Vascular expression of the chemokine CX3CL1 promotes osteoclast recruitment and exacerbates bone resorption in an irradiated murine model

详细信息    查看全文

• 作者：Ki Hoon Han^a ; ^{steadyhan@amc.seoul.kr" class="auth_mail} ; Jae Won Ryu^a ; Kyung-Eun Lim^b ; Soo-Han Lee^c ; Yuna Kim^c ; Chang Sun Hwang^d ; Je-Yong Choi^b ; Ki Ok Han^d ; ^e ; ^{hankiok@medigate.net" class="auth_mail}
• 关键词：渭CT ; micro-computed tomography ; BM ; bone marrow ; BMCs ; bone marrow cells ; BMD ; bone mineral density ; BMMs ; bone marrow macrophages ; BMT ; bone marrow transplantation ; BMU ; basic multicellular unit ; CX3CR1 ; CX3C chemokine receptor 1 ; ECs ; endothelial cells ; ELISA ; enzyme-linked immunosorbent assay ; GFP ; green fluorescent protein ; GAPDH ; glyceraldehyde-3 phosphate dehydrogenase ; HAECs ; human aortic endothelial cells ; HIF ; hypoxia-inducible factor ; IFN ; interferon ; IL ; interleukin ; IR ; ionizing rad
• 刊名：Bone
• 出版年：April, 2014
• 年：2014
• 卷：61
• 期：Complete
• 页码：91-101
• 全文大小：1770 K

文摘

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 伪 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.