RRC ID 61973
Author Kariya Y, Honma M, Hanamura A, Aoki S, Ninomiya T, Nakamichi Y, Udagawa N, Suzuki H.
Title Rab27a and Rab27b are involved in stimulation-dependent RANKL release from secretory lysosomes in osteoblastic cells.
Journal J Bone Miner Res
Abstract 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.
Volume 26(4)
Pages 689-703
Published 2011-4-1
DOI 10.1002/jbmr.268
PMID 20939018
MeSH Acid Phosphatase / metabolism Animals Bone Marrow Cells / cytology Bone and Bones / pathology Cell Count Cell Differentiation / drug effects Cell Differentiation / physiology Cell Line Cells, Cultured Coculture Techniques Collagen Type I / blood Gene Expression / genetics Isoenzymes / metabolism Lysosome-Associated Membrane Glycoproteins / metabolism Lysosomes / metabolism* Macrophages / cytology Membrane Fusion / physiology Membrane Proteins / genetics Membrane Proteins / metabolism Mice Mice, Inbred BALB C Mice, Mutant Strains Osteoblasts / cytology Osteoblasts / drug effects Osteoblasts / metabolism* Osteoclasts / cytology Osteoclasts / metabolism Osteoclasts / pathology Peptides / blood Protein Binding / physiology Protein Transport / physiology* RANK Ligand / genetics RANK Ligand / metabolism* RANK Ligand / pharmacology RNA, Small Interfering / genetics Recombinant Fusion Proteins / administration & dosage Recombinant Fusion Proteins / pharmacology Synaptotagmins / genetics Synaptotagmins / metabolism Tartrate-Resistant Acid Phosphatase Tibia / pathology Vesicular Transport Proteins / genetics Vesicular Transport Proteins / metabolism rab GTP-Binding Proteins / genetics rab GTP-Binding Proteins / metabolism* rab27 GTP-Binding Proteins
IF 5.854
Human and Animal Cells ST2(RCB0224)