title: Rab27A regulates transport of cell surface receptors modulating multinucleation and lysosome-related organelles in osteoclasts.
abstract: Rab27A regulates transport of lysosome-related organelles (LROs) and release of secretory granules in various types of cells. Here, we identified up-regulation of Rab27A during differentiation of osteoclasts (OCLs) from bone-marrow macrophages (BMMs), by DNA microarray analysis. Rab27A deficiency in OCLs, using small interfering RNA (siRNA) knockdown in RAW-D cell line or BMMs derived from ashen mice, which display genetic defects in Rab27A expression, induced multinucleated and giant cells. Upon stimulation with macrophage-colony stimulating factor (M-CSF) and receptor activator of nuclear factor kappa-B ligand (RANKL), essential cytokines for OCL differentiation, phosphorylation levels of extracellular signal-regulated kinase (Erk), proto-oncogene tyrosine-protein kinase (Src), and p-38 were slightly enhanced in ashen BMMs than in wild-type BMMs. The cell surface level of c-fms, an M-CSF receptor, was slightly higher in ashen BMMs than in wild-type BMMs, and down-regulation of RANK, a RANKL receptor, was delayed. In addition to receptors, OCLs derived from ashen mice exhibited aberrant actin ring formation, abnormal subcellular localization of lysosome-associated membrane protein (LAMP2) and cathepsin K (CTSK), and marked reduction in resorbing activity. Thus, these findings suggest that Rab27A regulates normal transport of cell surface receptors modulating multinucleation and LROs in OCLs.
authors.affiliation: 1] Division of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan [2] Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan.
authors.forename: Megumi
authors.initials: M
authors.lastname: Shimada-Sugawara
authors.affiliation: Division of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan.
authors.forename: Eiko
authors.initials: E
authors.lastname: Sakai
authors.affiliation: Division of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Okamoto
authors.affiliation: Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Aobayama, Aoba-ku, Sendai, Miyagi 980-8578, Japan.
authors.forename: Mitsunori
authors.initials: M
authors.lastname: Fukuda
authors.affiliation: Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Maebashi 371-8512, Japan.
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Izumi
authors.affiliation: Division of Orthodontics and Dentofacial Orthopedics, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan.
authors.forename: Noriaki
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Division of Dental Pharmacology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8588, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Tsukuba
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D056657:Cathepsin K / Q000378:metabolism; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism*; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology; D034622:RNA Interference; D016186:Receptor, Macrophage Colony-Stimulating Factor; D015854:Up-Regulation / Q000187:drug effects; D020691:rab GTP-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000075745:rab27 GTP-Binding Proteins
chemical_list: D052119:Lysosomal-Associated Membrane Protein 2; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D000075745:rab27 GTP-Binding Proteins; D016173:Macrophage Colony-Stimulating Factor; D016186:Receptor, Macrophage Colony-Stimulating Factor; D048049:Extracellular Signal-Regulated MAP Kinases; D056657:Cathepsin K; C512962:Rab27a protein, mouse; D020691:rab GTP-Binding Proteins