ATP-induced osteoclast function: the formation of sealing-zone like structure and the secretion of lytic granules via microtubule-deacetylation under the control of Syk
ATP-induced osteoclast function: the formation of sealing-zone like structure and the secretion of lytic granules via microtubule-deacetylation under the control of Syk
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DOI：
10.1111/j.1365-2443.2009.01317.x
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发表时间：
2009-07-01
期刊：
影响因子：
2.1
通讯作者：
Tohyama, Yumi
中科院分区：
文献类型：
--
作者：
Hazama, Ryoichi;Qu, Xiujuan;Tohyama, Yumi
破骨细胞是骨吸收细胞，在骨重塑中发挥独特作用，但骨质溶解的分子机制、破骨细胞如何被激活以及溶解颗粒如何最终释放到骨基质中仍知之甚少。在这里，我们证明能量分子 ATP 通过 P2X(7)-核苷酸受体诱导骨溶解，并且在酪氨酸激酶 Syk 的控制下，α-微管蛋白的脱乙酰化对于整个骨溶解过程至关重要。通过开发破骨细胞功能的可追踪和可重复的体外分析系统，我们发现 ATP 信号传导同时引起两个事件（i）细胞骨架重组以形成密封区、界定接触表面的环状粘附结构，以及（ii）向基质上的界定位点输送和分泌溶解颗粒。我们进一步发现α-微管蛋白的脱乙酰化是破骨细胞功能的关键反应。 α-微管蛋白脱乙酰化的药理抑制导致（i）密封区样结构形成失败和（ii）溶解颗粒停止分泌。此外，发现脱乙酰化动力学受 Syk 调节。这些数据表明与 Syk 相关的新型 P2X(7) 微管调节途径可作为溶骨性疾病的治疗靶点。
Osteoclasts are bone-resorbing cells which play an exclusive role in bone remodeling, but the molecular mechanisms of osteolysis, how osteoclasts are activated and how the lytic granules are finally released towards the bone matrix are poorly understood. Here we show that an energy molecule ATP induces osteolysis via P2X(7)-nucleotide receptor and that deacetylation of alpha-tubulin is essential for the whole process of osteolysis under the control of a tyrosine kinase Syk. By developing a traceable and reproducible in vitro analyzing system for osteoclast function, we found that ATP-signaling gives rise to two events simultaneously (i) cytoskeletal reorganization for the formation of sealing zones, ring-like adhesion structures which delimit the contact surface, and (ii) the delivery and secretion of lytic granules towards the delimited site on the matrix. We further found that deacetylation of alpha-tubulin is a critical reaction for osteoclast function. Pharmacological inhibition of alpha-tubulin deacetylation resulted in (i) failure of the sealing-zone like structure formation and (ii) ceased secretion of lytic granules. Additionally, kinetics of deacetylation was found to be regulated by Syk. These data suggest a novel P2X(7) microtubular regulation pathway related to Syk for a therapeutic target in osteolytic diseases.