Given the afferent functions, sensory nerves recently have been found exerting efferent influences and directly alter organ physiology. Moreover, studies have demonstrated the crucial role of sensory nerves in the physiological function of osteoclasts. However, the direct evidence of whether sensory nerve efferent influences osteoclast, remains lacking. Here, we found abundant efferent signals transported from sensory nerves into osteoclasts; sensory hypersensitivity significantly increased osteoclastic bone resorption; and sensory neurons (SN) directly promote osteoclastogenesis in vitro co-culture system. Then our screening identified a novel neuropeptide Cyp40, is the efferent signal from the sensory nerve and plays a critical role in the osteoclastogenesis, via aryl hydrocarbon receptor (AhR)-Ras/Raf-pErk-NFATc1 pathway. These findings revealed a novel mechanism of sensory nerves on bone regulation: the direct promotion of osteoclastogenesis by secreting Cyp40. Inhibiting the Cyp40 could therefore be a strategy to improve bone quality in osteoporosis and promote bone repair after bone injury.
