Def6 Restrains Osteoclastogenesis and Inflammatory Bone Resorption

Binder, Nikolaus B.; Miller, Christine H.; Yoshida, Masaki; Inoue, Kenzo; Nakano, Shinichi; Hu, Xiaoyu; Ivashkiv, Lionel B.; Schett, Georg; Pernis, Alessandra B.; Goldring, Steven R.; Ross, F. Patrick; Zhao, Baohong

doi:10.4049/jimmunol.1601716

Cited by 14 publications

(27 citation statements)

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“…6 ), suggesting a positive regulatory role of miR-182 in osteoclastogenesis and bone resorption under inflammatory conditions. To further test this hypothesis in vivo, we first used a well-established inflammatory calvarial osteolysis mouse model induced by TNF-α or lipopolysaccharides (LPS) 42 – 46 . Phosphate buffered saline (PBS) injection as a negative control did not induce resorptive pit formation on the calvarial bone surfaces (data not shown).…”

Section: Resultsmentioning

confidence: 99%

“…4d ). Previous literature demonstrates that interferon pathway (IFN α, β, or γ) inhibits osteoclast differentiation 42 , 44 , 51 , 52 . The endogenous IFN-β induction by RANKL in osteoclasts is an important inhibitory feedback loop to maintain a balanced differentiation state 44 , 52 .…”

Section: Resultsmentioning

confidence: 99%

“…For inflammatory osteolysis experiments, we used the established LPS-induced or TNF-induced supracalvarial osteolysis mouse model 42 – 46 with minor modifications. LPS was administrated at the dose of 12.5 mg/kg weight to the calvarial periosteum of age and gender-matched mice.…”

Section: Methodsmentioning

confidence: 99%

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Bone protection by inhibition of microRNA-182

et al. 2018

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Targeting microRNAs recently shows significant therapeutic promise; however, such progress is underdeveloped in treatment of skeletal diseases with osteolysis, such as osteoporosis and rheumatoid arthritis (RA). Here, we identified miR-182 as a key osteoclastogenic regulator in bone homeostasis and diseases. Myeloid-specific deletion of miR-182 protects mice against excessive osteoclastogenesis and bone resorption in disease models of ovariectomy-induced osteoporosis and inflammatory arthritis. Pharmacological treatment of these diseases with miR-182 inhibitors completely suppresses pathologic bone erosion. Mechanistically, we identify protein kinase double-stranded RNA-dependent (PKR) as a new and essential miR-182 target that is a novel inhibitor of osteoclastogenesis via regulation of the endogenous interferon (IFN)-β-mediated autocrine feedback loop. The expression levels of miR-182, PKR, and IFN-β are altered in RA and are significantly correlated with the osteoclastogenic capacity of RA monocytes. Our findings reveal a previously unrecognized regulatory network mediated by miR-182-PKR-IFN-β axis in osteoclastogenesis, and highlight the therapeutic implications of miR-182 inhibition in osteoprotection.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Bone protection by inhibition of microRNA-182

et al. 2018

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“…Meanwhile, intrinsic anti-osteoclastogenic mechanisms mediated by negative regulators, such as interferon regulatory factor (IRF8), v-maf musculoaponeurotic fibrosarcoma oncogene family protein B (MafB) and differentially expressed in FDCP 6 homolog (Def6), provide "a braking system" to prevent excessive osteoclastogenesis and bone resorption. 6,[8][9][10][11][12][13][14][15][16] These mechanisms can interact with each other and form regulatory networks to coordinately control osteoclastogenesis. Identification of these networks will broaden and deepen our understanding of the mechanisms that control osteoclastogenesis and bone metabolism, and help establish optimal and potential novel therapeutic strategies.…”

Section: Introductionmentioning

confidence: 99%

Regulatory network mediated by RBP‐J/NFATc1‐miR182 controls inflammatory bone resorption

Inoue

Zhao

2019

FASEB j.

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Abbreviations: Blimp1, B lymphocyte-induced maturation protein-1; BMM, bone marrow-derived macrophage; ChIP, chromatin immunoprecipitation; FAIRE, formaldehyde-assisted isolation of regulatory elements; FOXO3, Forkhead box class O 3; MNC, multinucleated cell; M-CSF, macrophage colony-stimulating factor; NFATc1, nuclear factor of activated T cells c1; PBMCs, peripheral blood monocytes; PKR, protein kinase double-stranded RNA dependent; RA, rheumatoid arthritis; RANKL, receptor activator for NF-kB ligand; RBP-J, recombination signal binding protein for immunoglobulin kappa J region; TNFα, tumor necrosis factor-α; TNFi, TNF inhibitor; TRAP, tartrate-resistant acid phosphatase; WT, wild-type; μCT, microcomputed tomography. AbstractBone resorption is a severe consequence of inflammatory diseases associated with osteolysis, such as rheumatoid arthritis (RA), often leading to disability in patients.In physiological conditions, the differentiation of bone-resorbing osteoclasts is delicately regulated by the balance between osteoclastogenic and anti-osteoclastogenic mechanisms. Inflammation has complex impact on osteoclastogenesis and bone destruction, and the underlying mechanisms of which, especially feedback inhibition, are underexplored. Here, we identify a novel regulatory network mediated by RBP-J/NFATc1-miR182 in TNF-induced osteoclastogenesis and inflammatory bone resorption. This network includes negative regulator RBP-J and positive regulators, NFATc1 and miR182, of osteoclast differentiation. In this network, miR182 is a direct target of both RBP-J and NFATc1. RBP-J represses, while NFATc1 activates miR182 expression through binding to specific open chromatin regions in the miR182 promoter. Inhibition of miR182 by RBP-J servers as a critical mechanism that limits TNF-induced osteoclast differentiation and inflammatory bone resorption. Inflammation, such as that which occurs in RA, shifts the expression levels of the components in this network mediated by RBP-J/NFATc1-miR182-FoxO3/ PKR (previously identified miR182 targets) towards more osteoclastogenic, rather than healthy conditions. Treatment with TNF inhibitors in RA patients reverses the expression changes of the network components and osteoclastogenic potential. Thus, this network controls the balance between activating and repressive signals that determine the extent of osteoclastogenesis. These findings collectively highlight the biological significance and translational implication of this newly identified intrinsic regulatory network in inflammatory osteoclastogenesis and osteolysis. K E Y W O R D Sinflammatory bone resorption, osteoclast, osteoimmunology, rheumatoid arthritis | 2393 INOUE Et al.

