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- Title
Response to tumor necrosis factor-α mediated inflammation involving activation of prostaglandin E<sub>2</sub> and Wnt signaling in nucleus pulposus cells.
- Authors
Hiyama, Akihiko; Yokoyama, Katsuya; Nukaga, Tadashi; Sakai, Daisuke; Mochida, Joji
- Abstract
ABSTRACT The cyclooxygenase 2 (COX-2) product, prostaglandin E2 (PGE2), acts through a family of G protein-coupled receptors designated E-prostanoid (EP) receptors that mediate intracellular signaling by multiple pathways. However, it is not known whether crosstalk between tumor necrosis factor-α(TNF-α)-PGE2-mediated signaling and Wnt signaling plays a role in the regulation of intervertebral disc (IVD) cells. In this study, we investigated the relationship between TNF-α-PGE2 signaling and Wnt signaling in IVD cells. TNF-α increased the expression of COX-2 in IVD cells. The EP receptors EP1, EP3, and EP4 were expressed in IVD cells, and TNF-α significantly increased PGE2 production. Stimulation with TNF-α also upregulated EP3 and EP4 mRNA and protein expression in IVD cells. The inductive effect of the EP3 and EP4 receptors on Topflash promoter activity was confirmed through gain- and loss-of-function studies using selective EP agonists and antagonists. PGE2 treatment activated Wnt-β-catenin signaling through activation of EP3. We conclude that TNF-α-induced COX-2 and PGE2 stimulate Wnt signaling and activate Wnt target genes. Suppression of the EP3 receptor via TNF-α-PGE2 signaling seems to suppress IVD degeneration by controlling the activation of Wnt signaling. These findings may help identify the underlying mechanism and role of Wnt signaling in IVD degeneration. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1756-1768, 2015.
- Subjects
NUCLEUS pulposus; DINOPROSTONE; TUMOR necrosis factors; CYCLOOXYGENASE 2; INTERVERTEBRAL disk
- Publication
Journal of Orthopaedic Research, 2015, Vol 33, Issue 12, p1756
- ISSN
0736-0266
- Publication type
Article
- DOI
10.1002/jor.22959