Several bone conditions, eg, bone cancer, osteoporosis, and rheumatoid arthritis (RA), are associated with a risk of developing persistent pain. Increased osteoclast activity is often the hallmark of these bony pathologies and not only leads to bone remodeling but is also a source of pronociceptive factors that sensitize the bone-innervating nociceptors. Although historically bone loss in RA has been believed to be a consequence of inflammation, both bone erosion and pain can occur years before the symptom onset. Here, we have addressed the disconnection between inflammation, pain, and bone erosion by using a combination of 2 monoclonal antibodies isolated from B cells of patients with RA. We have found that mice injected with B02/B09 monoclonal antibodies (mAbs) developed a long-lasting mechanical hypersensitivity that was accompanied by bone erosion in the absence of joint edema or synovitis. Intriguingly, we have noted a lack of analgesic effect of naproxen and a moderate elevation of few inflammatory factors in the ankle joints suggesting that B02/B09-induced pain-like behavior does not depend on inflammatory processes. By contrast, we found that inhibiting osteoclast activity and acid-sensing ion channel 3 signaling prevented the development of B02/B09-mediated mechanical hypersensitivity. Moreover, we have identified secretory phospholipase A2 and lysophosphatidylcholine 16:0 as critical components of B02/B09-induced pain-like behavior and shown that treatment with a secretory phospholipase A2 inhibitor reversed B02/B09-induced mechanical hypersensitivity and bone erosion. Taken together, our study suggests a potential link between bone erosion and pain in a state of subclinical inflammation and offers a step forward in understanding the mechanisms of bone pain in diseases such as RA.

几种骨骼疾病，例如骨癌、骨质疏松症和类风湿性关节炎（RA），与发生持续性疼痛的风险有关。破骨细胞活性增加通常是这些骨病理的标志，不仅导致骨重塑，而且还是使骨神经伤害感受器敏感的伤害性感受因子的来源。尽管从历史上看，RA 中的骨质流失被认为是炎症的结果，但骨侵蚀和疼痛可能在症状出现前数年就发生。在这里，我们通过使用从 RA 患者 B 细胞中分离出的 2 种单克隆抗体的组合，解决了炎症、疼痛和骨侵蚀之间的脱节问题。我们发现，注射 B02/B09 单克隆抗体 (mAb) 的小鼠出现了持久的机械超敏反应，在没有关节水肿或滑膜炎的情况下，伴有骨侵蚀。有趣的是，我们注意到萘普生缺乏镇痛作用，并且踝关节中少数炎症因子适度升高，这表明 B02/B09 诱导的疼痛样行为并不依赖于炎症过程。相比之下，我们发现抑制破骨细胞活性和酸敏感离子通道 3 信号传导可防止 B02/B09 介导的机械超敏反应的发生。此外，我们还发现分泌型磷脂酶 A2 和溶血磷脂酰胆碱 16:0 是 B02/B09 诱导的疼痛样行为的关键成分，并表明用分泌型磷脂酶 A2 抑制剂治疗可逆转 B02/B09 诱导的机械超敏反应和骨侵蚀。总而言之，我们的研究表明骨侵蚀和亚临床炎症状态下的疼痛之间存在潜在联系，并为理解 RA 等疾病中骨痛的机制迈出了一步。