DJ-1 controls bone homeostasis through the regulation of osteoclast differentiation.

Author(s): Kim HS,  Nam ST,  Mun SH,  Lee SK,  Kim HW,  Park YH,  Kim B,  Won KJ,  Kim HR,  Park YM,  Kim HS,  Beaven MA,  Kim YM,  Choi WS

Journal: Nat Commun

Date: 2017 Nov 15

Major Program(s) or Research Group(s): NSRG

PubMed ID: 29142196

PMC ID: PMC5688089

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.