Rac deletion in osteoclasts causes severe osteopetrosis
Rac deletion in osteoclasts causes severe osteopetrosis
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DOI：
10.1242/jcs.086280
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发表时间：
2011-11-15
影响因子：
4
通讯作者：
Teitelbaum, Steven L.
中科院分区：
文献类型：
--
作者：
Croke, Monica;Ross, F. Patrick;Teitelbaum, Steven L.
Cdc42主要通过刺激破骨细胞生成来调节骨吸收。它的姊妹GTPase， Rac，是否对破骨细胞有意义的影响，如果有，通过什么方式影响，目前还不清楚。我们发现，虽然单独删除Rac1或Rac2没有影响，但在Rac2（-/-）小鼠的破骨细胞中，Rac1的可变减少会导致严重的骨质疏松。同时缺乏Rac1和Rac2的破骨细胞（Rac双敲除，RacDKO）不能有效地吸收骨。相比之下，破骨细胞在RacDKO成骨小鼠中丰富，与Cdc42缺乏的小鼠不同，破骨细胞正常表达细胞的成熟标志物。因此，RacDKO小鼠的骨质疏松病变在很大程度上反映了吸收性多核细胞的功能受损，而不是分化受阻。RacDKO破骨细胞功能障碍代表细胞骨架组织失败，表现为细胞活力降低，无法扩散或产生关键的吸收细胞器（即肌动蛋白环和皱边），并伴有Arp3分布异常。Rac1的细胞骨架组织能力是通过其20个氨基酸的效应域介导的。因此，Rac1和Rac2是相互补偿的。与Cdc42缺乏不同，它们的联合缺乏不会影响分化，但会通过调节破骨细胞骨架而促进严重的骨质疏松。
Cdc42 mediates bone resorption principally by stimulating osteoclastogenesis. Whether its sister GTPase, Rac, meaningfully impacts upon the osteoclast and, if so, by what means, is unclear. We find that whereas deletion of Rac1 or Rac2 alone has no effect, variable reduction of Rac1 in osteoclastic cells of Rac2(-/-) mice causes severe osteopetrosis. Osteoclasts lacking Rac1 and Rac2 in combination (Rac double-knockout, RacDKO), fail to effectively resorb bone. By contrast, osteoclasts are abundant in RacDKO osteopetrotic mice and, unlike those deficient in Cdc42, express the maturation markers of the cells normally. Hence, the osteopetrotic lesion of RacDKO mice largely reflects impaired function, and not arrested differentiation, of the resorptive polykaryon. The dysfunction of RacDKO osteoclasts represents failed cytoskeleton organization as evidenced by reduced motility of the cells and their inability to spread or generate the key resorptive organelles (i.e. actin rings and ruffled borders), which is accompanied by abnormal Arp3 distribution. The cytoskeleton-organizing capacity of Rac1 is mediated through its 20-amino-acid effector domain. Thus, Rac1 and Rac2 are mutually compensatory. Unlike Cdc42 deficiency, their combined absence does not impact upon differentiation but promotes severe osteopetrosis by dysregulating the osteoclast cytoskeleton.