Bone Pain Induced by Multiple Myeloma Is Reduced by Targeting V-ATPase and ASIC3.
Bone Pain Induced by Multiple Myeloma Is Reduced by Targeting V-ATPase and ASIC3.
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DOI：
10.1158/0008-5472.can-15-3545
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发表时间：
2017-03-15
期刊：
影响因子：
11.2
通讯作者：
Yoneda T
中科院分区：
文献类型：
--
作者：
Hiasa M;Okui T;Allette YM;Ripsch MS;Sun-Wada GH;Wakabayashi H;Roodman GD;White FA;Yoneda T
多发性骨髓瘤（MM）患者会出现严重骨痛（MMBP），这种疼痛治疗不足且了解不多。在这项研究中，我们研究了MMBP在胫骨内小鼠异种移植模型，采用JJN 3人MM细胞。在该模型中，小鼠发展MMBP，其在骨中与降钙素基因相关肽阳性（CGRP+）感觉神经的发芽增加相关，并且在背根神经节（DRG）中与磷酸化ERK 1/2（pERK 1/2）和pCREB（神经元兴奋的两种分子指标）的上调相关。我们发现，JJN 3细胞表达一个空泡质子泵（V-ATP酶），诱导酸性骨微环境。通过单次注射选择性V-ATP酶抑制剂巴弗洛霉素A1抑制JJN 3-定殖的骨酸化，降低了DRG中的MMBP、CGRP+ SN发芽以及pERK 1/2和pCREB表达。CGRP+感觉神经也表达了酸敏感伤害感受器ASIC 3水平的增加。值得注意的是，单次注射选择性ASIC 3拮抗剂APETx 2显著降低了模型中的MMBP。与JJN 3细胞共培养的原代DRG神经元的机制研究显示，巴夫洛霉素A1或APETx 2抑制了神经突生长和兴奋。此外，将APETx 2与巴弗洛霉素A1组合降低MMBP的程度比单独使用任一种药剂更大。最后，联合巴弗洛霉素A1与破骨细胞抑制剂唑来膦酸足以改善唑来膦酸难治的MMBP。总的来说，我们的研究结果表明，破骨细胞和MM合作，诱导酸性骨微环境，引起MMBP作为ASIC 3激活的感觉神经元的兴奋的结果。此外，他们提出了将神经元上的ASIC 3与MM诱导的酸性骨微环境一起沿着作为缓解患者中MMBP的策略的机制原理。
Multiple myeloma (MM) patients experience severe bone pain (MMBP) that is undertreated and poorly understood. In this study, we studied MMBP in an intratibial mouse xenograft model which employs JJN3 human MM cells. In this model, mice develop MMBP associated in bone with increased sprouting of calcitonin gene-related peptide-positive (CGRP+) sensory nerves and in dorsal root ganglia (DRG) with upregulation of phosphorylated ERK1/2 (pERK1/2) and pCREB, two molecular indicators of neuron excitation. We found that JJN3 cells expressed a vacuolar proton pump (V-ATPase) that induced an acidic bone microenvironment. Inhibition of JJN3-colonized bone acidification by a single injection of the selective V-ATPase inhibitor, bafilomycin A1, decreased MMBP, CGRP+ SN sprouting, and pERK1/2 and pCREB expression in DRG. CGRP+ sensory nerves also expressed increased levels of the acid-sensing nociceptor ASIC3. Notably, a single injection of the selective ASIC3 antagonist APETx2 dramatically reduced MMBP in the model. Mechanistic investigations in primary DRG neurons co-cultured with JJN3 cells showed increased neurite outgrowth and excitation inhibited by bafilomycin A1 or APETx2. Further, combining APETx2 with bafilomycin A1 reduced MMBP to a greater extent than either agent alone. Lastly, combining bafilomycin A1 with the osteoclast inhibitor zoledronic acid was sufficient to ameliorate MMBP which was refractory to zoledronic acid. Overall, our results show that osteoclasts and MM cooperate to induce an acidic bone microenvironment that evokes MMBP as a result of the excitation of ASIC3-activated sensory neurons. Further, they present a mechanistic rationale for targeting ASIC3 on neurons along with the MM-induced acidic bone microenvironment as a strategy to relieve MMBP in patients.