title: RANKL-induced down-regulation of CX3CR1 via PI3K/Akt signaling pathway suppresses Fractalkine/CX3CL1-induced cellular responses in RAW264.7 cells.
abstract: The receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for osteoclast differentiation. In this study, we examined the effects of RANKL on chemokine receptor expression in osteoclast precursor cells, RAW264.7 cells. CX3CL1 (also called Fractalkine) receptor, CX3CR1 mRNA expression, was rapidly reduced by treatment with RANKL in contrast to the increased expression of CCR1 and tartrate-resistant acid phosphatase (TRAP). This reduction occurred within 12h and was maintained for 5days during osteoclastogenesis. Inhibitors of phosphatidylinositol 3-kinase (PI3K) and Akt, but not mitogen-activated protein kinases, restored the RANKL-induced reduction of CX3CR1 mRNA. The stability of CX3CR1 mRNA was not changed, suggesting transcriptional repression by RANKL. The down-regulation of CX3CR1 mRNA correlated with the suppression of CX3CL1-induced activation of Akt and ERK as well as chemotaxis. These results suggest a potential role for decreased CX3CL1-CX3CR1 interaction in osteoclastogenesis.
authors.affiliation: Division of Pathogenic Biochemistry, Institute of Natural Medicine, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
authors.forename: Yurika
authors.initials: Y
authors.lastname: Saitoh
authors.forename: Keiichi
authors.initials: K
authors.lastname: Koizumi
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Sakurai
authors.forename: Takayuki
authors.initials: T
authors.lastname: Minami
authors.forename: Ikuo
authors.initials: I
authors.lastname: Saiki
mesh_terms: D000818:Animals; D000073883:CX3C Chemokine Receptor 1; D002460:Cell Line; D054428:Chemokine CX3CL1 / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004347:Drug Interactions; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D053245:RANK Ligand / Q000008:administration & dosage*; D019707:Receptors, Chemokine / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D000073883:CX3C Chemokine Receptor 1; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C471885:Cx3cr1 protein, mouse; D053245:RANK Ligand; D019707:Receptors, Chemokine; C505689:Tnfsf11 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt