HMGB1 regulates RANKL-induced osteoclastogenesis in a manner dependent on RAGE.
High-mobility group box 1 (HMGB1), a nonhistone nuclear protein, is released by macrophages into the extracellular milieu consequent to cellular activation. Extracellular HMGB1 has properties of a pro-inflammatory cytokine through its interaction with receptor for advanced glycation endproducts (RAGE) and/or toll-like receptors (TLR2 and TLR4). Although HMGB1 is highly expressed in macrophages and differentiating osteoclasts, its role in osteoclastogenesis remains largely unknown. In this report, we present evidence for a function of HMGB1 in this event. HMGB1 is released from macrophages in response to RANKL stimulation and is required for RANKL-induced osteoclastogenesis in vitro and in vivo. In addition, HMGB1, like other osteoclastogenic cytokines (e.g., TNFalpha), enhances RANKL-induced osteoclastogenesis in vivo and in vitro at subthreshold concentrations of RANKL, which alone would be insufficient. The role of HMGB1 in osteoclastogenesis is mediated, in large part, by its interaction with RAGE, an immunoglobin domain containing family receptor that plays an important role in osteoclast terminal differentiation and activation. HMGB1-RAGE signaling seems to be important in regulating actin cytoskeleton reorganization, thereby participating in RANKL-induced and integrin-dependent osteoclastogenesis. Taken together, these observations show a novel function of HMGB1 in osteoclastogenesis and provide a new link between inflammatory mechanisms and bone resorption.
Zhou
Zheng
Z
Institute of Molecular Medicine and Genomics and Department of Neurology, Medical College of Georgia, Augusta, Georgia GA 30912, USA.
Han
Jun-Yan
JY
Xi
Cai-Xia
CX
Xie
Jian-Xin
JX
Feng
Xu
X
Wang
Cong-Yi
CY
Mei
Lin
L
Xiong
Wen-Cheng
WC
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D002455:Cell Division / Q000502:physiology*; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D024243:HMGB1 Protein / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology*; D053245:RANK Ligand / Q000502:physiology*; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000502:physiology*
D017931:DNA Primers; D024243:HMGB1 Protein; D053245:RANK Ligand; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic; C505689:Tnfsf11 protein, mouse