Osteoprotegerin ELISA Kit

To clarify the role of the TNFRSF11B gene encoding osteoprotegerin (OPG), in Paget's disease of bone (PDB) we studied TNFRSF11B polymorphisms in an association study of 690 UK subjects and in a worldwide familial study of 66 kindreds. We found that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to both sporadic and familial PDB. Introduction: Paget's disease of bone (PDB) is a common disorder characterized by focal abnormalities of bone turnover. Genetic factors are important in the pathogenesis of PDB, and studies have shown that inactivating mutations of the TNFRSF11B gene, encoding osteoprotegerin (OPG), cause the rare syndrome of juvenile Paget's disease. In this study, we sought to determine whether polymorphisms of the TNFRSF11B gene contribute to the pathogenesis of classical PDB. Materials and Methods: We screened for polymorphisms of the TNFRSF11B gene by DNA sequencing of the proximal promoter, coding exons, and intron-exon boundaries in 20 PDB patients and 10 controls. Informative single nucleotide polymorphisms (SNPs), including a G1181C SNP, which predicts a lysine-asparagine substitution at codon 3 of the OPG signal peptide and haplotypes, were related to the presence of PDB in 312 cases compared with 378 controls and to transmission of PDB in 140 affected offspring from 66 kindreds with familial PDB. Results and Conclusions: The G1181 allele was significantly over-represented in PDB patients (chi(2) = 5.7, df = 1, p = 0.017, adjusted alpha = 0.024), equivalent to an odds ratio for PDB of 1.55 (95% CI 1.11-2.16). The distribution of TNFRSF11B haplotypes significantly differed in sporadic PDB cases and controls (chi(2) = 30.2, df = 9, p < 0.001) because of over-representation of haplotypes containing the G1181 allele in cases. The family study showed that the most common haplotype containing the G1181 allele was transmitted more frequently than expected to 140 individuals with familial PDB (chi(2) = 7.35, df = 1, p < 0.01), and the transmission disequilibrium was even more pronounced in a Subgroup of 78 familial PDB patients who did not carry mutations of the SQSTM1 gene (chi(2) = 8.44, df = 1, p < 0.005). We conclude that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to the development of sporadic PDB and familial PDB that is not caused by SQSTM1 Mutations.

Identification of the RANKL/OPG/RANK/NF-kB (receptor activator of nuclear factor K-B ligand / osteoprotegerin) signaling pathway as the major regulatory system for osteoclastogenesis began with discovery of these ligands and receptors in the tumor necrosis factor (TNF) superfamily. Subsequently, genetically altered mice revealed physiologic roles for these proteins in bone biology. However, full appreciation of their significance for the human skeleton came from clinical characterization of several extremely rare, heritable disorders followed by discovery of their genetic bases. Familial expansile osteolysis (FEO) is an autosomal dominant disorder featuring constitutive activation of RANK due to an 18-bp tandem duplication in its gene (TNFRSF11A). A similar, 27-bp duplication causes what has been called a familial form of early-onset Paget's disease of bone (PDB2). Expansile skeletal hyperphosphatasia (ESH) is allelic to FEO and PDB2 and involves a 15-bp tandem duplication in TNFRSF11A. Autosomal recessive inheritance of deactivating mutations of the gene encoding OPG (TNFRSF11B) causes most cases of juvenile Paget disease. These disorders feature high bone turnover, deafness during early childhood, "idiopathic external lysis" of adult teeth, and sometimes focal lesions in appendicular bones that mimic active PDB. Biochemical markers indicate rapid skeletal remodeling. In FEO, osteolysis progresses to fat-filled bone rather than to osteosclerosis. Antiresorptive therapy with bisphosphonates can be effective for each disorder.