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Abstract
Receptor activator of NF-kB ligand (RANKL) generates intracellular reactive oxygen species (ROS), which increase RANKL-mediated signaling in osteoclast (OC) precursor bone marrow macrophages (BMMs). Here we show that a ROS scavenging protein DJ-1 negatively regulates RANKL-driven OC differentiation, also called osteoclastogenesis. DJ-1 ablation in mice leads to a decreased bone volume and an increase in OC numbers. In vitro, the activation of RANK-dependent signals is enhanced in DJ-1-deficient BMMs as compared to wild-type BMMs. DJ-1 suppresses the activation of both RANK-TRAF6 and RANK-FcRγ/Syk signaling pathways because of activation of Src homology region 2 domain-containing phosphatase-1, which is inhibited by ROS. Ablation of DJ-1 in mouse models of arthritis and RANKL-induced bone disease leads to an increase in the number of OCs, and exacerbation of bone damage. Overall, our results suggest that DJ-1 plays a role in bone homeostasis in normal physiology and in bone-associated pathology by negatively regulating osteoclastogenesis.
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Details
1 Department of Immunology and Physiology, School of Medicine, Konkuk University, Chungju, Republic of Korea
2 Department of Immunology and Physiology, School of Medicine, Konkuk University, Chungju, Republic of Korea; Department of Medicine, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT, USA
3 Department of Medicine, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT, USA
4 Department of Rheumatology, School of Medicine, Konkuk University, Chungju, Republic of Korea
5 Department of Toxicology, School of Pharmacy, Sungkyunkwan University, Suwon, Republic of Korea
6 Laboratory of Molecular Immunology, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA
7 Department of Preventive Pharmacy, College of Pharmacy, Duksung Women’s University, Seoul, Republic of Korea