WASp deficiency in mice results in failure to form osteoclast sealing zones and defects in bone resorption
WASp deficiency in mice results in failure to form osteoclast sealing zones and defects in bone resorption
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DOI：
10.1182/blood-2003-04-1259
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发表时间：
2004-05-01
期刊：
影响因子：
20.3
通讯作者：
Thrasher, AJ
中科院分区：
文献类型：
--
作者：
Calle, Y;Jones, GE;Thrasher, AJ
在破骨细胞中没有描述与Wiskott-Aldrich综合征蛋白（WASp）缺乏相关的缺陷。在这里，我们发现有显着的形态和功能异常。WASp无效细胞分布在更大的表面积上，并且是高度多聚的。在它们的迁移阶段，正常细胞在它们的前缘后面组装成podosome簇，而在骨吸收阶段，多个podosome密集地聚集在形成密封区的明确的肌动蛋白环中。相比之下，WASP无效的破骨细胞在任何阶段显着耗尽的podosomes。在骨表面上，这导致在密封区形成肌动蛋白环失败。用增强型绿色荧光蛋白（eGFP）-WASp融合蛋白补充WASp缺失的破骨细胞可恢复正常的细胞结构。这些结构紊乱转化为骨吸收的异常模式，无论是在体外骨切片和体内。虽然保持了骨吸收的生理稳态水平，但当WASP缺失动物暴露于吸收挑战时，观察到了重大损害。我们的研究结果提供了明确的证据表明，WASp是破骨细胞中podosomes的关键组成部分，并表明WASp在骨吸收过程中这些肌动蛋白结构的动态组织中的非冗余作用。(C)2004年，美国血液学会。
No defects related to deficiency of the Wiskott-Aldrich Syndrome protein (WASp) have been described in osteoclasts. Here we show that there are significant morphologic and functional abnormalities. WASp-null cells spread over a much larger surface area and are highly polykaryotic. In their migratory phase, normal cells assemble clusters of podosomes behind their leading edges, whereas during the bone resorptive phase multiple podosomes are densely aggregated in well-defined actin rings forming the sealing zone. In comparison, WASp-null osteoclasts in either phase are markedly depleted of podosomes. On bone surfaces, this results in a failure to form actin rings at sealing zones. Complementation of WASp-null osteoclasts with an enhanced green fluorescent protein (eGFP)-WASp fusion protein restores normal cytoarchitecture. These structural disturbances translate into abnormal patterns of bone resorption both in vitro on bone slices and in vivo. Although physiologic steady-state levels of bone resorption are maintained, a major impairment is observed when WASp-null animals are exposed to a resorptive challenge. Our results provide clear evidence that WASp is a critical component of podosomes in osteoclasts and indicate a nonredundant role for WASp in the dynamic organization of these actin structures during bone resorption. (C) 2004 by The American Society of Hematology.