TNFRSF11B (tumor necrosis factor receptor superfamily, member 11b)

2008-08-01   Maria Grazia Di Iasio , Federica Corallini , Paola Secchiero , Silvano Capitani 

Department of Morfology, Embryology, Human Anatomy Section - Ferrara University, 44100 ferrara, Italy

Identity

HGNC
LOCATION
8q24.12
LOCUSID
ALIAS
OCIF,OPG,PDB5,TR1
FUSION GENES

DNA/RNA

Atlas Image
Organization of the human OPG gene.

Description

START: 120,004,977 BP from PTER
END: 120,033,492 BP from PTER
SIZE: 28,516 bases
ORIENTATION: Minus strand
REFSEQ GENOMIC ASSEMBLIES: NC-000008.9 NT-008046.15

Transcription

5 exons; cDNA SIZE 2354 BP (NM-002546); CDS: 1206 nt.

Pseudogene

No known pseudogenes.

Proteins

Note

RefSeq NP-002537.3; Size: 401 amino acids; 46040 Da; Subunit: Homodimer; Subcellular location: Secreted.
Osteoprotegerin (OPG) was isolated independently by two laboratories in 1997 (Tsuda et al., 1997; Simonet et al., 1997), as being a protein that exhibits a protective effect on bone. OPG is a member of the TNF-receptor superfamily, which consists of proteins that evoke different signal transduction, mediating several biological responses, such as cytotoxicity, apoptosis and cell survival, proliferation and differentiation. OPG has two known TNF family ligands: receptor activator of NF-kB ligand (RANKL) (Yasuda et al., 1998b) and TRAIL (Emery et al.,1998) (Diagram 1). RANKL normally binds to its membrane receptor RANK inducing differentiation, activation, and survival of osteoclasts. By binding to RANKL, OPG acts as a soluble inhibitor that prevents RANKL/RANK interaction and subsequent osteoclastogenesis (Yasuda et al., 1998b) (Diagram 1). However, it has been reported that also OPG binding to TRAIL inhibits TRAIL/TRAIL-receptors (TR-R1/R2) interaction, as revealed by the inhibition of TRAIL-induced apoptosis (Emery et al.,1998) (Diagram 1). Vice-versa, TRAIL can block the inhibitory activity of OPG on osteoclastogenesis (Emery et al.,1998).
Atlas Image
Diagram 1. Schematic representation of OPG/OPG-ligands and cellular processes inhibited from their interactions.
Diagram 2. Schematic representation of the structure of OPG protein.

Description

OPG comprises 401 amino acids of which 21 are a signal peptide which is cleaved, generating a mature form of 380 amino acids. OPG is produced as a monomer (55-62 kDa), but undergoes homodimerization and is secreted as a disulphide-linked homodimeric glycoprotein with four or five potential glycosylation sites, generating a mature form of OPG of 110-120 kDa (Yamaguchi et al., 1998). OPG consists of 7 structural domains, of which the amino-terminal cysteine rich domains 1 to 4 (D1-D4) are necessary for binding to RANKL (Schneeweis et al., 2005) and share some features with the extracellular domains of other members of the TNF-receptor family (Diagram 2) (Baker et al., 1998). The carboxy-terminal portion of the protein contains two putative death domain homologous regions (D5 and D6). Finally, domain 7 (D7) harbors a heparin-binding region, a common feature of peptide growth factors and signal molecules, as well as an unpaired cysteine residue, at position 400, required for disulfide bond formation and dimerization (Diagram 2) (Yamaguchi et al., 1998). It is the dimeric form of the protein, which has the highest heparin-binding capacity and also the highest hypocalcemic ability.

Expression

OPG is expressed ubiquitously and abundantly in many tissues and cell types. First of all it is produced from osteoblasts (Wada et al., 2006), where its expression is regulated by most of the factors that induce RANKL expression by osteoblasts. Although there are contradictory data, in general upregulation of RANKL is associated with downregulation of OPG, or at least lower induction of OPG, such that the ratio of RANKL to OPG changes in favor of osteoclastogenesis. Many reports have supported the assertion that the RANKL/OPG ratio is a major determinant of bone mass (Hofbauer et al., 2004). Concerning the cellular sources of OPG, it has been shown that besides cells belonging to the osteoblastic lineage, also bone marrow stromal cells (reviewed in Theoleyre et al., 2004), hematopoietic and immune cells (B cells and dendritic cells) (Tan et al., 1997) produce and release OPG. Importantly, OPG is also produced by endothelial (Collin-Osdoby et al., 2001) and vascular smooth muscle cells (Olesen et al., 2005), which likely represent the major contributors to the circulating pool of OPG. Recent studies on the intracellular localization of OPG in endothelial cells have indicated that OPG protein is found in the Weibel-Palade Bodies (WPB), in physical association with von Willebrand Factor (Zannettino et al., 2005).
Finally, OPG is produced by a variety of tissues including the cardiovascular system (heart, arteries, veins), lung, kidney, liver, spleen, intestine, stomach (Simonet et al., 1997; Wada et al., 2006).

