Osteocytes' response to dynamic loading plays a crucial role in regulating the bone mass but quickly becomes saturated such that downstream induction of bone formation plateaus. The underlying mechanisms that downregulate osteocytes' sensitivity and overall response to loading remain unknown. In other cell types, purinergic signaling through the P2Y2 receptor has the potential to downregulate the sensitivity to loading by modifying cell stiffness through actin polymerization and cytoskeleton organization. Herein, we examined the role of P2Y2 activation in regulating osteocytes' mechanotransduction using a P2Y2 knockout cell line alongside conditional knockout mice. Our findings demonstrate that the absence of P2Y2 expression in MLO-Y4 cells prevents actin polymerization while increasing the sensitivity to fluid flow-induced shear stress. Deleting osteocytes' P2Y2 expression in conditional-knockout mice enabled bone formation to increase when increasing the duration of exercise. Overall, P2Y2 activation under loading produces a negative feedback loop, limiting osteocytes' response to continuous loading by shifting the sensitivity to mechanical strain through actin stress fiber formation.

中文翻译：

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通过 P2Y2 受体的嘌呤能信号传导调节骨细胞的机械敏感性。


骨细胞对动态负荷的反应在调节骨量方面起着至关重要的作用，但很快就会变得饱和，以至于下游诱导骨形成趋于平稳。下调骨细胞敏感性和对负荷的总体反应的潜在机制仍然未知。在其他细胞类型中，通过 P2Y2 受体的嘌呤能信号转导有可能通过肌动蛋白聚合和细胞骨架组织改变细胞刚度，从而下调对负载的敏感性。在此，我们使用 P2Y2 敲除细胞系和条件性敲除小鼠研究了 P2Y2 激活在调节骨细胞机械转导中的作用。我们的研究结果表明，MLO-Y4 细胞中不存在 P2Y2 表达会阻止肌动蛋白聚合，同时增加对流体流动诱导的剪切应力的敏感性。在条件性敲除小鼠中删除骨细胞的 P2Y2 表达，使骨骼形成在增加运动持续时间时增加。总体而言，负载下的 P2Y2 激活会产生负反馈回路，通过肌动蛋白应力纤维的形成改变对机械应变的敏感性，从而限制骨细胞对连续负载的反应。