Y Kariya and M Honma contributed equally to this work.
Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells†
Version of Record online: 23 MAR 2011
Copyright © 2011 American Society for Bone and Mineral Research
Journal of Bone and Mineral Research
Volume 26, Issue 4, pages 689–703, April 2011
How to Cite
Kariya, Y., Honma, M., Hanamura, A., Aoki, S., Ninomiya, T., Nakamichi, Y., Udagawa, N. and Suzuki, H. (2011), Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells. J Bone Miner Res, 26: 689–703. doi: 10.1002/jbmr.268
- Issue online: 23 MAR 2011
- Version of Record online: 23 MAR 2011
- Accepted manuscript online: 11 OCT 2010 02:32PM EST
- Manuscript Accepted: 22 SEP 2010
- Manuscript Revised: 20 AUG 2010
- Manuscript Received: 27 FEB 2010
- SECRETORY LYSOSOMES;
The quantity of the receptor activator of NF-κB 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. © 2011 American Society for Bone and Mineral Research.