Localisation

OPG, unlike all other receptors of the family, lacks a transmembrane and cytoplasmic domain and is secreted as a soluble protein (Yamaguchi et al., 1998). It has also been detected in a cell surface-associated form with some cell types (Yun et al., 1998), although sequence analysis failed to detect a classical hydrophobic transmembrane domain.

Function

The best characterized activity of OPG is the inhibition of osteoclast differentiation and activity (Simonet et al., 1997; Yasuda et al., 1998a), by binding to RANKL. Initially, the physiological roles of OPG have been revealed by studies in OPG knockout mice, produced by targeted disruption of the gene (Bucay et al., 1998; Mizuno et al.,1998). OPG (-/-) mice were viable and fertile, but they exhibited severe osteoporosis caused by enhanced osteoclast formation and function. These results have indicated that OPG is a physiological regulator of osteoclast-mediated bone resorption during postnatal bone growth.
In the context of vascular system, it has been reported that exposure of both micro and macro-vascular endothelial cells to the inflammatory cytokines elevates OPG expression and release (Collin-Osdoby et al., 2001; Secchiero et al., 2006), and OPG in turn promotes leukocyte adhesion (Zauli et al., 2007; Mangan et al., 2007), acting as a chemotactic factor for monocyte. These observations strongly support a modulatory role of OPG in hemostasis, vascular injury and inflammation, suggesting an involvement of OPG in the inflammatory functions of endothelial cells, with endothelium acting as both cellular source and target of vascular OPG production. In this respect, there are accumulating data in vitro indicating a role for OPG in endothelial cell biology and angiogenesis; in particular in the regulation of endothelial cell survival (Scatena et al., 2002; Pritzker et al., 2004), stimulation of endothelial cell growth, as well as the formation of cord-like structures on a matrigel substrate (Cross et al., 2006), providing the evidence that OPG may modulate also endothelial cell migration and differentiation. In this context, OPG also appears to protect large blood vessels from medial calcification, based on the observation of renal and aortic calcification occurring in OPG knockout mice (Bucay et al., 1998). Furthermore, the absence of OPG in OPG/apolipoprotein E double knockout mice accelerates the calcific atherosclerosis that develops in apolipoprotein E knockout mice, suggesting that OPG protects against this complication of atherosclerosis (Bennett et al., 2006).
Moreover, OPG has also been shown to regulate B-cell development and function and dendritic cell function (Yun et al., 1998; Yun et al., 2001), making OPG a paracrine mediator of both bone metabolism and immune functions.
Atlas Image
For details see: http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=homologene&dopt=AlignmentScores&list_uids=1912

Mutations

Note

http://www.ncbi.nlm.nih.gov/sites/entrez (look for TNFRSF11B into dbSNP)
Atlas Image
11 Exonic variations
For details see: http://www.ncbi.nlm.nih.gov/SNP/snp_ref.cgi?locusId=4982

