Sema6A-plexin-A2 axis stimulates RANKL-induced osteoclastogenesis through PLC gamma-mediated NFATc1 activation
Sema6A-plexin-A2 axis stimulates RANKL-induced osteoclastogenesis through PLC gamma-mediated NFATc1 activation
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Sema6A-plexin-A2 轴通过 PLC γ 介导的 NFATc1 激活刺激 RANKL 诱导的破骨细胞生成
DOI：
10.1016/j.lfs.2019.01.060
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发表时间：
2019
期刊：
影响因子：
6.1
通讯作者：
Hu Min
中科院分区：
文献类型：
--
作者：
Zhuang Jinliang;Li Xun;Zhang Yi;Shi Ruixin;Shi Ce;Yu Dongsheng;Bao Xingfu;Hu Min
最近，一些丛蛋白和信号蛋白已与破骨细胞生成，骨重建的一个重要过程。丛蛋白A2与骨稳态有关，但其是否参与破骨细胞的生成及其机制尚不清楚。我们发现，丛蛋白A2的表达上调RANKL诱导破骨细胞生成。此外，可溶性Sema 6A与IgG 1 Fc区融合（Fc-Sema 6A）与来自破骨细胞裂解物的丛蛋白-A2相互作用，表明丛蛋白-A2在破骨细胞中充当Sema 6A的受体。此外，Sema 6A处理刺激RANKL诱导的破骨细胞生成，并且当丛蛋白-A2被中和时，这种作用被消除，这说明丛蛋白-A2在介导Sema 6A对破骨细胞生成的作用中不可或缺的作用。从机制上讲，Sema 6A-plexin-A2轴增强了RANKL诱导的PLCγ活化以及下游靶点NFATc 1（破骨细胞生成的主要转录因子之一）。最后，通过药理学抑制剂U 73122抑制PLCγ消除了Sema 6A刺激的NFATc 1激活和RANKL诱导的破骨细胞生成，从而证明PLCγ介导的NFATc 1激活解释了Sema 6A-plexin-A2轴在RANKL诱导的破骨细胞生成中的促进作用。综上所述，本研究揭示了Sema 6A和plexin-A2在破骨细胞生成中的新作用，也为它们在溶骨性疾病的干预中提供了可能的治疗靶点。
Recently, several plexins and semaphorins have been associated with osteoclastogenesis, a vital process for bone remodeling. Plexin-A2 is implicated in bone homeostasis, however, whether it plays a role in osteoclastogenesis and the underlying mechanism remain unknown. We show that plexin-A2 expression is upregulated during RANKL-induced osteoclastogenesis. In addition, the soluble Sema6A fused with IgG1 Fc region (Fc-Sema6A) interacts with plexin-A2 from cell lysates of osteoclasts, suggesting that plexin-A2 acts as a receptor of Sema6A in osteoclasts. Moreover, Sema6A treatment stimulates RANKL-induced osteoclastogenesis, and this effect is abolished when plexin-A2 is neutralized, which illustrates an indispensable role of plexin-A2 in mediating Sema6A effect on osteoclastogenesis. Mechanistically, Sema6A-plexin-A2 axis enhances RANKL-induced activation of PLCγ as well as downstream target NFATc1, one master transcriptional factor of osteoclastogenesis. Lastly, inhibition of PLCγ by pharmacological inhibitor U73122 abrogates Sema6A-stimulated NFATc1 activation and RANKL-induced osteoclastogenesis, thus demonstrating that the PLCγ-mediated NFATc1 activation accounts for the promotive role of Sema6A-plexin-A2 axis in RANKL-induced osteoclastogenesis. Taken together, this study uncovers a novel role of Sema6A and plexin-A2 in osteoclastogenesis, and also offers them as possible therapeutic targets in the intervention of osteolytic diseases.