Inhibition of p38-MAPK signaling pathway attenuates breast cancer induced bone pain and disease progression in a murine model of cancer-induced bone pain.
Inhibition of p38-MAPK signaling pathway attenuates breast cancer induced bone pain and disease progression in a murine model of cancer-induced bone pain.
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DOI：
10.1186/1744-8069-7-81
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发表时间：
2011-10-20
期刊：
影响因子：
3.3
通讯作者：
King T
中科院分区：
文献类型：
--
作者：
Sukhtankar D;Okun A;Chandramouli A;Nelson MA;Vanderah TW;Cress AE;Porreca F;King T
癌症引起的骨痛的驱动机制还知之甚少。在肿瘤发生、破骨细胞形成和伤害性感受过程中起关键作用的一个中心因子是p38MAPK。我们确定了p38MAPK在乳腺癌诱导的骨痛小鼠模型中的作用，在该模型中，发生了溶骨性和成骨细胞的混合重塑。在接受癌症治疗的小鼠中，SB203580对p38MAPK的急性和慢性抑制以剂量依赖的方式阻止了小鼠的退缩和警戒行为，而对触觉刺激的阈值没有影响。对骨骼的放射分析表明，长期抑制p38MAPK可以减少癌症治疗小鼠的骨丢失和自发性骨折的发生率。对接受p38 MAPK抑制剂治疗的小鼠的骨骼进行的组织学分析显示，髓内间隙完全没有成骨细胞生长，肿瘤负担显著减轻。阻断非诱发疼痛行为，但不阻断超敏反应，表明疼痛综合征特定组成部分的潜在机制不同，并有可能使疼痛管理的各个方面个体化。虽然目前还不清楚p38 MAPK信号通路的作用是否可以扩展到其他癌症，但数据表明，有必要了解启动和维持癌症诱导的骨痛的分子机制和细胞事件，以便有效地治疗持续性疼痛和突破性疼痛。
Mechanisms driving cancer-induced bone pain are poorly understood. A central factor implicated to be a key player in the process of tumorigenesis, osteoclastogenesis and nociception is p38 MAPK. We determined the role of p38 MAPK in a mouse model of breast cancer induced bone pain in which mixed osteolytic and osteoblastic remodeling occurs. In cancer-treated mice, acute as well as chronic inhibition of p38 MAPK with SB203580 blocked flinching and guarding behaviors in a dose-dependent manner whereas no effect on thresholds to tactile stimuli was observed. Radiographic analyses of bones demonstrated that chronic inhibition of p38 MAPK reduced bone loss and incidence of spontaneous fracture in cancer-treated mice. Histological analysis of bones collected from mice treated with the p38 MAPK inhibitor showed complete absence of osteoblastic growth in the intramedullary space as well as significantly reduced tumor burden. Blockade of non-evoked pain behaviors but not hypersensitivity suggests differences in the underlying mechanisms of specific components of the pain syndrome and a possibility to individualize aspects of pain management. While it is not known whether the role of p38 MAPK signaling can be expanded to other cancers, the data suggest a need for understanding molecular mechanisms and cellular events that initiate and maintain cancer-induced bone pain for effective management for both ongoing pain as well as breakthrough pain.
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