Rab27a and Rab27b Are Involved in Stimulation-Dependent RANKL Release From Secretory Lysosomes in Osteoblastic Cells
Rab27a and Rab27b Are Involved in Stimulation-Dependent RANKL Release From Secretory Lysosomes in Osteoblastic Cells
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DOI：
10.1002/jbmr.268
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发表时间：
2011-04-01
影响因子：
6.2
通讯作者：
Suzuki, Hiroshi
中科院分区：
文献类型：
--
作者：
Kariya, Yoshiaki;Honma, Masashi;Suzuki, Hiroshi
成骨细胞表面表达的NF-κ B配体受体激活因子（RANKL）的数量是调节破骨细胞活化的重要因素。之前，发现RANKL定位于成骨细胞的分泌溶酶体，并在RANK-Fc偶联珠刺激下移位至细胞表面。然而，尚未阐明刺激依赖性RANKL释放的体内意义。在这项研究中，我们表明，小GTP酶Rab 27 a和Rab 27 b参与刺激依赖性RANKL释放途径在成骨细胞。Rab 27 a或Rab 27 b的抑制导致刺激后RANKL释放显著减少。Slp 4-a、Slp 5和Munc 13 -4作为效应分子在该途径中协调Rab 27 a/B活性。抑制Rab 27 a/B或这些效应分子不会抑制RANKL在受刺激部位周围溶酶体囊泡中的蓄积，但会抑制这些囊泡与质膜的融合。在成骨细胞中，抑制效应分子导致破骨细胞生成能力降低。此外，缺乏功能性Munc 13 -4基因的Jinx小鼠表现出特征在于由低骨吸收活性引起的胫骨干骺端附近骨体积增加的表型。总之，刺激依赖性RANKL释放是由Rab 27 a/B及其效应分子介导的，这种机制可能对体内破骨细胞活化很重要。(C)2011年美国骨与矿物质研究学会。
The quantity of the receptor activator of NF-kappa B ligand ( RANKL) expressed at the cell surface of osteoblastic cells is an important factor regulating osteoclast activation. Previously, RANKL was found to be localized to secretory lysosomes in osteoblastic cells and to translocate to the cell surface in response to stimulation with RANK-Fc-conjugated beads. However, the in vivo significance of stimulation-dependent RANKL release has not been elucidated. In this study we show that small GTPases Rab27a and Rab27b are involved in the stimulation-dependent RANKL release pathway in osteoblastic cells. Suppression of either Rab27a or Rab27b resulted in a marked reduction in RANKL release after stimulation. Slp4-a, Slp5, and Munc13-4 acted as effector molecules that coordinated Rab27a/b activity in this pathway. Suppression of Rab27a/b or these effector molecules did not inhibit accumulation of RANKL in lysosomal vesicles around the stimulated sites but did inhibit the fusion of these vesicles to the plasma membrane. In osteoblastic cells, suppression of the effector molecules resulted in reduced osteoclastogenic ability. Furthermore, Jinx mice, which lack a functional Munc13-4 gene, exhibited a phenotype characterized by increased bone volume near the tibial metaphysis caused by low bone resorptive activity. In conclusion, stimulation-dependent RANKL release is mediated by Rab27a/b and their effector molecules, and this mechanism may be important for osteoclast activation in vivo. (C) 2011 American Society for Bone and Mineral Research.