Response to tumor necrosis factor‐α mediated inflammation involving activation of prostaglandin E2 and Wnt signaling in nucleus pulposus cells |
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| Authors: | Akihiko Hiyama Katsuya Yokoyama Tadashi Nukaga Daisuke Sakai Joji Mochida |
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| Affiliation: | 1. Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259‐1193, Japan;2. Research Center for Regenerative Medicine, Tokai University School of Medicine, 143 Shimokasuya, Isehara, Kanagawa 259‐1193, Japan |
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| 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. |
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| Keywords: | intervertebral disc cells nucleus pulposus cells Wnt signaling tumor necrosis factor‐α prostaglandin E2 |
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