Regulation of osteoclast function and bone mass by RAGE.
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 alphavbeta3 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.
Zhou
Zheng
Z
Institute of Molecular Medicine and Genomics and Department of Neurology, Medical College of Georgia, Augusta, GA, 30912, USA.
Immel
David
D
Xi
Cai-Xia
CX
Bierhaus
Angelika
A
Feng
Xu
X
Mei
Lin
L
Nawroth
Peter
P
Stern
David M
DM
Xiong
Wen-Cheng
WC
D000199:Actins / Q000502:physiology; D000818:Animals; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D003599:Cytoskeleton / Q000502:physiology; D015536:Down-Regulation / Q000502:physiology; D017127:Glycation End Products, Advanced; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000199:Actins; D017127:Glycation End Products, Advanced; D039302:Integrin alphaVbeta3; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; D016173:Macrophage Colony-Stimulating Factor