Department of Immunology and Physiology, School of Medicine, Konkuk University, Chungju, 380-701, Republic of Korea.
Department of Medicine, University of Connecticut Health Center, 263 Farmington Ave, Farmington, CT, 06030, USA.
Nat Commun. 2017 Nov 15;8(1):1519. doi: 10.1038/s41467-017-01527-y.
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.
核因子-κB 受体激活物配体（RANKL）产生细胞内活性氧（ROS），从而增加破骨细胞（OC）前体细胞骨髓巨噬细胞（BMM）中 RANKL 介导的信号转导。在这里，我们表明，一种 ROS 清除蛋白 DJ-1 负调节 RANKL 驱动的 OC 分化，也称为破骨细胞形成。与野生型 BMM 相比，DJ-1 缺失的小鼠中 RANK 依赖性信号的激活增强。DJ-1 抑制 RANK-TRAF6 和 RANK-FcRγ/Syk 信号通路的激活，因为 Src 同源区域 2 结构域包含磷酸酶-1 的激活被 ROS 抑制。DJ-1 在关节炎和 RANKL 诱导的骨病的小鼠模型中的缺失导致 OC 数量增加，并加剧骨损伤。总的来说，我们的研究结果表明，DJ-1 通过负调节破骨细胞形成在正常生理和与骨相关的病理中发挥作用，维持骨稳态。
