Influence of RANKL inhibition on immune system in the treatment of bone diseases

Fouque-Aubert, Anne; Chapurlat, Roland

doi:10.1016/j.jbspin.2007.05.004

Cited by 40 publications

(26 citation statements)

References 41 publications

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“…The OPG/RANKL/RANK axis has been shown to have pleiotropic effects on both bone metabolism [32] and the immune system [33], and was recently implicated in the development of atherosclerotic disorders [34]. To our knowledge, the present study is the first report of dysregulated OPG levels in COPD.…”

Section: Discussionmentioning

confidence: 58%

Systemic inflammatory markers in COPD: results from the Bergen COPD Cohort Study

Eagan¹,

Ueland²,

Wagner³

et al. 2009

European Respiratory Journal

172

161

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Chronic obstructive pulmonary disease (COPD) is considered an inflammatory pulmonary disorder with systemic inflammatory manifestations. The aim of this study was to assess the systemic levels of six inflammatory mediators in a large cohort of COPD patients and controls.409 COPD patients and 231 healthy subjects, aged 40-75 yrs, were included from the first phase of the Bergen COPD Cohort Study. All COPD patients were clinically diagnosed by a physician, and had a forced expiratory volume in 1 s/forced vital capacity ratio less than 0.7 and a smoking history of .10 pack-yrs. The plasma levels of C-reactive protein (CRP), soluble tumour necrosis factor receptor (sTNFR)-1, osteoprotegrin, neutrophil activating peptide-2, CXCL16 and monocyte chemoattractant protein-4 were determined by ELISA.After adjustment for all known confounders, COPD patients had significantly lower levels of osteoprotegrin than subjects without COPD (p,0.05), and higher levels of CRP (p,0.01). Among COPD patients, CRP was elevated in patients with frequent exacerbations (p,0.05). sTNFR-1 and osteoprotegrin were both related to Global Initiative for Chronic Obstructive Lung Disease stage and frequency of exacerbations in the last 12 months (p,0.05). In addition, sTNFR-1 was significantly associated with important comorbidities such as hypertension and depression (p,0.05).The present study confirms that certain circulating inflammatory mediators are an important phenotypic feature of COPD.

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Section: Discussionmentioning

confidence: 58%

Systemic inflammatory markers in COPD: results from the Bergen COPD Cohort Study

Eagan¹,

Ueland²,

Wagner³

et al. 2009

European Respiratory Journal

172

161

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“…Because the RANKL/RANK/OPG axis not only plays a pivotal role in osteoclast formation and function (19) but is also involved in other biological processes such as dendritic cell survival and activation (47), T cell activation (48), and B cell differentiation (48), use of agents that function to inhibit RANKL-RANK interaction may cause deleterious effects on immune responses (49). Previously, we demonstrated that the IVVY motif plays an essential role in RANKL-mediated osteoclastogenesis by committing BMMs into the osteoclast lineage (14).…”

Section: Discussionmentioning

confidence: 99%

Receptor Activator of NF-κB (RANK) Cytoplasmic IVVY535–538 Motif Plays an Essential Role in Tumor Necrosis Factor-α (TNF)-mediated Osteoclastogenesis

Jules

Shi

Liu

et al. 2010

Journal of Biological Chemistry

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Tumor necrosis factor-␣ (TNF) enhances osteoclast formation and activity leading to bone loss in various pathological conditions, but its precise role in osteoclastogenesis remains controversial. Although several groups showed that TNF can promote osteoclastogenesis independently of the receptor activator of NF-B (RANK) ligand (RANKL), others demonstrated that TNF-mediated osteoclastogenesis needs permissive levels of RANKL. Here, we independently reveal that although TNF cannot stimulate osteoclastogenesis on bone slices, it can induce the formation of functional osteoclasts on bone slices in the presence of permissive levels of RANKL or from bone marrow macrophages (BMMs) pretreated by RANKL. TNF can still promote the formation of functional osteoclasts 2 days after transient RANKL pretreatment. These data have confirmed that TNF-mediated osteoclastogenesis requires priming of BMMs by RANKL. Moreover, we investigated the molecular mechanism underlying the dependence of TNF-mediated osteoclastogenesis on RANKL. RANK, the receptor for RANKL, contains an IVVY 535-538 motif that has been shown to play a vital role in osteoclastogenesis by committing BMMs to the osteoclast lineage. We show that TNF-induced osteoclastogenesis depends on RANKL to commit BMMs to the osteoclast lineage and RANKL regulates the lineage commitment through the IVVY motif. Mechanistically, the IVVY motif controls the lineage commitment by reprogramming osteoclast genes into an inducible state in which they can be activated by TNF. Our findings not only provide important mechanistic insights into the action of RANKL in TNF-mediated osteoclastogenesis but also establish that the IVVY motif may serve as an attractive therapeutic target for bone loss in various bone disorders.TNF, a proinflammatory cytokine produced by many cells including fibroblasts, endothelial cells, and macrophages, plays a critical role in immune and inflammatory responses (1). Consequently, aberration in TNF expression and function has been associated with many autoimmune disorders and inflammatory complications (2). Moreover, this potent proinflammatory cytokine has also been shown to be a pro-osteoclastogenic factor and thus promotes bone loss in postmenopausal osteoporosis (3) and inflammatory conditions such as rheumatoid arthritis (4) and periodontitis (5) by stimulating osteoclast formation and function.Osteoclasts, the sole bone-resorbing cells in the body, are multinucleated giant cells derived from mononuclear cells of the monocyte-macrophage lineage upon stimulation by the macrophage/monocyte colony-stimulating factor (M-CSF) 2 and RANKL (6). RANKL (also known as OPGL, ODF, and TRANCE), identified as a member of the TNF superfamily (7, 8), stimulates osteoclast formation and function by activating its receptor RANK, a member of the TNF receptor (TNFR) superfamily (8). RANKL also has a soluble decoy receptor, osteoprotegerin (OPG), which inhibits RANKL functions by competing with RANK for binding RANKL (9). Members of the TNFR superfamily primarily employ TNF re...

