Given afferent functions, sensory nerves have recently been found to exert efferent effects and directly alter organ physiology. Additionally, several studies have highlighted the indirect but crucial role of sensory nerves in the regulation of the physiological function of osteoclasts. Nonetheless, evidence regarding the direct sensory nerve efferent influence on osteoclasts is lacking. In the current study, we found that high levels of efferent signals were transported directly from the sensory nerves into osteoclasts. Furthermore, sensory hypersensitivity significantly increased osteoclastic bone resorption, and sensory neurons (SNs) directly promoted osteoclastogenesis in an in vitro coculture system. Moreover, we screened a novel neuropeptide, Cyp40, using an isobaric tag for relative and absolute quantitation (iTRAQ). We observed that Cyp40 is the efferent signal from sensory nerves, and it plays a critical role in osteoclastogenesis via the aryl hydrocarbon receptor (AhR)-Ras/Raf-p-Erk-NFATc1 pathway. These findings revealed a novel mechanism regarding the influence of sensory nerves on bone regulation, i.e., a direct promoting effect on osteoclastogenesis by the secretion of Cyp40. Therefore, inhibiting Cyp40 could serve as a strategy to improve bone quality in osteoporosis and promote bone repair after bone injury.

鉴于传入功能，最近发现感觉神经可以发挥传出作用并直接改变器官生理机能。此外，一些研究强调了感觉神经在破骨细胞生理功能调节中的间接但至关重要的作用。尽管如此，缺乏关于感觉神经传出对破骨细胞的直接影响的证据。在当前的研究中，我们发现高水平的传出信号直接从感觉神经传输到破骨细胞中。此外，感觉过敏显着增加破骨细胞骨吸收，感觉神经元（SN）直接促进体外共培养系统中的破骨细胞生成。此外，我们使用同量异序标签进行相对和绝对定量 (iTRAQ) 筛选了一种新型神经肽 Cyp40。我们观察到 Cyp40 是来自感觉神经的传出信号，它通过芳烃受体 (AhR)-Ras/Raf-p-Erk-NFATc1 途径在破骨细胞生成中发挥关键作用。这些发现揭示了感觉神经影响骨调节的新机制，即Cyp40的分泌对破骨细胞生成的直接促进作用。因此，抑制Cyp40可以作为改善骨质疏松症骨质量并促进骨损伤后骨修复的策略。