Osteoclasts play a part in pain due to the inflammation adjacent to bone
Osteoclasts play a part in pain due to the inflammation adjacent to bone
复制标题
DOI：
10.1016/j.bone.2006.04.033
复制
发表时间：
2006-11-01
期刊：
影响因子：
4.1
通讯作者：
Yoneda, Toshiyuki
中科院分区：
文献类型：
--
作者：
Nagae, Maho;Hiraga, Toru;Yoneda, Toshiyuki
骨吸收增加的骨疾病通常与骨痛有关，破骨细胞抑制剂可减轻骨痛。破骨细胞通过液泡H+-ATP酶分泌质子降解骨矿物质，产生酸性微环境。因为酸中毒是一个众所周知的疼痛原因，我们推断破骨细胞通过质子分泌引起疼痛。我们使用动物模型对此进行了探索，在该动物模型中，在后爪中单次皮下注射完全弗氏佐剂（CFA）引起炎性痛觉过敏（对伤害性刺激的高反应性）。在注射CFA的后爪中，跖骨中的骨吸收增加。CFA诱导的痛觉过敏显着抑制双膦酸盐，唑来膦酸（ZOL）和阿仑膦酸盐和骨保护素。其中破骨细胞固有功能障碍的c-src缺陷小鼠表现出减少的CFA诱导的痛觉过敏。重复皮下注射甲状旁腺相关蛋白到后爪也引起痛觉过敏，骨吸收增加。RT-PCR结果显示，痛敏与同侧背根神经节（DRG）酸敏感离子通道（ASIC）1a、1b和3的mRNA表达增加有关;免疫组化结果显示，同侧脊髓背角c-Fos的mRNA表达增加。值得注意的是，ZOL降低ASIC 1a mRNA表达和c-Fos。用pH5.5的酸处理DRG细胞系F-11可增加ASIC 1a、1b和3 mRNA的表达和核c-Fos的表达。ASIC阻断剂阿米洛利抑制酸诱导的F-11细胞c-Fos表达。此外，与亲本F-11细胞相比，瞬时受体电位通道香草酸亚家族成员1（TRPV 1）转染的F-11细胞显示酸诱导的核c-Fos表达增加。最后，巴弗洛霉素A I，液泡H+-ATP酶的抑制剂，逆转了痛觉过敏和下调ASIC 1a mRNA在DRG中的表达。这些结果使我们提出，破骨细胞通过激活酸敏感受体（包括ASIC和TRPV 1），在CFA诱导的炎症性疼痛中发挥作用，从而产生酸中毒。(c)2006年爱思唯尔公司All rights reserved.
Bone disorders with increased osteoclastic bone resorption are frequently associated with bone pain and inhibitors of osteoclasts reduce bone pain. Osteoclasts degrade bone minerals by secreting protons through the vacuolar H+-ATPase, creating acidic microenvironments. Because acidosis is a well-known cause of pain, we reasoned that osteoclasts cause pain through proton secretion. We explored this using an animal model in which a single subcutaneous injection of the complete Freund's adjuvant (CFA) in the hind-paw caused inflammatory hyperalgesia (hyperresponsiveness to noxious stimuli). Osteoclastic bone resorption was increased in the metatarsal bones in the CFA-injected hind-paws. CFA-induced hyperalgesia was significantly suppressed by the bisphosphonates, zoledronic acid (ZOL) and alendronate and osteoprotegerin. c-src-deficient mice in which osteoclasts are inherently dysfunctional exhibited reduced CFA-induced hyperalgesia. Repeated subcutaneous injections of parathyroid hormone-related protein into the hind-paw also induced hyperalgesia with increased osteoclastic bone resorption. The hyperalgesia was associated with increased mRNA expression of acid-sensing ion channel (ASIC) 1a, 1b and 3 in the ipsi-lateral dorsal root ganglions (DRGs) by RT-PCR and c-Fos in the ipsi-lateral spinal dorsal horn by immunohistochemistry. Of note, ZOL decreased the ASIC1a mRNA expression and c-Fos. Treatment of the DRG cell line F-11 with acid (pH5.5) increased ASIC1a, 1b and 3 mRNA expression and nuclear c-Fos expression. The ASIC blocker amiloride inhibited acid-induced c-Fos expression in F-11 cells. Moreover, F-11 cells transfected with the transient receptor potential channel vanilloid subfamily member 1 (TRPV1) showed increased acid-induced nuclear c-Fos expression compared with parental F-11 cells. Finally, bafilomycin A I, an inhibitor of the vacuolar H+-ATPase, reversed the hyperalgesia and down-regulated ASIC1a mRNA expression in the DRGs. These results led us to propose that osteoclasts play a part in CFA-induced inflammatory pain through an activation of the acid-sensing receptors including ASICs and TRPV1 by creating acidosis. (c) 2006 Elsevier Inc. All rights reserved.