Contradictory Role of CD97 in Basal and Tumor Necrosis Factor–Induced Osteoclastogenesis In Vivo

Won, Hee Yeon; Mun, Se Hwan; Shin, Bongjin; Lee, Sun Kyeong

doi:10.1002/art.39538

Cited by 14 publications

(12 citation statements)

References 61 publications

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“…1 ). This was not surprising, as we and others have previously observed in several gene-inactivated KO mice model that those animals exhibited a sex-specific bone phenotype at the same age examined in this study 50 – 52 . While male mice showed changes in the trabecular and cortical bone, female mice showed none (Fig.…”

Section: Discussionsupporting

confidence: 88%

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

et al. 2017

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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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Section: Discussionsupporting

confidence: 88%

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

et al. 2017

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“…However, at 8 weeks of age, we observed the increased trabecular bone phenotype only in female in Srgap2‐cKO mice. Sex‐restricted phenotypes in genetic mouse models are not uncommon . Skeletal sexual dimorphism depends not only on androgen action in males and estrogen action in females, but also on complex sex‐specific and time‐specific interactions between sex hormones, the growth hormone/insulin‐like growth factor‐1 (GH/IGF‐1) axis, and mechanical loading.…”

Section: Discussionmentioning

confidence: 99%

Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3

Shin

Kupferman

Schmidt

et al. 2019

Journal of Bone and Mineral Research

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The Rac1‐specific guanosine triphosphatase (GTPase)‐activating protein Slit‐Robo GAP2 (Srgap2) is dramatically upregulated during RANKL‐induced osteoclastogenesis. Srgap2 interacts with the cell membrane to locally inhibit activity of Rac1. In this study, we determined the role of Srgap2 in the myeloid lineage on bone homeostasis and the osteoclastic response to TNFα treatment. The bone phenotype of mice specifically lacking Srgap2 in the myeloid lineage (Srgap2 f/f:LysM‐Cre; Srgap2 conditional knockout [cKO]) was investigated using histomorphometric analysis, in vitro cultures and Western blot analysis. Similar methods were used to determine the impact of TNFα challenge on osteoclast formation in Srgap2 cKO mice. Bone parameters in male Srgap2 cKO mice were unaffected. However, female cKO mice displayed higher trabecular bone volume due to increased osteoblast surface and bone formation rate, whereas osteoclastic parameters were unaltered. In vitro, cells from Srgap2 cKO had strongly enhanced Rac1 activation, but RANKL‐induced osteoclast formation was unaffected. In contrast, conditioned medium from Srgap2 cKO osteoclasts promoted osteoblast differentiation and had increased levels of the bone anabolic clastokine SLIT3, providing a possible mechanism for increased bone formation in vivo. Rac1 is rapidly activated by the inflammatory cytokine TNFα. Supracalvarial injection of TNFα caused an augmented osteoclastic response in Srgap2 cKO mice. In vitro, cells from Srgap2 cKO mice displayed increased osteoclast formation in response to TNFα. We conclude that Srgap2 plays a prominent role in limiting osteoclastogenesis during inflammation through Rac1, and restricts expression of the paracrine clastokine SLIT3, a positive regulator of bone formation. © 2019 American Society for Bone and Mineral Research.

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“…Two days after the second injection, femurs were collected, fixed in 4% paraformaldehyde, embedded in OCT compound (Thermo Fisher Scientific, Whaltham, MA), and then cut into 7 μm sections, as described previously (16). Histomorphometry analysis using Osteometric software (Osteomeasure) was performed on trabecular bone within the femur metaphysis.…”

Section: Methodsmentioning

confidence: 99%

Cutting Edge: EZH2 Promotes Osteoclastogenesis by Epigenetic Silencing of the Negative Regulator IRF8

Fang

Qiao

Mun

et al. 2016

The Journal of Immunology

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Osteoclasts are resorptive cells important for homeostatic bone remodeling and pathological bone resorption. Emerging evidence suggests an important role for epigenetic mechanisms in osteoclastogenesis. A recent study showed that epigenetic silencing of the negative regulator of osteoclastogenesis Irf8 by DNA methylation is required for osteoclast differentiation. In this study, we investigated the role of EZH2, which epigenetically silences gene expression by histone methylation, in osteoclastogenesis. Inhibition of EZH2 by the small molecule GSK126, or decreasing its expression using antisense oligonucleotides, impeded osteoclast differentiation. Mechanistically, EZH2 was recruited to the IRF8 promoter after RANKL stimulation to deposit the negative histone mark H3K27me3 and downregulate IRF8 expression. GSK126 attenuated bone loss in the ovariectomy mouse model of postmenopausal osteoporosis. Our findings provide evidence for an additional mechanism of epigenetic IRF8 silencing during osteoclastogenesis that likely works cooperatively with DNA methylation, further emphasizing the importance of IRF8 as a negative regulator of osteoclastogenesis.

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Contradictory Role of CD97 in Basal and Tumor Necrosis Factor–Induced Osteoclastogenesis In Vivo

Cited by 14 publications

References 61 publications

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

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

Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3

Cutting Edge: EZH2 Promotes Osteoclastogenesis by Epigenetic Silencing of the Negative Regulator IRF8

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