-inflammatory and osteoclastogenic cytokines (17). Inflammatory cytokines are considered to play a major role in disease progression as, together with WNT signaling, they can form a positive feedback loop for modulation of bone remodeling (18). WNT signaling is considered to be an important pathway in bone formation and loss (19).…”