title: EphrinB-EphB receptor signaling contributes to bone cancer pain via Toll-like receptor and proinflammatory cytokines in rat spinal cord.
abstract: Treating bone cancer pain poses a major clinical challenge, and the mechanisms underlying bone cancer pain remain elusive. EphrinB-EphB receptor signaling may contribute to bone cancer pain through N-methyl-d-aspartate receptor neuronal mechanisms. Here, we report that ephrinB-EphB signaling may also act through a Toll-like receptor 4 (TLR4)-glial cell mechanism in the spinal cord. Bone cancer pain was induced by tibia bone cavity tumor cell implantation (TCI) in rats. TCI increased the expression of TLR4 and the EphB1 receptor, the activation of astrocytes and microglial cells, and increased levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). The increased expression of TLR4 and EphB1 were colocalized with each other in astrocytes and microglial cells. Spinal knockdown of TLR4 suppressed TCI-induced behavioral signs of bone cancer pain. The TCI-induced activation of astrocytes and microglial cells, as well as the increased levels of IL-1β and TNF-α, were inhibited by intrathecal administration of TLR4-targeting siRNA2 and the EphB receptor antagonist EphB2-Fc, respectively. The administration of EphB2-Fc suppressed the TCI-induced increase of TLR4 expression but siRNA2 failed to affect TCI-induced EphB1 expression. Intrathecal administration of an exogenous EphB1 receptor activator, ephrinB2-Fc, increased the expression of TLR4 and the levels of IL-1β and TNF-α, activated astrocytes and microglial cells, and induced thermal hypersensitivity. These ephrinB2-Fc-induced alterations were suppressed by spinal knockdown of TLR4. This study suggests that TLR4 may be a potential target for preventing or reversing bone cancer pain and other similar painful processes mediated by ephrinB-EphB receptor signaling.
authors: Neuroscience Research Institute and Center for Pain Medicine, Peking University, 38 Xueyuan Road, Beijing 100191, China Department of Neurobiology, Parker University Research Institute, 2540 Walnut Hill Lane, Dallas, TX 75229, USA.
authors: Su
authors: S
authors: Liu
authors: Yue-Peng
authors: YP
authors: Liu
authors: William B
authors: WB
authors: Song
authors: Xue-Jun
authors: XJ
authors: Song
mesh_terms: D000818:Animals; D001859:Bone Neoplasms / Q000378:metabolism* / Q000473:pathology; D036388:Ephrin-B2 / Q000008:administration & dosage*; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism*; D007278:Injections, Spinal; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D017207:Rats, Sprague-Dawley; D036225:Receptor, EphB1 / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D036388:Ephrin-B2; D018836:Inflammation Mediators; C495347:Tlr4 protein, rat; D051197:Toll-Like Receptor 4; D036225:Receptor, EphB1
keywords: Bone cancer; EphB1; IL-1β; TLR4; TNF-α
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