Osteoprotegerin Deficiency and Juvenile Paget's Disease

Whyte, Michael P.; Obrecht, Sara E; Finnegan, Patrick M.; Jones, Jonathan L; Podgornik, Michelle N.; McAlister, William H.; Mumm, Steven

doi:10.1056/nejmoa013096

Cited by 407 publications

(268 citation statements)

References 27 publications

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“…(20) We identified a second interesting locus on chromosome 8, near TNFRSF11B gene (encoding OPG), the gene associated with juvenile PDB (JPD; OMIM 239000). (23,24) This association was suggested by both parametric and nonparametric analysis. However, we did not identify any mutation in both TNFRSF11B and OPTN genes, indicating that genetic variation in other genes located in these regions might confer susceptibility to PDB and possibly to GCT.…”

Section: Discussionmentioning

confidence: 81%

“…(23)(24)(25) As shown in Table 4, genome-wide screening allowed us to identify five possible candidate regions containing putative genes predisposing to PDB on chromosomes 8 (39 Mb between rs278559 and rs2280871), 5 (50 Mb between rs12514992 and rs17597145; 15 Mb between rs353287 and rs10462946), 6 (56 Mb from 6pter), 20 (2 Mb near the SNP rs11905231), and 1 (47 Mb between rs12142090 and rs6702754). Assuming a dominant model and a 100% penetrance, parametric analysis resulted in Table 3.…”

Section: Genetic Analysismentioning

confidence: 99%

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Giant cell tumor occurring in familial Paget's disease of bone: Report of clinical characteristics and linkage analysis of a large pedigree

Gianfrancesco¹,

Rendina²,

Merlotti³

et al. 2012

Journal of Bone and Mineral Research

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Neoplastic degeneration represents a rare but serious complication of Paget's disease of bone (PDB). Although osteosarcomas have been described in up to 1% of PDB cases, giant cell tumors are less frequent and mainly occur in patients with polyostotic disease. We recently characterized a large pedigree with 14 affected members of whom four developed giant cell tumors at pagetic sites. The high number of affected subjects across multiple generations allowed us to better characterize the clinical phenotype and look for possible susceptibility loci. Of interest, all the affected members had polyostotic PDB, but subjects developing giant cell tumors showed an increased disease severity with a reduced clinical response to bisphosphonate treatment and an increased prevalence of bone pain, deformities, and fractures. Together with an increased occurrence of common pagetic complications, affected patients of this pedigree also evidenced a fivefold higher prevalence of coronary artery disease with respect to either the unaffected family members or a comparative cohort of 150 unrelated PDB cases from the same geographical area. This association was further enhanced in the four cases with PDB and giant cell tumors, all of them developing coronary artery disease before 60 years of age. Despite the early onset and the severe phenotype, PDB patients from this pedigree were negative for the presence of SQSTM1 or TNFRSF11A mutations, previously associated with enhanced disease severity. Genome-wide linkage analysis identified six possible candidate regions on chromosomes 1, 5, 6, 8, 10, and 20. Because the chromosome 8 and 10 loci were next to the TNFRSF11B and OPTN genes, we extended the genetic screening to these two genes, but we failed to identify any causative mutation at both the genomic and transcription level, suggesting that a different genetic defect is associated with PDB and potentially giant cell tumor of bone in this pedigree. ß

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Section: Discussionmentioning

confidence: 81%

Section: Genetic Analysismentioning

confidence: 99%

Giant cell tumor occurring in familial Paget's disease of bone: Report of clinical characteristics and linkage analysis of a large pedigree

Gianfrancesco¹,

Rendina²,

Merlotti³

et al. 2012

Journal of Bone and Mineral Research

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“…This disease presents in infancy or early childhood with pain from debilitating fractures and deformities owing to a markedly accelerated rate of bone remodeling throughout the skeleton. (43) Some missense mutations in the CRD are associated with severe osteoporotic phenotypes, (44,45) probably owing to the lack of ligand binding of OPG. In addition, a frameshift mutation (D198RfsX7) resulting in deletion of the DDHDs and the HBD has been reported in a severe juvenile Paget disease patient.…”

Section: Discussionmentioning

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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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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“…Cross-sections of femora of OPG Ϫ/Ϫ mice showed excessive osteoclastic bone resorption even in cortical bones (22,23). OPG deficiency in humans results in juvenile Paget's disease characterized by rapidly bone remodeling (24). Thus, OPG is a critical regulator of bone homeostasis in humans as well as mice.…”

Section: Discussionmentioning

confidence: 99%

“…Juvenile Paget's disease, an autosomal recessive osteopathy, is characterized by rapidly remodeling woven bone. A homozygous deletion of the OPG gene was found in patients with juvenile Paget's disease and the serum level of free RANKL was markedly elevated in one such patient (24). Serum levels of RANKL were markedly elevated in OPG Ϫ/Ϫ mice as well.…”

mentioning

confidence: 96%

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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Osteoprotegerin Deficiency and Juvenile Paget's Disease

Abstract: Juvenile Paget's disease can result from osteoprotegerin deficiency caused by homozygous deletion of TNFRSF11B.

Cited by 407 publications

References 27 publications

Giant cell tumor occurring in familial Paget's disease of bone: Report of clinical characteristics and linkage analysis of a large pedigree

Giant cell tumor occurring in familial Paget's disease of bone: Report of clinical characteristics and linkage analysis of a large pedigree

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

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

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