Journal
BONE
Volume 61, Issue -, Pages 91-101Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.bone.2013.12.032
Keywords
Osteoclast; Recruitment; CX3CL1; Chemokine; Radiation; Bone loss
Categories
Funding
- Ministry for Health, Welfare and Family Affairs, Republic of Korea [A080016, A050020]
- Basic Science Research Program through the National Research Foundation (NRF) of Korea
- Ministry of Education, Science and Technology [2009-0072141]
- Korea Health Promotion Institute [A080016, A050020] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2009-0072141] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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 alpha 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 nova 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. (C) 2014 Elsevier Inc. All rights reserved.
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