v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation
v-ATPase V0 subunit d2-deficient mice exhibit impaired osteoclast fusion and increased bone formation
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DOI：
10.1038/nm1514
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发表时间：
2006-12-01
期刊：
影响因子：
82.9
通讯作者：
Choi, Yongwon
中科院分区：
文献类型：
--
作者：
Lee, Seoung-Hoon;Rho, Jaerang;Choi, Yongwon
产生基质的成骨细胞和吸收骨的破骨细胞维持骨骼的动态平衡。破骨细胞是由髓系细胞(1，2)来源的单核前破骨细胞融合而成的多核巨细胞，源于造血细胞。融合介导的巨细胞形成是破骨细胞成熟的关键；如果没有它，骨吸收是无效的(2，3)。为了了解破骨细胞与其他髓系细胞的不同之处，我们先前比较了这些细胞的整体mRNA表达模式，并确定了功能未知的基因主要在破骨细胞中表达，其中之一是D2亚型的空泡(H+)ATPase(v-ATPase)V-0结构域(Atp6v0d2)(4-7)。在这里，我们表明，在小鼠中，由于破骨细胞缺陷和骨形成增强，Atp6v0d2的失活导致骨量显著增加。Atp6v0d2缺失不影响破骨细胞的分化和v-ATPase活性。相反，Atp6v0d2是有效的破骨细胞前融合所必需的。骨形成的增加可能是由于成骨细胞的外在因素，因为Atp6v02在成骨细胞中不表达，并且在没有Atp6v02的情况下，其体外分化不会改变。我们的结果证实Atp6v0d2是破骨细胞融合和骨形成的调节因子，并提供了遗传学数据，表明通过治疗靶向单个基因的功能，可以同时抑制破骨细胞成熟和刺激骨形成。
Matrix-producing osteoblasts and bone-resorbing osteoclasts maintain bone homeostasis. Osteoclasts are multinucleated, giant cells of hematopoietic origin formed by the fusion of mononuclear pre-osteoclasts derived from myeloid cells(1,2). Fusion-mediated giant cell formation is critical for osteoclast maturation; without it, bone resorption is inefficient(2,3). To understand how osteoclasts differ from other myeloid lineage cells, we previously compared global mRNA expression patterns in these cells and identified genes of unknown function predominantly expressed in osteoclasts, one of which is the d2 isoform of vacuolar (H+) ATPase (v-ATPase) V-0 domain (Atp6v0d2)(4-7). Here we show that inactivation of Atp6v0d2 in mice results in markedly increased bone mass due to defective osteoclasts and enhanced bone formation. Atp6v0d2 deficiency did not affect differentiation or the v-ATPase activity of osteoclasts. Rather, Atp6v0d2 was required for efficient pre-osteoclast fusion. Increased bone formation was probably due to osteoblast-extrinsic factors, as Atp6v02 was not expressed in osteoblasts and their differentiation ex vivo was not altered in the absence of Atp6v02. Our results identify Atp6v0d2 as a regulator of osteoclast fusion and bone formation, and provide genetic data showing that it is possible to simultaneously inhibit osteoclast maturation and stimulate bone formation by therapeutically targeting the function of a single gene.