Implicated in

Entity name
Cancer
Note
A potential role of full-lenght OPG in tumor cell biology is supported by different studies that have investigated the OPG serum levels, OPG tissue expression and OPG polymorphisms in cancer patients. In fact, it has been shown that the serum levels of OPG are elevated in a variety of human malignancies, in particular in patients with more advanced cancer. Of note, OPG levels were increased in the serum of patients with prostate or breast cancer metastatized to the bone (Lipton et al., 2001). Surprisingly, OPG serum levels were elevated also in other types of tumors, which do not show a preferential tropism for bone, such as B cell lymphomas (Lipton et al., 2001), but also in patients with bladder carcinoma (Mizutani et al., 2004), where OPG levels were found to be associated with high tumour stage and grade. After a follow up period of 5 years, patients who had low serum OPG levels had a longer post-operative tumour-free interval and increased survival compared with patients with high levels of serum OPG (Mizutani et al., 2004), suggesting that serum OPG correlates with tumour stage and is also predictive of early recurrence of bladder carcinoma.
Moreover, in different studies, it was shown that OPG is overexpressed in epithelial carcinomas of the gastroenteric tract (Ito et al., 2003; Pettersen et al., 2005). In particular, it was reported a significant correlation between OPG expression and tumor stage, suggesting that OPG expression may be a marker of aggressive gastric carcinomas. In addition, investigation of various human cancers demonstrated that OPG is highly expressed by endothelial cells in the majority of malignant tumors examined (60% of malignant tumors), although endothelial cells in benign tumors do not express high levels of OPG. In particular, in breast cancers endothelial expression of OPG seems to be associated with increasing tumor grade (Cross et al., 2006). Taken together, these observations suggest that the increased levels of OPG expression may be associated with tumor development and/or progression.
Finally, a recent study has addressed the possible role of OPG promoter polymorphisms as genetic modifiers in the etiology of prostate cancer and disease progression (Narita et al., 2008). Patients affected by prostate cancer with TC and TT genotypes in the 950 T/C polymorphism had a significantly increased risk of extraprostatic and metastatic disease compared with those with the CC genotype. In addition, analysis of the metastatic prostatic cancer patients showed that the presence of the T allele of the OPG 950 T/C polymorphism was an independent risk factor, predicting survival by Cox proportional hazard regression analyses (Narita et al., 2008).
Entity name
Vascular diseases
Note
A growing number of experimental data have demonstrated that the serum levels of OPG are significantly increased in both diabetic and non-diabetic patients affected by coronary artery disease (Jono et al., 2002; Schoppet et al., 2003; Avignon et al., 2005; Rasmussen et al., 2006), with a strong association between levels of OPG and the presence and severity of coronary artery disease (Browner et al., 2001). Serum OPG levels have shown to have prognostic value in heart failure after acute myocardial infarction as well as in patients affected by abdominal aortic aneurysm and peripheral artery disease (Karan et al., 2005; Ziegler et al., 2005). Remarkably, two OPG genetic polymorphisms have been associated with an increased risk of coronary artery disease in Caucasian men, and serum OPG levels correlated with one of these polymorphisms (Soufi et al., 2004). Thus, these studies strongly indicate that serum OPG levels frequently rise in clinical conditions that favor vascular dysfunction or atherosclerosis. In this respect, the presence of OPG has been documented in atherosclerotic lesions (Schoppet et al., 2004). Moreover, in a large observational study, plasma concentrations of OPG were higher in diabetic than in non-diabetic subjects, in particular in diabetic patients with vascular complications (Knudsen et al., 2003), suggesting that elevated levels of OPG may reflect vascular damage among patients with diabetes rather than the diabetic state per se.
At present it is unclear whether OPG plays a pathogenetic or compensatory role in the vascular dysfunction and atherosclerosis. However, the ability of recombinant OPG to enhance the recruitment and infiltration of monocyte/macrophages ( Mosheimer et al., 2005) is particularly noteworthy in the hypothesis that an abnormal and prolonged elevation of OPG levels may be involved in the devolopment of vascular dysfunction.

