title: Vascular expression of the chemokine CX3CL1 promotes osteoclast recruitment and exacerbates bone resorption in an irradiated murine model.
abstract: Circulating osteoclast precursor cells highly express CX3C chemokine receptor 1 (CX3CR1), which is the only receptor for the unique CX3C membrane-anchored chemokine, fractalkine (CX3CL1). An irradiated murine model was used to evaluate the role of the CX3CL1-CX3CR1 axis in osteoclast recruitment and osteoclastogenesis. Ionizing radiation (IR) promoted the migration of circulating CD11b+ cells to irradiated bones and dose-dependently increased the number of differentiated osteoclasts in irradiated bones. Notably, CX3CL1 was dramatically upregulated in the vascular endothelium after IR. IR-induced production of CX3CL1 by skeletal vascular endothelium promoted chemoattraction of circulating CX3CR1+/CD11b+ cells and triggered homing of these osteoclast precursor cells toward the bone remodeling surface, a specific site for osteoclast differentiation. CX3CL1 also increased the endothelium-derived expression of other chemokines including stromal cell-derived factor-1 (CXCL12) and macrophage inflammatory protein-2 (CXCL2) by activating the hypoxia-inducible factor-1 α pathway. These effects may further enhance osteoclastogenesis. A series of in vivo experiments confirmed that knockout of CX3CR1 in bone marrow-derived cells and functional inhibition of CX3CL1 using a specific neutralizing antibody significantly ameliorated osteoclastogenesis and prevented bone loss after IR. These results demonstrate that the de novo CX3CL1-CX3CR1 axis plays a pivotal role in osteoclast recruitment and subsequent bone resorption, and verify its therapeutic potential as a new target for anti-resorptive treatment.
authors.affiliation: Department of Cardiology, School of Medicine, University of Ulsan, Asan Medical Center, Seoul 138-736, Republic of Korea. Electronic address: steadyhan@amc.seoul.kr.
authors.forename: Ki Hoon
authors.initials: KH
authors.lastname: Han
authors.affiliation: Department of Cardiology, School of Medicine, University of Ulsan, Asan Medical Center, Seoul 138-736, Republic of Korea.
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Ryu
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, WCU Program, Skeletal Diseases Genome Research Center, Kyungpook National University, Daegu 700-422, Republic of Korea.
authors.forename: Kyung-Eun
authors.initials: KE
authors.lastname: Lim
authors.affiliation: Department of Cardiology and Pharmacology, School of Medicine, University of Ulsan, Asan Medical Center, Seoul 138-736, Republic of Korea.
authors.forename: Soo-Han
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Cardiology and Pharmacology, School of Medicine, University of Ulsan, Asan Medical Center, Seoul 138-736, Republic of Korea.
authors.forename: Yuna
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Department of Endocrinology and Metabolism, School of Medicine, Kwandong University, Seoul 100-380, Republic of Korea.
authors.forename: Chang Sun
authors.initials: CS
authors.lastname: Hwang
authors.affiliation: Department of Biochemistry and Cell Biology, School of Medicine, WCU Program, Skeletal Diseases Genome Research Center, Kyungpook National University, Daegu 700-422, Republic of Korea.
authors.forename: Je-Yong
authors.initials: JY
authors.lastname: Choi
authors.affiliation: Department of Endocrinology and Metabolism, School of Medicine, Kwandong University, Seoul 100-380, Republic of Korea; Department of Endocrinology and Metabolism, G-SAM Medical Center, Gunpo-si 435-010, Republic of Korea. Electronic address: hankiok@medigate.net.
authors.forename: Ki Ok
authors.initials: KO
authors.lastname: Han
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000378:metabolism*; D001842:Bone and Bones / Q000378:metabolism* / Q000528:radiation effects*; D000073883:CX3C Chemokine Receptor 1; D002478:Cells, Cultured; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D019707:Receptors, Chemokine / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D000073883:CX3C Chemokine Receptor 1; C515538:CX3CL1 protein, human; D054428:Chemokine CX3CL1; C515539:Cx3cl1 protein, mouse; C471885:Cx3cr1 protein, mouse; D019707:Receptors, Chemokine
keywords: Bone loss; CX3CL1; Chemokine; Osteoclast; Radiation; Recruitment