Osteoprotegerin Is a Receptor for the Cytotoxic Ligand TRAIL

Emery, John G.; McDonnell, Peter; Burke, Michael Brigham; Deen, Keith C.; Lyn, Sally D.; Silverman, Carol; Dul, Edward; Appelbaum, Edward R.; Eichman, Chris; DiPrinzio, Rocco; Dodds, Robert A.; James, Ian E.; Rosenberg, Martin; Lee, John C.; Young, Peter R.

doi:10.1074/jbc.273.23.14363

Cited by 1,078 publications

(831 citation statements)

References 36 publications

(39 reference statements)

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“…Tumor necrosis factor-related apoptosis-inducing ligand also binds to the decoy receptors DcR1 (TRAIL-R3) (Sheridan et al, 1997) and DcR2 (TRAIL-R4) , but these receptors contain either no cytoplasmic death domain or a truncated death domain and, therefore, are unable to induce apoptosis. Finally, TRAIL interacts with osteoprotegerin, a secreted soluble protein; however, the functional significance of this interaction is less clear (Emery et al, 1998). The current model of TRAIL signaling suggests that engagement of death receptors, that is DR4 and DR5, by the ligand leads to a recruitment of the cytoplasmic adapter protein FADD, which in turn activates caspase 8 (Mariani et al, 1997;Walczak et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

2006

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We have previously shown that activation of the acid sphingomyelinase (ASM), the release of ceramide and the formation of ceramide-enriched membrane domains are central for the induction of apoptosis by CD95. Here, we demonstrate that tumor necrosis factor-related apoptosisinducing ligand (TRAIL) and CD95 activate the ASM via a redox mechanism resulting in release of ceramide and formation of ceramide-enriched membrane platforms. Ceramide-enriched membrane platforms serve to cluster DR5 upon stimulation. Antioxidants prevent TRAILmediated stimulation of ASM, the release of ceramide, the formation of ceramide-enriched membrane platforms and the induction of apoptosis by TRAIL. Further, ASMdeficient splenocytes fail to cluster DR5 in ceramideenriched membrane domains upon TRAIL stimulation and resist TRAIL-induced apoptosis, events that were restored by addition of natural C 16 -ceramide. A dose-response analysis indicates that ceramide-enriched membrane platforms greatly sensitized tumor cells to TRAIL-induced apoptosis. Our data indicate that ceramide-enriched membrane platforms are required for the signaling of TRAIL-DR5 complexes under physiological conditions.

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Section: Introductionmentioning

confidence: 99%

TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

2006

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“…To test whether the TRAIL‐induced death of VOT‐33 cells occurred via activation of the TRAIL‐DR5 pathway, we pretreated VOT‐33 cells with OPG that binds TRAIL and prevents TRAIL from binding DR5 (Emery et al ., 1998). TRAIL‐MG132 treatment activated caspase 8, a crucial downstream molecule for TRAIL signal transduction (Crowder and El‐Deiry, 2012), as shown by the presence of cleaved caspase 8 in Western blot (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, OPG was found to interact with another member of the TNF family of cytokines: TNF‐related apoptosis‐inducing ligand (TRAIL). By binding TRAIL, OPG prevents TRAIL from interacting with its receptor and thereby exerts its anti‐apoptosis function (Emery et al ., 1998). These studies have prompted us to explore physiological and pathological roles of TRAIL in the inner ear.…”

Section: Introductionmentioning

confidence: 99%

Activation of TRAIL‐DR5 pathway promotes sensorineural degeneration in the inner ear

et al. 2016

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SummaryTumor necrosis factor (TNF) family cytokines are important mediators of inflammation. Elevated levels of serum TNF‐α are associated with human sensorineural hearing loss via poorly understood mechanisms. We demonstrate, for the first time, expression of TNF‐related apoptosis‐inducing ligand (TRAIL) and its signaling death receptor 5 (DR5) in the murine inner ear and show that exogenous TRAIL can trigger hair cell and neuronal degeneration, which can be partly prevented with DR5‐blocking antibodies.

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“…Inhibition of the RANK/RANKL pathway results in less osteoclast differentiation as well as reduced activation and survival of mature osteoclasts 2, 3. TNF‐related apoptosis‐inducing ligand, a protein that belongs to the TNF superfamily as well, also serves as an osteoprotegerin ligand 4. Osteoprotegerin thereby contributes to maintaining the balance between bone resorption and bone formation 2, 5…”

Section: Introductionmentioning

confidence: 99%

Osteoprotegerin and Cardiovascular Events in High‐Risk Populations: Meta‐Analysis of 19 Prospective Studies Involving 27 450 Participants

Tschiderer

Klingenschmid

Nagrani

et al. 2018

JAHA

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BackgroundOsteoprotegerin is a cytokine involved in bone metabolism as well as vascular calcification and atherogenesis. Although circulating osteoprotegerin levels are robustly associated with incident cardiovascular disease (CVD) in the general population, its relevance as a biomarker among populations at high CVD risk is less clear.Methods and ResultsThree independent reviewers systematically searched PubMed, EMBASE, and Web of Science to identify prospective studies that had recruited participants on the basis of having conditions related to high CVD risk. A total of 19 studies were eligible for inclusion, reporting on 27 450 patients with diabetes mellitus (2 studies), kidney disease (7 studies), preexisting heart disease (5 studies), or recent acute coronary syndromes (5 studies) at baseline. Over a mean follow‐up of 4.2 years, 4066 CVD events were recorded. In a random‐effects meta‐analysis, the pooled risk ratio for CVD events comparing people in the top versus the bottom tertile of osteoprotegerin concentration was 1.30 (95% confidence interval, 1.12–1.50; P<0.001; I2=68.3%). There was evidence for presence of publication bias (P value from Egger's test=0.013). Correction for publication bias using the trim‐and‐fill method reduced the risk ratio to 1.21 (95% confidence interval, 1.03–1.42; P<0.001). The risk ratios did not vary significantly by population type, geographical region, statistical adjustment, sample or assay type, age, sex, or length of follow‐up.ConclusionsIn populations at high CVD risk, elevated circulating osteoprotegerin levels are associated with a higher risk for future CVD events. The magnitude of association appears weaker than in the general population.

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Osteoprotegerin Is a Receptor for the Cytotoxic Ligand TRAIL

Cited by 1,078 publications

References 36 publications

TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

TRAIL activates acid sphingomyelinase via a redox mechanism and releases ceramide to trigger apoptosis

Activation of TRAIL‐DR5 pathway promotes sensorineural degeneration in the inner ear

Osteoprotegerin and Cardiovascular Events in High‐Risk Populations: Meta‐Analysis of 19 Prospective Studies Involving 27 450 Participants

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