Bibliography

Pubmed IDLast YearTitleAuthors
161234862005Osteoprotegerin is associated with silent coronary artery disease in high-risk but asymptomatic type 2 diabetic patients.Avignon A et al
99169881998Modulation of life and death by the TNF receptor superfamily.Baker SJ et al
168407152006Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE-/- mice.Bennett BJ et al
111580212001Associations of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women.Browner WS et al
95730431998osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification.Bucay N et al
112741432001Receptor activator of NF-kappa B and osteoprotegerin expression by human microvascular endothelial cells, regulation by inflammatory cytokines, and role in human osteoclastogenesis.Collin-Osdoby P et al
162870882006Osteoprotegerin (OPG)--a potential new role in the regulation of endothelial cell phenotype and tumour angiogenesis?Cross SS et al
96039451998Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL.Emery JG et al
152803472004Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases.Hofbauer LC et al
128384182003Expression of osteoprotegerin correlates with aggressiveness and poor prognosis of gastric carcinoma.Ito R et al
122087912002Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease.Jono S et al
128248642003Increased plasma concentrations of osteoprotegerin in type 2 diabetic patients with microvascular complications.Knudsen ST et al
121144352002Serum osteoprotegerin levels in healthy controls and cancer patients.Lipton A et al
177069532007Osteoprotegerin upregulates endothelial cell adhesion molecule response to tumor necrosis factor-alpha associated with induction of angiopoietin-2.Mangan SH et al
96477411998Severe osteoporosis in mice lacking osteoclastogenesis inhibitory factor/osteoprotegerin.Mizuno A et al
153863102004Prognostic significance of serum osteoprotegerin levels in patients with bladder carcinoma.Mizutani Y et al
159398232005Association of osteoprotegerin with human abdominal aortic aneurysm progression.Moran CS et al
157282092005Syndecan-1 is involved in osteoprotegerin-induced chemotaxis in human peripheral blood monocytes.Mosheimer BA et al
186843182008A genetic polymorphism of the osteoprotegerin gene is associated with an increased risk of advanced prostate cancer.Narita N et al
157001362005Arterial osteoprotegerin: increased amounts in diabetes and modifiable synthesis from vascular smooth muscle cells by insulin and TNF-alpha.Olesen P et al
163091672005Osteoprotegerin is expressed in colon carcinoma cells.Pettersen I et al
150643582004The role of osteoprotegerin and tumor necrosis factor-related apoptosis-inducing ligand in human microvascular endothelial cell survival.Pritzker LB et al
163819942006Plasma osteoprotegerin levels are associated with glycaemic status, systolic blood pressure, kidney function and cardiovascular morbidity in type 1 diabetic patients.Rasmussen LM et al
162152612005Functional dissection of osteoprotegerin and its interaction with receptor activator of NF-kappaB ligand.Schneeweis LA et al
152923542004Localization of osteoprotegerin, tumor necrosis factor-related apoptosis-inducing ligand, and receptor activator of nuclear factor-kappaB ligand in Mönckeberg's sclerosis and atherosclerosis.Schoppet M et al
171486842006An increased osteoprotegerin serum release characterizes the early onset of diabetes mellitus and may contribute to endothelial cell dysfunction.Secchiero P et al
91084851997Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.Simonet WS et al
152923022004Osteoprotegerin gene polymorphisms in men with coronary artery disease.Soufi M et al
94341631997Characterization of a novel TNF-like ligand and recently described TNF ligand and TNF receptor superfamily genes and their constitutive and inducible expression in hematopoietic and non-hematopoietic cells.Tan KB et al
155616022004The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling.Theoleyre S et al
91689771997Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis.Tsuda E et al
163567702006RANKL-RANK signaling in osteoclastogenesis and bone disease.Wada T et al
94789641998Characterization of structural domains of human osteoclastogenesis inhibitory factor.Yamaguchi K et al
95204111998Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL.Yasuda H et al
98340951998OPG/FDCR-1, a TNF receptor family member, is expressed in lymphoid cells and is up-regulated by ligating CD40.Yun TJ et al
111601872001Osteoprotegerin, a crucial regulator of bone metabolism, also regulates B cell development and function.Yun TJ et al
157990292005Osteoprotegerin (OPG) is localized to the Weibel-Palade bodies of human vascular endothelial cells and is physically associated with von Willebrand factor.Zannettino AC et al
173637292007Osteoprotegerin increases leukocyte adhesion to endothelial cells both in vitro and in vivo.Zauli G et al
161154892005Osteoprotegerin plasma concentrations correlate with severity of peripheral artery disease.Ziegler S et al

Other Information

Locus ID:

NCBI: 4982
MIM: 602643
HGNC: 11909
Ensembl: ENSG00000164761

Variants:

dbSNP: 4982
ClinVar: 4982
TCGA: ENSG00000164761
COSMIC: TNFRSF11B

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000164761ENST00000297350O00300
ENSG00000164761ENST00000517352E5RFV7

Expression (GTEx)

0
50
100
150
200
250
300

Pathways

PathwaySourceExternal ID
Cytokine-cytokine receptor interactionKEGGko04060
Cytokine-cytokine receptor interactionKEGGhsa04060
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
Immune SystemREACTOMER-HSA-168256
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
TNFR2 non-canonical NF-kB pathwayREACTOMER-HSA-5668541
TNFs bind their physiological receptorsREACTOMER-HSA-5669034

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA443560Breast NeoplasmsDiseaseClinicalAnnotationassociatedPD
PA448432anastrozoleChemicalClinicalAnnotationassociatedPD
PA450196letrozoleChemicalClinicalAnnotationassociatedPD

References

Pubmed IDYearTitleCitations
184457772008Multiple genetic loci for bone mineral density and fractures.214
184457772008Multiple genetic loci for bone mineral density and fractures.214
184552282008Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study.213
184552282008Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study.213
176341402007Biology of RANK, RANKL, and osteoprotegerin.172
155645642004Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin.99
205489442010An integration of genome-wide association study and gene expression profiling to prioritize the discovery of novel susceptibility Loci for osteoporosis-related traits.90
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
227051162012New insights into osteoclastogenic signaling mechanisms.79
121244062002Osteoprotegerin deficiency and juvenile Paget's disease.73

Citation

Maria Grazia Di Iasio ; Federica Corallini ; Paola Secchiero ; Silvano Capitani

TNFRSF11B (tumor necrosis factor receptor superfamily, member 11b)

Atlas Genet Cytogenet Oncol Haematol. 2008-08-01

Online version: http://atlasgeneticsoncology.org/gene/42610/tnfrsf11b