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

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-FcR?/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.

SUBMITTER: Kim HS

PROVIDER: S-EPMC5688089 | biostudies-other | 2017 Nov

REPOSITORIES: biostudies-other

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

Kim Hyuk Soon HS Nam Seung Taek ST Mun Se Hwan SH Lee Sun-Kyeong SK Kim Hyun Woo HW Park Young Hwan YH Kim Bokyung B Won Kyung-Jong KJ Kim Hae-Rim HR Park Yeong-Min YM Kim Hyung Sik HS Beaven Michael A MA Kim Young Mi YM Choi Wahn Soo WS

Nature communications 20171115 1

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 ...[more]

PMID: 29142196

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Project description:Osteoclast lineage commitment and differentiation have been studied extensively, although the mechanism by which transcription factor(s) control osteoclast terminal differentiation, activation, and function remains unclear. CCAAT/enhancer-binding protein ? (C/ebp?) has been reported to be a key regulator of osteoclast cell lineage commitment, yet C/ebp?'s roles in osteoclast terminal differentiation, activation and function, and bone homeostasis, under physiological or pathological conditions, have not been studied because newborn C/ebp?-null mice die within several hours after birth. Furthermore, the function of C/ebp? in osteoclast terminal differentiation, activation, and function is largely unknown. Herein, we generated and analyzed an osteoclast-specific C/ebp? conditional knockout (CKO) mouse model via Ctsk-Cre mice and found that C/ebp?-deficient mice exhibited a severe osteopetrosis phenotype due to impaired osteoclast terminal differentiation, activation, and function, including mildly reduced osteoclast number, impaired osteoclast polarization, actin formation, and bone resorption, which demonstrated the novel function of C/ebp? in cell function and terminal differentiation. Interestingly, C/ebp? deficiency did not affect bone formation or monocyte/macrophage development. Our results further demonstrated that C/ebp? deficiency suppressed the expression of osteoclast functional genes, e.g. encoding cathepsin K (Ctsk), Atp6i (Tcirg1), and osteoclast regulator genes, e.g. encoding c-fos (Fos), and nuclear factor of activated T-cells 1 (Nfatc1), while having no effect on Pu.1 (Spi1) expression. Promoter activity mapping and ChIP assay defined the critical cis-regulatory element (CCRE) in the promoter region of Nfatc1, and also showed that the CCREs were directly associated with C/ebp?, which enhanced the promoter's activity. The deficiency of C/ebp? in osteoclasts completely blocked ovariectomy-induced bone loss, indicating that C/ebp? is a promising new target for the treatment of osteolytic diseases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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

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

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