Function of OPG as a Traffic Regulator for RANKL Is Crucial for Controlled Osteoclastogenesis
Function of OPG as a Traffic Regulator for RANKL Is Crucial for Controlled Osteoclastogenesis
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DOI：
10.1002/jbmr.89
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发表时间：
2010-09-01
影响因子：
6.2
通讯作者：
Suzuki, Hiroshi
中科院分区：
文献类型：
--
作者：
Aoki, Shigeki;Honma, Masashi;Suzuki, Hiroshi
成骨细胞表面核因子-kappaB受体激活剂配体(RANKL)的数量被认为是决定破骨细胞前体信号输入的大小和破骨细胞形成的程度。以前，我们已经证明RANKL主要定位于溶酶体细胞器，但在成骨细胞表面很少发现，因此，调节RANKL在成骨细胞中的亚细胞转运对于控制破骨细胞的形成具有重要意义。在这里，我们研究了护骨素(OPG)的参与，它目前被认为是RANKL的诱饵受体，参与调节RANKL的行为。提示OPG在高尔基体中已经与RANKL形成了复合体，这种复合体的形成是RANKL分选分泌型溶酶体所必需的。研究还表明，OPG的每个结构域对于发挥OPG作为交通调节器的功能是不可或缺的。特别是，OPG的后一个结构域，其生理功能尚不清楚，被认为是将RANKL分子分类为高尔基体中的溶酶体。此外，尽管诱骗受体分子数量增加，但RANK-OPG嵌合蛋白的过度表达仍保留了OPG作为诱饵受体的功能，但失去了交通调节功能，选择性地抑制了内源性OPG作为交通调节因子的功能，并导致破骨细胞的成骨能力上调。综上所述，OPG作为RANKL的交通调节器对调节破骨细胞的生成以及作为诱饵受体是至关重要的。(C)2010年美国骨与矿物研究学会。
The amount of the receptor activator of NF-kappa B ligand (RANKL) on the osteoblastic cell surface is considered to determine the magnitude of the signal input to osteoclast precursors and the degree of osteoclastogenesis. Previously, we have shown that RANKL is localized predominantly in lysosomal organelles, but little is found on the osteoblastic cell surface, and consequently, the regulated subcellular trafficking of RANKL in osteoblastic cells is important for controlled osteoclastogenesis. Here we have examined the involvement of osteoprotegerin (OPG), which is currently recognized as a decoy receptor for RANKL, in the regulation of RANKL behavior. It was suggested that OPG already makes a complex with RANKL in the Golgi apparatus and that the complex formation is necessary for RANKL sorting to the secretory lysosomes. It was also shown that each structural domain of OPG is indispensable for exerting OPG function as a traffic regulator. In particular, the latter domains of OPG, whose physiologic functions have been unclear, were indicated to sort RANKL molecules to lysosomes from the Golgi apparatus. In addition, the overexpression of RANK-OPG chimeric protein, which retained OPG function as a decoy receptor but lost the function as a traffic regulator, inhibited endogenous OPG function as a traffic regulator selectively in osteoblastic cells and resulted in the upregulation of osteoclastogenic ability despite the increased number of decoy receptor molecules. Conclusively, OPG function as a traffic regulator for RANKL is crucial for regulating osteoclastogenesis at least as well as that as a decoy receptor. (C) 2010 American Society for Bone and Mineral Research.