Disease relevance of Tnfrsf11b

• High systemic levels of osteoprotegerin (OPG) in OPG transgenic mice cause osteopetrosis with normal tooth eruption and bone elongation and inhibit the development and activity of endosteal, but not periosteal, osteoclasts [1].
• Osteoprotegerin (OPG)/osteoclastogenesis inhibitory factor (OCIF) is a recently identified cytokine that belongs to the tumor necrosis factor receptor superfamily and regulates bone mass by inhibiting osteoclastic bone resorption [2].
• We determined that the breast cancer cell lines MDA-MB-231, MCF-7, and T47D as well as primary breast cancers do not express RANKL but express OPG and RANK [3].
• The OPG effectively inhibits wear debris-induced osteoclastogenesis and osteolysis [4].
• METHODS: A recombinant adeno-associated virus (rAAV) vector co-expressing OPG (rAAV-OPG-IRES-EGFP) was generated [4].

Psychiatry related information on Tnfrsf11b

• Passive administration of osteoprotegerin, the soluble decoy receptor of TRANCE/RANKL, is efficient in blocking disease progression, but may not find widespread clinical use due to patient compliance problems and the expected high costs [5].

High impact information on Tnfrsf11b

• In vitro, osteoclast differentiation from precursor cells is blocked in a dose-dependent manner by recombinant OPG [6].
• Osteoprotegerin: a novel secreted protein involved in the regulation of bone density [6].
• In vivo, hepatic expression of OPG in transgenic mice results in a profound yet nonlethal osteopetrosis, coincident with a decrease in later stages of osteoclast differentiation [6].
• Unexpectedly, OPG-deficient mice also exhibit medial calcification of the aorta and renal arteries, suggesting that regulation of OPG, its signaling pathway, or its ligand(s) may play a role in the long observed association between osteoporosis and vascular calcification [7].
• Adolescent and adult OPG-/- mice exhibit a decrease in total bone density characterized by severe trabecular and cortical bone porosity, marked thinning of the parietal bones of the skull, and a high incidence of fractures [7].

Chemical compound and disease context of Tnfrsf11b

• In both models, OPG (0.2-5 mg/kg) caused rapid reversal of established hypercalcemia, and the speed and duration of hypercalcemia suppression were significantly greater with OPG (5 mg/kg) than with high-dose bisphosphonates (pamidronate or zoledronic acid, 5 mg/kg) [8].
• OPG is a new member of the tumor necrosis factor (TNF) receptor family which plays a key role in the physiological regulation of osteoclastic bone resorption [9].
• Moreover, OPG expression is induced by estrogen which provides a molecular explanation of postmenopausal osteoporosis in women [10].
• The effect of zoledronic acid and osteoprotegerin on growth of human lung cancer in the tibias of nude mice [11].
• Inhibition of bone resorption, rather than direct cytotoxicity, mediates the anti-tumour actions of ibandronate and osteoprotegerin in a murine model of breast cancer bone metastasis [12].

Biological context of Tnfrsf11b

• These findings indicate that the OPG/OPGL/RANK signaling pathway may play an important role in both pathological and physiological calcification processes [1].
• OPG/OCIF is a secreted member of the tumor necrosis factor receptor family and inhibits osteoclastogenesis by interrupting the cell-to-cell interaction [13].
• Here we report the expression cloning of a ligand for OPG/OCIF from a complementary DNA library of mouse stromal cells [13].
• The up-regulation of OPG/OCIF mRNA by TGF-beta1 in ST2 cells did not require de novo protein synthesis and involved both a transcriptional and a post-transcriptional mechanism [2].
• However, the roles of RANKL and OPG in innate immunity remain obscure [14].

