Disease relevance of TNFRSF11B

• T cells support osteoclastogenesis in an in vitro model derived from human multiple myeloma bone disease: the role of the OPG/TRAIL interaction [1].
• Osteoprotegerin (OPG) is a member of the tumor necrosis factor (TNF) receptor family, which binds to the ligand for receptor activator of nuclear factor kappa B and inhibits bone resorption [2].
• This may indicate the presence of inhibitors within the cells, but resistance to apoptosis could not be correlated with expression of the caspase inhibitor FLICE-inhibitory protein. mRNA for another TRAIL receptor, osteoprotegerin, was expressed in 22 of the melanoma lines but not on melanocytes [3].
• The in vivo effects of hPTH(1-38) on OPG mRNA were confirmed in isolated primary osteoblast cultures derived from either metaphyseal or diaphyseal bone as well as in ROS 17/2.8 osteosarcoma cells [4].
• When OCIF was administered into rats with established hypercalcemia, it decreased serum calcium rapidly (within 2 hr) and dramatically [5].
• The further understanding of this pathway led to the development of new therapeutic modalities including the human monoclonal antibody to RANKL and recombinant OPG as a target for treatment of postmenopausal osteoporosis and multiple myeloma [6].
• We found production of OPG in colorectal cancer cells to be regulated by beta-catenin/Tcf-4 [7].
• These results require confirmation but suggest a role for the OPG Lys3Asn polymorphism in the genetic susceptibility to hip fractures among older white women [8].
• Among patients with diabetic nephropathy, individuals with high osteoprotegerin levels (fourth quartile) had significantly higher all-cause mortality than patients with low levels (first quartile) (covariate-adjusted hazard ratio [HR] 3.00 [1.24-7.27]) [9].

Psychiatry related information on TNFRSF11B

• In a multiple regression analysis including age, duration of diabetes, physical activity, calcium intake, mean HbA1c and Z-score BUA, only HbA1c significantly predicted serum OPG levels (beta 0.67; P = 0.003) [10].
• Serum osteoprotegerin in adolescent girls with anorexia nervosa [11].
• Our study demonstrates that OPG may be regarded as a novel biomarker of dementia in the Italian population [12].
• Plasma osteoprotegerin as a biochemical marker for vascular dementia and Alzheimer's disease [12].
• Bone mineral density, bone turnover, and osteoprotegerin in depressed women with and without borderline personality disorder [13].

High impact information on TNFRSF11B

• Here we show that osteoprotegerin, a secreted 'decoy' receptor that inhibits osteoclast activity, also blocks behaviors indicative of pain in mice with bone cancer [14].
• These results demonstrate that excessive tumor-induced bone destruction is involved in the generation of bone cancer pain and that osteoprotegerin may provide an effective treatment for this common human condition [14].
• Osteoprotegerin blocks bone cancer-induced skeletal destruction, skeletal pain and pain-related neurochemical reorganization of the spinal cord [14].
• RANKL, RANK, and OPG are three key molecules that regulate osteoclast recruitment and function [15].
• At the same time, bone resorption is inhibited by decreased IL-6 and increased OPG secretion into the bone microenvironment [16].

Chemical compound and disease context of TNFRSF11B

• The present study was designed to examine whether hypothyroidism causes an increase in serum OPG, and to determine whether levothyroxine (L-T4) replacement therapy might suppress serum OPG levels in hypothyroid patients [17].
• The results suggest a novel biologic mechanism for the bone disease associated with MM and that treatment of the bone disease with OPG lacking the heparin-binding domain should be considered [18].
• Estrogen is known to suppress bone resorption, and the action of estrogen on bone may be mediated by OPG [19].
• Interleukin-6 and osteoprotegerin systems in Paget's disease of bone: relationship to risedronate treatment [20].
• The effect of zoledronic acid and osteoprotegerin on growth of human lung cancer in the tibias of nude mice [21].

Biological context of TNFRSF11B

• A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype [22].
• Idiopathic hyperphosphatasia and TNFRSF11B mutations: relationships between phenotype and genotype [23].
• 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 [24].
• 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 [24].
• RESULTS: Both patients had a homozygous deletion of TNFRSF11B, with identical break points, on chromosome 8q24 [25].

Anatomical context of TNFRSF11B

• Our results highlight that MM T cells support OC formation and survival, possibly involving OPG/TRAIL interaction and unbalanced OC expression of TRAIL death and decoy receptors [1].
• In the present study MG63 osteoblast-like cells and primary bone marrow stromal cells were both shown to produce OPG, whereas human myeloma cells did not produce OPG but down-regulated release of OPG from MG63 cells [2].
• These observations suggest that OPG may function as a paracrine survival factor in the bone marrow microenvironment in multiple myeloma [2].
• To investigate this issue, reverse transcriptase-polymerase chain reaction using specific primers for OPG/OCIF was performed with total RNAs isolated from human gingival keratinocytes (HGKs), human gingival fibroblasts (HGFs), human periodontal ligament cells (HPDLs), and human pulp cells (HPCs) in culture [26].
• Expression of osteoprotegerin (osteoclastogenesis inhibitory factor) in cultures of human dental mesenchymal cells and epithelial cells [26].