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“…Given that RANK signaling has been shown to be an important regulator of dendritic cell survival and activation, T-cell activation, and Bcell differentiation, the possibility that total RANK inhibition may perturb immune responses may preclude such an approach. 20,41,42 Our goal is to identify small molecule inhibitors of downstream RANK signaling that is essential to osteoclastogenesis. Such inhibitors could have the potency of total RANK inhibition, but because small molecules are relatively less expensive to produce than peptides, they would be more affordable than antibody therapy.…”

Section: Discussionmentioning

confidence: 99%

“…20 As such, while targeting the RANKL-RANK interaction is a viable means for reducing bone resorption, a better approach would be to target individual RANK signaling pathways that are more specific to osteoclast formation and function. RANK was identified as a member of the tumor necrosis factor receptor (TNFR) superfamily.…”

mentioning

confidence: 99%

Development of Cell-Based High-Throughput Assays for the Identification of Inhibitors of Receptor Activator of Nuclear Factor-Kappa B Signaling

Ashley

McCoy²,

Clements³

et al. 2011

ASSAY and Drug Development Technologies

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Bone loss due to metabolic or hormonal disorders and osteolytic tumor metastasis continues to be a costly health problem, but current therapeutics offer only modest efficacy. Unraveling of the critical role for the receptor activator of nuclear factor-kappa B (RANK) and its ligand, RANK ligand (RANKL), in osteoclast biology provides an opportunity to develop more effective antiresorptive drugs. The in vivo effectiveness of RANKL inhibitors demonstrates the potency of the RANKL/RANK system as a drug target. Here, we report the development of cell-based assays for high-throughput screening to identify compounds that inhibit signaling from two RANK cytoplasmic motifs (PVQEET 559-564 and PVQEQG [604][605][606][607][608][609] ), which play potent roles in osteoclast formation and function. Inhibitors of these motifs' signaling have the potential to be developed into new antiresorptive drugs that can complement current therapies. The cell-based assays consist of cell lines generated from RAW264.7 macrophages stably expressing a nuclear factor-kappa Bresponsive luciferase reporter and a chimeric receptor containing the human Fas external domain linked to a murine RANK transmembrane and intracellular domain in which only one of the RANK motifs is functional. With these cells, specific RANK motif activation after chimeric receptor stimulation can be measured as an increase in luciferase activity. These assays demonstrated >300% increases in luciferase activity after RANK motif activation and Z ¢ -factor values over 0.55. Our assays will be used to screen compound libraries for molecules that exhibit inhibitory activity. Follow-up assays will refine hits to a smaller group of more specific inhibitors of RANK signaling.

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Influence of RANKL inhibition on immune system in the treatment of bone diseases

Cited by 40 publications

References 41 publications

Systemic inflammatory markers in COPD: results from the Bergen COPD Cohort Study

Systemic inflammatory markers in COPD: results from the Bergen COPD Cohort Study

Receptor Activator of NF-κB (RANK) Cytoplasmic IVVY535–538 Motif Plays an Essential Role in Tumor Necrosis Factor-α (TNF)-mediated Osteoclastogenesis

Development of Cell-Based High-Throughput Assays for the Identification of Inhibitors of Receptor Activator of Nuclear Factor-Kappa B Signaling

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