The Journal of Experimental Medicine
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Published online 10 April 2006 doi:10.1084/jem.20051947
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 203, Number 4, 1067-1080
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ARTICLE

 Regulation of osteoclast function and bone mass by RAGE

Zheng Zhou1, David Immel2, Cai-Xia Xi1, Angelika Bierhaus3, Xu Feng4, Lin Mei1, Peter Nawroth3, David M. Stern5, and Wen-Cheng Xiong1

1 Institute of Molecular Medicine and Genomics and Department of Neurology, Medical College of Georgia, Augusta, GA, 30912
2 Savannah River National Laboratory, Aiken, SC 29808
3 Department of Medicine I, University of Heidelberg, 69120 Heidelberg, Germany
4 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294
5 Dean's Office, College of Medicine, University of Cincinnati, Cincinnati, OH 45267

CORRESPONDENCE Wen-Cheng Xiong: wxiong{at}mcg.edu

The receptor for advanced glycation end products (RAGE) is a member of the immunoglobulin superfamily that has multiple ligands and is implicated in the pathogenesis of various diseases, including diabetic complications, neurodegenerative disorders, and inflammatory responses. However, the role of RAGE in normal physiology is largely undefined. Here, we present evidence for a role of RAGE in osteoclast maturation and function, which has consequences for bone remodeling. Mice lacking RAGE had increased bone mass and bone mineral density and decreased bone resorptive activity in vivo. In vitro–differentiated RAGE-deficient osteoclasts exhibited disrupted actin ring and sealing zone structures, impaired maturation, and reduced bone resorptive activity. Impaired signaling downstream of {alpha}vß3 integrin was observed in RAGE–/– bone marrow macrophages and precursors of OCs. These results demonstrate a role for RAGE in osteoclast actin cytoskeletal reorganization, adhesion, and function, and suggest that the osteosclerotic-like phenotype observed in RAGE knockout mice is due to a defect in osteoclast function.

Abbreviations used: BMD, bone mineral density; BMM, bone marrow macrophage; BV, bone volume; HMGB, high mobility group box; M-CSF, macrophage colony-stimulating factor; MMP9, matrix metaloproteinase 9; µCT, microcomputer tomographic; pre-OC, preosteoclast; Pyd, deoxypyridinoline; RAGE, receptor for advanced glycation end products; RANKL, receptor activator of NF-{kappa}B ligand; ROS, reactive oxygen species; TRAP, tartrate-resistant acid phosphatase; TREM, triggering receptors expressed by myeloid cells; TV, tissue volume; VN, vitronectin.


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