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“…Irisin increases cortical bone mass and its low levels are related to muscle atrophy and obesity[, 1, 2 while myostatin is a negative regulator of muscle growth and regeneration and has a direct role in osteoclastogenesis of inflammatory bone destruction[. 3,4 Objectives: To evaluate serum levels of irisin and myostatin and body composition of RA patients and controls. Methods: 122 female patients with RA, mean age 53 years, mean disease activity score (DAS28) 4.09, mean disease duration 11.2 years and mean body mass index 27.33 kg/m 2 were included.…”

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THU0082 Impaired left ventricular relaxation and its association with inflammatory markers in collagen-induced arthritis

Mokotedi

Michel

Mogane

et al. 2018

Thursday, 14 June 2018

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BackgroundPatients with rheumatoid arthritis (RA) experience an increased risk of developing heart failure with a preserved ejection fraction. Although there is some evidence to support a role of chronic inflammation in the pathogenesis of impaired left ventricular (LV) function in RA,1 the direct effects of inflammatory cytokines on the LV function in collagen-induced arthritis (CIA) (an experimental model most similar to RA) require further elucidation.ObjectivesThe aim of this study was to determine LV systolic and diastolic function and their association with circulating inflammatory markers in CIA.MethodsMale Sprague Dawley rats were randomly divided into two groups: a control group (n=12) and a collagen-induced arthritis group (CIA, n=21). Rats in the CIA group were immunised with 0.2 ml type-II bovine collagen emulsified in incomplete Freund’s adjuvant at the base of the tail followed by a 0.1 ml booster injection 7 days later. Eight weeks post-immunisation, markers of LV systolic function and geometry including ejection fraction (EF), fractional shortening (FS), stroke volume (SV) and LV end systolic diameter (ESD) were assessed echocardiographically using two-dimensional directed M-mode imaging. Markers of LV diastolic function including the early-to-late diastolic filling velocity ratio (E/A), the lateral (Lat e’) and septal (Sep e’) wall myocardial tissue lengthening at the mitral annulus and the ratio between early mitral inflow velocity and mitral annular early diastolic velocity (E/e’) were assessed using pulsed Doppler and tissue Doppler echocardiography. Serum concentrations of interleukin 6 (IL-6), interleukin 1β (IL-1β), tumour necrosis factor alpha (TNF-α) and C-reactive protein (CRP) were determined by an enzyme-linked immunosorbent assay.ResultsNo significant differences in markers of systolic function or geometry (EF, FS, SV and ESD) were observed between the groups (p>0.05). Compared to the control group, E/A (control=2.17±0.39; CIA=1.46±0.46; p=0.0001) and Sep e’ (control=3.75±0.69; CIA=3.23±0.47; p=0.04) were lower in the CIA group. By contrast, E/e’ (control=29.94±6.99; CIA=24.17±8.49; p=0.13) and Lat e’ (control=3.99±0.43; CIA=3.79±0.78; p=0.31) did not differ amongst the two groups. IL-6 (115±70.09 versus 365.3±88.96 pg/mL; p<0.0001), IL-1β (14.1±55.7 versus 238.6±49.01 pg/mL; p<0.0001), TNF-α (293.5±87.16 versus 626.0±119.7 pg/mL; p<0.0001) and CRP concentrations (0.23±0.34 versus 0.97±0.35 ng/mL; p<0.0001) were higher in the CIA compared to control group. A lower E/A was associated with TNF-α (r=−0.63; p=0.0003), IL-6 (−0.56; p=0.0001), IL-1β (r=−0.48; p=0.001) and CRP concentrations (r=−0.60; p=0.001) in the total sample. Lower TNF-α (r=−0.39 p=0.04) and IL-1β (r=−0.47, p=0.01) levels were associated with E/e’ in the total sample.ConclusionsDiastolic function is impaired in male Sprague Dawley rats with CIA. Our results indicate that exposure to high grade inflammation can reduce LV relaxation without impairing systolic function in CIA. Markers of inflammation were also associated wi...

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Def6 Restrains Osteoclastogenesis and Inflammatory Bone Resorption

Cited by 14 publications

References 60 publications

Bone protection by inhibition of microRNA-182

Bone protection by inhibition of microRNA-182

Regulatory network mediated by RBP‐J/NFATc1‐miR182 controls inflammatory bone resorption

THU0082 Impaired left ventricular relaxation and its association with inflammatory markers in collagen-induced arthritis

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