Functional Dissection of Osteoprotegerin and Its Interaction with Receptor Activator of NF-κB Ligand

Schneeweis, Lumelle A.; Willard, Derril H.; Milla, Marcos E.

doi:10.1074/jbc.m506366200

Cited by 109 publications

(91 citation statements)

References 35 publications

(36 reference statements)

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“…As for the DDHDs, it is reported that the DDHDs contribute to the dimer stability of OPG based on a comparison of OPG-CRD (¼ only CRD) protein and OPG-DHBD (¼ CRD þ DDHD) protein. (29) Considering this and the results of our coexpression experiments in HeLa cells using OPG-CRD (RANKL; plasma membrane), OPG-CRD-Fc (RANKL; plasma membrane), and OPG-DHBD (RANKL; Golgi apparatus), it appears that the DDHDs also contribute to the regulation of RANKL subcellular trafficking, which is not fully explained by the function of the DDHDs of stabilizing OPG dimer conformation. In addition, we also have shown that RANK-CRD-OPG-DCRD was not able to lead RANKL to lysosomes efficiently (Fig.…”

Section: Discussionmentioning

confidence: 73%

“…A previous report showed that DDHDs and HBD of OPG contribute to the noncovalent dimerization of OPG, (29) and thus the structural integrity was not considered to be affected when C400 was substituted with a serine residue. The results of the experiments using the various OPG mutants are summarized in Fig.…”

Section: Rankl Localization Is Affected By Coexpression Of Opg In Nonmentioning

confidence: 99%

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Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

Aoki

Honma

Kariya

et al. 2010

Journal of Bone and Mineral Research

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The amount of the receptor activator of NF-kB ligand (RANKL) on the osteoblastic cell surface is considered to determine the magnitude of the signal input to osteoclast precursors and the degree of osteoclastogenesis. Previously, we have shown that RANKL is localized predominantly in lysosomal organelles, but little is found on the osteoblastic cell surface, and consequently, the regulated subcellular trafficking of RANKL in osteoblastic cells is important for controlled osteoclastogenesis. Here we have examined the involvement of osteoprotegerin (OPG), which is currently recognized as a decoy receptor for RANKL, in the regulation of RANKL behavior. It was suggested that OPG already makes a complex with RANKL in the Golgi apparatus and that the complex formation is necessary for RANKL sorting to the secretory lysosomes. It was also shown that each structural domain of OPG is indispensable for exerting OPG function as a traffic regulator. In particular, the latter domains of OPG, whose physiologic functions have been unclear, were indicated to sort RANKL molecules to lysosomes from the Golgi apparatus. In addition, the overexpression of RANK-OPG chimeric protein, which retained OPG function as a decoy receptor but lost the function as a traffic regulator, inhibited endogenous OPG function as a traffic regulator selectively in osteoblastic cells and resulted in the upregulation of osteoclastogenic ability despite the increased number of decoy receptor molecules. Conclusively, OPG function as a traffic regulator for RANKL is crucial for regulating osteoclastogenesis at least as well as that as a decoy receptor. ß

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Section: Discussionmentioning

confidence: 73%

Section: Rankl Localization Is Affected By Coexpression Of Opg In Nonmentioning

confidence: 99%

Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

Aoki

Honma

Kariya

et al. 2010

Journal of Bone and Mineral Research

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“…These primers were designed on the basis of the OPG structure which consists of 7 structural domains ( Figure 2A). The recombinant plasmids pET-OPG1 and pET-OPG2 express the amino-terminal cysteine rich domains (D1-D4) which are necessary for binding to RANKL (15,16). The third recombinant plasmid, pET-OPG3, was designed to express the carboxy-terminal portion of the protein that contains two putative death domain homologous regions (D5 and D6) which have been related to cytotoxic signals in mammalian cells (15,17), and a heparin-binding region (D7).…”

Section: Expression and Purification Of Osteoprotegerin Recombinant Fmentioning

confidence: 99%

Characterisation of Osteoprotegerin Autoantibodies in Coeliac Disease

et al. 2015

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ObjectivesAutoantibodies neutralising the effect of the bone regulatory cytokine osteoprotegerin (OPG) have been described in a patient with severe osteoporosis and coeliac disease. This study aimed to determine the prevalence and epitope specificity of autoantibodies to OPG in patients with coeliac disease, and correlate their presence with bone mineral density. MethodsA direct enzyme linked immunosorbent assay was developed and used to screen patients with coeliac disease for autoantibodies to OPG. Recombinant fragments of OPG were made to evaluate the epitope specificity and affinity of these antibodies. Phenotype information of the patients was obtained by case note review. ResultsRaised titres of antibodies to OPG were found in 7/71 (9.8%) patients with coeliac disease, compared with 1/72 (1.4%) non-coeliac osteoporosis clinic control patients (p<0.05). Our results suggest a polyclonal antibody response to OPG is raised in these patients capable of recognising different epitopes of OPG with varying affinity. The titre of OPG antibodies was associated with lower bone mineral density Z score of the hip in coeliac patients on univariate (p<0.05) and multivariate analysis including age, sex height and weight as covariates (p<0.01). ConclusionPolyclonal antibodies to OPG are more common in patients with coeliac disease and are independently associated with lower bone mineral density Z scores of the hip. Further work is required to establish the clinical utility of testing for OPG antibodies.3

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“…3A). It was reported that OPG exists and acts as a homodimeric form (35). OPG-Fc also exists as a homodimer (35), suggesting that OPG-Fc similarly behaves like a native protein.…”

Section: Inhibition Of the Shedding Of Rankl From Osteoblasts By Opg mentioning

confidence: 99%

Osteoprotegerin Reduces the Serum Level of Receptor Activator of NF-κB Ligand Derived from Osteoblasts

Nakamichi

Udagawa

Kobayashi

et al. 2007

The Journal of Immunology

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Osteoprotegerin (OPG) is a decoy receptor for receptor activator of NF-κB ligand (RANKL). We previously reported that OPG deficiency elevated the circulating level of RANKL in mice. Using OPG−/− mice, we investigated whether OPG is involved in the shedding of RANKL by cells expressing RANKL. Osteoblasts and activated T cells in culture released a large amount of RANKL in the absence of OPG. OPG or a soluble form of receptor activator of NF-κB (the receptor of RANKL) suppressed the release of RANKL from those cells. OPG- and T cell-double-deficient mice showed an elevated serum RANKL level equivalent to that of OPG−/− mice, indicating that circulating RANKL is mainly derived from bone. The serum level of RANKL in OPG−/− mice was increased by ovariectomy or administration of 1α,25-dihydroxyvitamin D3. Expression of RANKL mRNA in bone, but not thymus or spleen, was increased in wild-type and OPG−/− mice by 1α,25-dihydroxyvitamin D3. These results suggest that OPG suppresses the shedding of RANKL from osteoblasts and that the serum RANKL in OPG−/− mice exactly reflects the state of bone resorption.

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Functional Dissection of Osteoprotegerin and Its Interaction with Receptor Activator of NF-κB Ligand

Cited by 109 publications

References 35 publications

Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

Function of OPG as a traffic regulator for RANKL is crucial for controlled osteoclastogenesis

Characterisation of Osteoprotegerin Autoantibodies in Coeliac Disease

Osteoprotegerin Reduces the Serum Level of Receptor Activator of NF-κB Ligand Derived from Osteoblasts

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