RANKL subcellular trafficking and regulatory mechanisms in osteocytes
RANKL subcellular trafficking and regulatory mechanisms in osteocytes
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DOI：
10.1002/jbmr.1941
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发表时间：
2013-09-01
影响因子：
6.2
通讯作者：
Suzuki, Hiroshi
中科院分区：
文献类型：
--
作者：
Honma, Masashi;Ikebuchi, Yuki;Suzuki, Hiroshi
NF-B配体的受体激活剂（RANKL）是调节破骨细胞生成的中心参与者，并且呈递给破骨细胞前体的RANKL的量是决定破骨细胞形成的大小的重要因素。由于成骨细胞被认为是RANKL的主要来源，因此已在成骨细胞中研究了RANKL亚细胞运输的调节机制。然而，最近的报告显示，骨细胞是RANKL呈递给破骨细胞前体的主要来源，这促使需要重新研究骨细胞中RANKL的亚细胞运输。详细研究分子机制需要设计良好的体外实验系统。因此，我们开发了一种新的破骨细胞前体细胞和骨细胞包埋在胶原凝胶共培养系统。使用该模型的实验表明，骨细胞RANKL通过骨细胞树突状过程以膜结合形式提供给破骨细胞前体，可溶性RANKL对骨细胞支持的破骨细胞生成的贡献很小。此外，RANKL亚细胞运输的调节，如OPG介导的新合成RANKL分子转运至溶酶体储存室，以及RANK刺激后RANKL释放至细胞表面，已证实在骨细胞中具有功能。这些结果为破骨细胞生成的调控提供了新的认识。(C)2013年美国骨与矿物质研究学会。
The receptor activator of the NF-B ligand (RANKL) is the central player in the regulation of osteoclastogenesis, and the quantity of RANKL presented to osteoclast precursors is an important factor determining the magnitude of osteoclast formation. Because osteoblastic cells are thought to be a major source of RANKL, the regulatory mechanisms of RANKL subcellular trafficking have been studied in osteoblastic cells. However, recent reports showed that osteocytes are a major source of RANKL presentation to osteoclast precursors, prompting a need to reinvestigate RANKL subcellular trafficking in osteocytes. Investigation of molecular mechanisms in detail needs well-designed in vitro experimental systems. Thus, we developed a novel co-culture system of osteoclast precursors and osteocytes embedded in collagen gel. Experiments using this model revealed that osteocytic RANKL is provided as a membrane-bound form to osteoclast precursors through osteocyte dendritic processes and that the contribution of soluble RANKL to the osteoclastogenesis supported by osteocytes is minor. Moreover, the regulation of RANKL subcellular trafficking, such as OPG-mediated transport of newly synthesized RANKL molecules to lysosomal storage compartments, and the release of RANKL to the cell surface upon stimulation with RANK are confirmed to be functional in osteocytes. These results provide a novel understanding of the regulation of osteoclastogenesis. (C) 2013 American Society for Bone and Mineral Research.