Anatomical context of Tnfrsf11b

• Osteoprotegerin reverses osteoporosis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling osteoclastogenesis [1].
• Transforming growth factor-beta stimulates the production of osteoprotegerin/osteoclastogenesis inhibitory factor by bone marrow stromal cells [2].
• A Runx2-/- calvaria-derived cell line (CA120-4), which expressed OPG strongly but RANKL barely, severely suppressed osteoclast differentiation from normal bone marrow cells in co-cultures [15].
• Osteoblasts might also influence the process of eruption, the most important physiologic role likely being at the eruptive site, in the formation of osteoclasts through signaling via the RANKL/OPG pathway [16].
• We test the hypothesis that OPG mediates the inhibition of osteoclast activity that occurs with indomethacin in the mouse calvaria [17].

Associations of Tnfrsf11b with chemical compounds

• In murine bone marrow cultures, TGF-beta1 markedly inhibited the formation of tartrate-resistant acid phosphatase-positive multinucleated osteoclast-like cells in the presence of 1,25-dihydroxyvitamin D3, whose effect was significantly reversed by a neutralizing antibody against OPG/OCIF [2].
• Receptor Activator of NF-{kappa}B Ligand and Osteoprotegerin Regulate Proinflammatory Cytokine Production in Mice [14].
• Stimulation of (45)Ca release by dexamethasone and hydrocortisone in calvariae was blocked by OPG [18].
• OPG/OCIF, a secreted member of the tumor necrosis factor (TNF) receptor family, inhibited differentiation and activation of osteoclasts [19].
• Recombinant human OPG, like indomethacin, was found to cause osteoclasts to detach from the bone surface and attach to the adjacent endocranial membrane (periosteum) [17].

Physical interactions of Tnfrsf11b

• Receptor activator of NF-kB Ligand (RANKL) is an essential requirement for osteoclastogenesis and its activity is neutralized by binding to the soluble decoy receptor osteoprotegerin (OPG) [20].

Regulatory relationships of Tnfrsf11b

• Interleukin-18 up-regulates osteoprotegerin expression in stromal/osteoblastic cells [21].
• In both cell lines, RANKL mRNA was induced and osteoprotegerin (OPG) mRNA was decreased in response to treatment with 1alpha,25(OH)(2)D(3) for 2 days [22].
• This M-CSF plus LPS-induced osteoclastogenesis was not inhibited by an anti-TNFalpha antagonistic antibody or by osteoprotegerin, a decoy receptor for RANKL [23].
• Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation [24].
• Cellular and molecular studies showed that beta-catenin together with TCF proteins regulates osteoblast expression of Osteoprotegerin, a major inhibitor of osteoclast differentiation [25].

Other interactions of Tnfrsf11b

• Expression of osteoprotegerin, receptor activator of NF-kappaB ligand (osteoprotegerin ligand) and related proinflammatory cytokines during fracture healing [26].
• Single heterozygous mutation in the opg gene locus alone (without klotho mutation) did not show phenotype (trabecular bone volume, 5.84%; not significantly different from wild type) [27].
• Expression of Opg and Rank was observed in both the internal and the external enamel epithelium as well as in the dental papilla mesenchyme [28].
• Furthermore, coadminstration of soluble tumor necrosis factor receptor inhibitor/Fc chimera (TNFRSF1A) but not osteoprotegerin inhibited the action of DcR3 [29].
• Treatment of the cells with IL-11 (10 ng/mL) or PGE(2) (1 microM) increased ODF and OCIF mRNA levels as observed with epinephrine [30].

Analytical, diagnostic and therapeutic context of Tnfrsf11b

• However, intravenous injection of recombinant OPG over a 4-wk period could not reverse the arterial calcification observed in OPG(-/-) mice [1].
• Western blot analysis and an enzyme-linked immunosorbent assay revealed that TGF-beta1 significantly increased the secretion of OPG/OCIF protein by ST2 cells at 6-24 h [2].
• We previously showed by semiquantitative RT-PCR that osteoprotegerin (opg) expression levels in klotho mice were about 2-fold higher than those in wild-type mice in the bone marrow, spleen, and lung [27].
• This study investigated whether gene therapy using a recombinant adeno-associated viral vector that expresses OPG can inhibit wear debris-induced osteolysis [4].
• The OCIF/OPG knockout mice provide the first animal model for osteoporosis without other obvious abnormalities [31].

References