Associations of TNFRSF11B with chemical compounds

• All three affected siblings were homozygous for a 3 bp inframe deletion in exon 3 of the TNFRSF11B gene, resulting in the loss of an aspartate residue [22].
• We found that the G1181 allele of TNFRSF11B, encoding lysine at codon 3 of the OPG protein, predisposes to both sporadic and familial PDB [24].
• Osteoclastogenesis inhibitory factor (OCIF) is a heparin-binding secretory glycoprotein that belongs to the tumor necrosis factor receptor (TNFR) family [27].
• We attempted to characterize the seven structural domains of OCIF by determining the capabilities of various OCIF mutants to inhibit osteoclastogenesis, to interact with heparin, and to form dimers [27].
• In contrast to PTH, prostaglandin E2 (PGE2) had no effect on OPG mRNA expression in vivo in the metaphyseal bone cells, under conditions in which PGE2 does promote expression of the c-fos gene [4].
• Both 5-HT and interleukin-1 also increased OPG secretion [28].

Physical interactions of TNFRSF11B

• Reciprocal immunoprecipitation experiments revealed that while not associated with P-Selectin, OPG is physically complexed with vWF both within the WPB and following secretion from endothelial cells [29].
• BACKGROUND: Osteoprotegerin (OPG) is involved in the regulation of bone turnover through binding to the receptor activator of nuclear factor kappaB ligand (RANKL), and has also been reported to be a potential survival factor for several different cell types [30].
• OCIF is a heparin-binding basic glycoprotein and has been isolated as a monomer with an apparent molecular weight (Mr) of 60,000 and a homodimer with a Mr of 120,000 [31].
• The potential survival effects of OPG are mediated through binding to a member of the TNF super family, TNF-related Apoptosis Inducing Ligand (TRAIL), preventing association between TRAIL and its death-inducing receptors present on a number of tumour cell types [32].
• The discovery that OPG can bind to and inhibit the activity of TRAIL (TNF-related apoptosis-inducing ligand) triggered extensive research into the potential role of OPG in the regulation of tumour cell survival [33].
• These data suggest that OPG can bind both RANKL and TRAIL and that the affinity of OPG for these two ligands is of a similar order of magnitude [34].

Co-localisations of TNFRSF11B

• In HUVEC, OPG co-localizes with P-selectin and von Willebrand factor (vWF), within the Weibel-Palade bodies (WPB) [29].

Regulatory relationships of TNFRSF11B

• Osteoprotegerin is a soluble decoy receptor for tumor necrosis factor-related apoptosis-inducing ligand/Apo2 ligand and can function as a paracrine survival factor for human myeloma cells [2].
• In vivo demonstration that human parathyroid hormone 1-38 inhibits the expression of osteoprotegerin in bone with the kinetics of an immediate early gene [4].
• Activation of peroxisome proliferator-activated receptor gamma inhibits osteoprotegerin gene expression in human aortic smooth muscle cells [35].
• The OPG-inducing activity of the culture medium was neutralized by the anti-interleukin-11 (IL-11) antibody [36].
• Osteoprotegerin deficiency could explain juvenile Paget's disease because osteoprotegerin suppresses bone turnover by functioning as a decoy receptor for osteoclast differentiation factor (also called RANK ligand) [25].

Other interactions of TNFRSF11B

• Medium conditioned by cocultures of MG63 cells with myeloma cells had a reduced effect on TRAIL/Apo2L-induced apoptosis, reflecting the decreased concentrations of OPG in cocultures of myeloma cells with bone cells [2].
• However, IL-6 and transforming growth factor-beta had little effect on OPG/OCIF mRNA levels in HPDL [26].
• In summary, the intracellular localization of OPG in HUVEC, in association with vWF, together with its rapid and sustained secretory response to inflammatory stimuli, strongly support a modulatory role in vascular injury, inflammation and hemostasis [29].
• This mechanism has been highlighted by the discovery of osteoprotegerin (OPG), a soluble tumor necrosis factor (TNF) family member that inhibits osteoclast formation [37].
• The OPG/GAPDH mRNA levels in iliac bone before surgery correlated with serum osteocalcin (r = 0.52, P < 0.01), but not with bone resorption markers [38].

Analytical, diagnostic and therapeutic context of TNFRSF11B

• Genetic markers near TNFRSF11B were evaluated by both a PCR method that involved sequence-tagged site-content mapping of a deletion of TNFRSF11B and PCR spanning the DNA break points [25].
• Despite high OPG levels, the persistence of osteoclastogenesis can be related to the formation of the OPG/TRAIL complex demonstrated by immunoprecipitation experiments and the addition of anti-TRAIL antibody which decreases OC formation [1].
• Immunohistochemistry of OPG protein expression in the rat distal femur metaphysis revealed that it was localized predominantly in preosteoblasts, osteoblasts, lining cells, and the osteoid layer, with occasional immunoreactivity in osteocytes and cells of the bone marrow [4].
• Northern blot analyses also showed that HGFs, HPDLs, and HPCs, but not HGKs, expressed OPG/OCIF transcripts of approximately 2.5 kb [26].
• Immunohistochemistry and in situ hybridization revealed OPG immunoreactivity and mRNA expression surrounding calcified areas in the medial layer (Mönckeberg's sclerosis), whereas OPG was mainly expressed adjacent to calcified neointimal lesions (atherosclerosis) [39].

References