Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA.
Next generation Optical Immune-imaging, WPI-Immunology Frontier Research Center, Osaka University, Suita, Osaka, 565-0871, Japan.
Sci Rep. 2017 Mar 15;7(1):196. doi: 10.1038/s41598-017-00139-2.
Excessive bone resorption by osteoclasts (OCs) can result in serious clinical outcomes, including bone loss that may weaken skeletal or periodontal strength. Proper bone homeostasis and skeletal strength are maintained by balancing OC function with the bone-forming function of osteoblasts. Unfortunately, current treatments that broadly inhibit OC differentiation or function may also interfere with coupled bone formation. We therefore identified a factor, the purinergic receptor P2X5 that is highly expressed during the OC maturation phase, and which we show here plays no apparent role in early bone development and homeostasis, but which is required for osteoclast-mediated inflammatory bone loss and hyper-multinucleation of OCs. We further demonstrate that P2X5 is required for ATP-mediated inflammasome activation and IL-1β production by OCs, and that P2X5-deficient OC maturation is rescued in vitro by addition of exogenous IL-1β. These findings identify a mechanism by which OCs react to inflammatory stimuli, and may identify purinergic signaling as a therapeutic target for bone loss-related inflammatory conditions.
破骨细胞（OCs）过度的骨质吸收可能导致严重的临床后果，包括可能削弱骨骼或牙周强度的骨质流失。OC 功能与成骨细胞的骨形成功能之间的平衡维持着适当的骨稳态和骨骼强度。不幸的是，目前广泛抑制 OC 分化或功能的治疗方法也可能干扰耦联的骨形成。因此，我们鉴定出一种因子，即嘌呤能受体 P2X5，其在 OC 成熟阶段高度表达，我们在这里表明，它在早期骨发育和稳态中没有明显作用，但对于破骨细胞介导的炎症性骨丢失和 OC 的过度多核化是必需的。我们进一步证明，P2X5 是 OC 中 ATP 介导的炎症小体激活和 IL-1β 产生所必需的，并且体外添加外源性 IL-1β可挽救 P2X5 缺陷型 OC 的成熟。这些发现确定了 OCs 对炎症刺激反应的机制，并可能确定嘌呤能信号作为与骨丢失相关的炎症状态的治疗靶点。
