The long-term goal of this proposal is to understand molecular mechanisms of bone resorption, a process that requires osteoclast (OC) differentiation and activation, and is altered in multiple bone disorders such as osteopetrosis and osteoporosis. OC differentiation is regulated by several factors, including M-CSF (macrophage-colony stimulating factor) and RANKL (receptor activator of NF-kB ligand). OC activation is initiated by cell adhesion to the bone surface. Although molecular mechanisms of OC differentiation and activation have been extensively studied, modulation of these processes in bone loss-associated diseases (e.g., diabetes) remains largely unknown. The receptor for advanced glycation end products (RAGE), a member of the immunoglobin superfamily of cell surface receptors, has been implicated in the pathogenesis of age-related and/or bone loss-associated disorders, including diabetic complications, neurodegeneration, and inflammatory disorders. The link between RAGE and these pathologic situations is the multi-ligand character of the receptor and its ability to induce sustained cellular activation. Ligands of RAGE include (but are not limited to) diabetes-associated AGEs (advanced glycation endproducts) and proinflammatory cytokines of the S100 family and HMGB1. In preliminary studies, we present evidence for a role of RAGE and its ligand HMGB1 in OC differentiation and function with consequences for bone remodeling. Based on our preliminary results and in light of a potential role of RAGE in age-associated bone loss, we hypothesize that HMGB1-RAGE signaling is involved in RANKL induced OC differentiation and function, contributing to bone-loss associated disorders, such as diabetes.
Three aims are proposed to test this hypothesis.
Aim 1. To investigate mechanisms by which RAGE regulates OC maturation and function.
Aim 2. To further investigate the role of HMGB1, as an autocrine ligand of RAGE, in the regulating OC differentiation and function.
Aim 3. To determine the role of RAGE in diabetes-associated bone loss. Our ability to test this hypothsis is facilitated by access to RAGE mutant mice and innovative collaboration among experts in RAGE signaling transduction and osteoclast biology at MCG. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR048120-07
Application #
7491157
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Sharrock, William J
Project Start
2001-10-01
Project End
2012-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
7
Fiscal Year
2008
Total Cost
$309,729
Indirect Cost
Name
Georgia Regents University
Department
Neurology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
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Xiong, Fei; Leonov, Sergey; Howard, Amber Cyan et al. (2011) Receptor for advanced glycation end products (RAGE) prevents endothelial cell membrane resealing and regulates F-actin remodeling in a beta-catenin-dependent manner. J Biol Chem 286:35061-70
Cui, Shun; Xiong, Fei; Hong, Yan et al. (2011) APPswe/A? regulation of osteoclast activation and RAGE expression in an age-dependent manner. J Bone Miner Res 26:1084-98
Zhou, Zheng; Xie, Jianxin; Lee, Daehoon et al. (2010) Neogenin regulation of BMP-induced canonical Smad signaling and endochondral bone formation. Dev Cell 19:90-102
Xi, Cai-Xia; Xiong, Fei; Zhou, Zheng et al. (2010) PYK2 interacts with MyD88 and regulates MyD88-mediated NF-kappaB activation in macrophages. J Leukoc Biol 87:415-23
Zhou, Zheng; Han, Jun-Yan; Xi, Cai-Xia et al. (2008) HMGB1 regulates RANKL-induced osteoclastogenesis in a manner dependent on RAGE. J Bone Miner Res 23:1084-96
Xie, Yi; Hong, Yan; Ma, Xiao-Yue et al. (2006) DCC-dependent phospholipase C signaling in netrin-1-induced neurite elongation. J Biol Chem 281:2605-11
Xie, Yi; Ding, Yu-Qiang; Hong, Yan et al. (2005) Phosphatidylinositol transfer protein-alpha in netrin-1-induced PLC signalling and neurite outgrowth. Nat Cell Biol 7:1124-32
Wu, Xiaojun; Pan, George; McKenna, Margaret A et al. (2005) RANKL regulates Fas expression and Fas-mediated apoptosis in osteoclasts. J Bone Miner Res 20:107-16
Xiong, Wen-Cheng; Mei, Lin (2003) Roles of FAK family kinases in nervous system. Front Biosci 8:s676-82

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