Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling.
Vps35 loss promotes hyperresorptive osteoclastogenesis and osteoporosis via sustained RANKL signaling.
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DOI：
10.1083/jcb.201207154
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发表时间：
2013-03-18
期刊：
影响因子：
--
通讯作者：
Xiong WC
中科院分区：
文献类型：
--
作者：
Xia WF;Tang FL;Xiong L;Xiong S;Jung JU;Lee DH;Li XS;Feng X;Mei L;Xiong WC
VPS35缺乏可导致RANKL信号转导受损，破骨细胞生成和功能增强，骨质疏松。核因子受体激活剂B(Receptor Actiator of NF-κB，RANK)在破骨细胞形成中起着关键作用，破骨细胞是启动骨重建以维持健康骨量和结构的重要过程。虽然RANK的信号转导和功能已被广泛研究，但对其负调控机制知之甚少。我们在本文中证明了RANK转运、信号和功能由VPS35调节，VPS35是选择性内体到高尔基体检索膜蛋白所必需的逆转录单体的主要组成部分。VPS35功能丧失改变了等级配基(RANKL)诱导的等级分布，增强了RANKL的敏感性，持续了RANKL信号，并增加了高吸收破骨细胞(OC)的形成。在小鼠中，VPS35基因的半合子缺失促进了高吸收破骨细胞的形成，减少了骨形成，并导致了随后的骨质疏松缺陷，包括骨小梁体积减少，长骨中的骨小梁厚度和密度减少。这些结果表明，VPS35严重地解除了对RANK信号的调控，从而抑制了增加的高吸收OCS的形成，防止了骨质疏松缺陷。
Vps35 deficiency leads to impaired RANK trafficking, enhanced RANKL signaling, increased osteoclastogenesis and function, and osteoporotic deficits. Receptor activator of NF-κB (RANK) plays a critical role in osteoclastogenesis, an essential process for the initiation of bone remodeling to maintain healthy bone mass and structure. Although the signaling and function of RANK have been investigated extensively, much less is known about the negative regulatory mechanisms of its signaling. We demonstrate in this paper that RANK trafficking, signaling, and function are regulated by VPS35, a major component of the retromer essential for selective endosome to Golgi retrieval of membrane proteins. VPS35 loss of function altered RANK ligand (RANKL)–induced RANK distribution, enhanced RANKL sensitivity, sustained RANKL signaling, and increased hyperresorptive osteoclast (OC) formation. Hemizygous deletion of the Vps35 gene in mice promoted hyperresorptive osteoclastogenesis, decreased bone formation, and caused a subsequent osteoporotic deficit, including decreased trabecular bone volumes and reduced trabecular thickness and density in long bones. These results indicate that VPS35 critically deregulates RANK signaling, thus restraining increased formation of hyperresorptive OCs and preventing osteoporotic deficits.
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DOI：
10.1083/jcb.137.1.79
发表时间：
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影响因子：
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