Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation.
Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation.
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DOI：
10.1097/j.pain.0000000000000965
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发表时间：
2017-09
期刊：
影响因子：
7.4
通讯作者：
Salvemini D
中科院分区：
文献类型：
--
作者：
Grenald SA;Doyle TM;Zhang H;Slosky LM;Chen Z;Largent-Milnes TM;Spiegel S;Vanderah TW;Salvemini D
转移性骨痛是一种最常见的癌症疼痛，由于外周和中枢性炎症以及神经病理机制而持续存在。在这里，我们首次描述了在癌性骨痛(CIBP)过程中脊髓鞘磷脂代谢的改变。在小鼠股骨关节切开和同种肿瘤移植后，神经酰胺减少，鞘氨醇和神经鞘糖脂的生物活性代谢物1-磷酸鞘氨醇(S1P)相应增加。有趣的是，二氢神经酰胺和二氢S1P的升高表明，神经鞘脂的生物合成增加了。接下来，我们确定S1P受体亚型1(S1PR1)是治疗干预的新靶点。鞘内或全身注射竞争性和功能性S1PR1拮抗剂，分别为TASP0277308和FTY720/Fingolimod，可减弱癌症诱导的自发退缩和保护。全身注射FTY720抑制CIBP不会导致超过7天的抗伤害耐受性。FTY720可增强CIBP动物同侧脊髓中IL-10的表达，鞘内注射IL-10中和抗体可降低FTY720逆转CIBP的能力。FTY720治疗与体内骨代谢的改变无关。本研究确定了一种通过阻断骨癌引起的腰髓活性代谢物S1P和二氢S1P的作用来抑制骨癌疼痛的新机制，并支持FDA批准的药物FTY720作为CIBP的治疗途径的潜在快速临床应用。
Metastatic bone pain is the single most common form of cancer pain and persists as a result of peripheral and central inflammatory, as well as neuropathic mechanisms. Here, we provide the first characterization of sphingolipid metabolism alterations in the spinal cord occurring during cancer-induced bone pain (CIBP). Following femoral arthrotomy and syngenic tumor implantation in mice, ceramides decreased with corresponding increases in sphingosine and the bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P). Intriguingly, de novo sphingolipid biosynthesis was increased as shown by the elevations of dihydro-ceramides and dihydro-S1P. We next identified the S1P receptor subtype 1 (S1PR1) as a novel target for therapeutic intervention. Intrathecal or systemic administration of the competitive and functional S1PR1 antagonists, TASP0277308 and FTY720/Fingolimod, respectively, attenuated cancer-induced spontaneous flinching and guarding. Inhibiting CIBP by systemic delivery of FTY720 did not result in antinociceptive tolerance over 7 days. FTY720 administration enhanced IL-10 in the lumbar ipsilateral spinal cord of CIBP animals and intrathecal injection of an IL-10 neutralizing antibody mitigated the ability of systemic FTY720 to reverse CIBP. FTY720 treatment was not associated with alterations in bone metabolism in vivo. Studies here identify a novel mechanism to inhibit bone cancer pain by blocking the actions of the bioactive metabolites S1P and dihydro-S1P in lumbar spinal cord induced by bone cancer and support potential fast-track clinical application of the FDA-approved drug, FTY720, as a therapeutic avenue for CIBP.
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影响因子：
6.2
作者：
Hait NC;Avni D;Yamada A;Nagahashi M;Aoyagi T;Aoki H;Dumur CI;Zelenko Z;Gallagher EJ;Leroith D;Milstien S;Takabe K;Spiegel S
通讯作者：
Spiegel S
影响因子：
4.8
作者：
Brinkmann, V;Davis, MD;Lynch, KR
通讯作者：
Lynch, KR
影响因子：
3.7
作者：
Finley A;Chen Z;Esposito E;Cuzzocrea S;Sabbadini R;Salvemini D
通讯作者：
Salvemini D
影响因子：
15.1
作者：
Almolda, Beatriz;de Labra, Carmen;Castellano, Bernardo
通讯作者：
Castellano, Bernardo
影响因子：
7.3
作者：
Bolli, Martin H.;Abele, Stefan;Weller, Thomas
通讯作者：
Weller, Thomas