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FLASH GENE

Symbol

TNFRSF11B

contributors: mct/npt/shn - updated : 19-09-2015

HGNC name	tumor necrosis factor receptor superfamily, member 11b
HGNC id	11909

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	PDB7 Paget bone disease 7
Location	8q24.12      Physical location : 119.935.796 - 119.964.383
Synonym name	osteoprotegerin
	osteoclastogenesis inhibitory factor
	tumor necrosis factor receptor superfamily member 11B
Synonym symbol(s)	OPG, OCIF, TR1, FDCR1, MGC29565

DNA

TYPE	functioning gene
STRUCTURE	28.59 kb     5 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	Binding site
motif
text structure	two binding sites for HOXC8 (mediating OPG activation in response to BMP stimulation)
	RUNX2 and SMAD binding element for responsiveness to TGFB1 and RUNX2

MAPPING

cloned

Y

linked

N

status

confirmed

Map	see COLEC10

regionally located

cen - D8S1016 - D8S522 - TNFRSF11B - D8S1823 - D8S269 - qter

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_002546 5 - 2354 NP_002537 60 401 - - 9168977

EXPRESSION

Type

widely

expressed in

(based on citations)

organ(s)

System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       lowly Homo sapiens Digestive liver       highly Homo sapiens Nervous brain       highly Homo sapiens Reproductive female system placenta     highly Homo sapiens   male system testis     lowly Homo sapiens Respiratory lung       highly Homo sapiens Urinary kidney       lowly Homo sapiens

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Blood / hematopoietic bone marrow     highly

cells

System Cell Pubmed Species Stage Rna symbol Nervous neuron Skeleton osteoblast Homo sapiens

cell lineage	lymphoid cells
cell lines
fluid/secretion

at STAGE

physiological period

fetal

Text	kidney, liver, lung

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	four extracytoplasmic cysteine-rich pseudo-repeats typical for the TNFR superfamily, ligand binding domain
	a preligand assembly domain (PLAD) in CRD1 mediating ligand-independent receptor assembly and signaling
	a small cytoplasmic tail with two DEATH domains, also existing as a secreted form OPG

conjugated

GlycoP

mono polymer

homomer , dimer , trimer

HOMOLOGY

interspecies	ortholog to Tnfrsf11b, mus musculus
	ortholog to Tnfrsf11b, Rattus norvegicus
	ortholog to TNFRSF11B, Pan troglodytes

Homologene

FAMILY

tumor necrosis factor receptor superfamily

CATEGORY

signaling cytokine , receptor

SUBCELLULAR LOCALIZATION	extracellular
	plasma membrane
text	localized to the Weibel-Palade bodies of vascular endothelial cells

basic FUNCTION	cell to cell signaling between stromal cells and osteoclast progenitor
	can act as a soluble factor in the regulation of bone mass
	specifically inhibits osteoclastogenesis
	playing a role in the vascular system
	involved in RANKL/RANK signaling
	regulates dendritic cells survival, monocyte chemotaxis, and B cell development and function by ligating TNF family member receptor activator of NF-kappaB ligand (TNFSF11)
	acts as an autocrine/paracrine growth factor for vascular smooth muscle cells, which might contribute to the progression of atherosclerotic lesions (Corallini 2009)
	key factor linking bone formation to resorption during bone remodeling
	expression of TNFRSF11B, TNFRSF11A and TNFSF11 genes exert a crucial role in the progression of Femoral head avascular necrosis (AVN), suggesting their roles in mediating bone homeostasis and potential effects on bone destruction

CELLULAR PROCESS	cell life, antiapoptosis

PHYSIOLOGICAL PROCESS

development

text	skeletal development

PATHWAY

metabolism

signaling

a component

involvement of the TNFRSF11A/TNFSF11/TNFRSF11B axis in osteosarcoma biology (Mori 2007)

INTERACTION

DNA

RNA

small molecule

protein	Osteoclast differentiation factor
	von Willebrand factor, vWF
	CTGF significantly bound to TNFRSF11B, which is a decoy receptor of TNFSF11
	CTGF canceled the inhibitory effect of TNFRSF11B on osteoclast differentiation

cell & other

REGULATION

activated by

upregulated by CD40 (TNFRSF5) stimulation

ASSOCIATED DISORDERS

corresponding disease(s)

PDB7

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function tumoral     --over   in hormone- resistant prostate tumor with good prognosis constitutional germinal mutation       associated with bone mineral density at different skeletal sites in adult men, but not in women constitutional     --over   in cirrhotic chronic liver disease, which could modulate bone loss constitutional     --over   by dendritic cells, increases with maturation and is NF-kappaB-dependent, possibly regulating immune responses in lymphoid tissues

Susceptibility

to osteoporotic fracture (to hip fractures) to the progression of atherosclerosis and cardiovascular disease to periodontitis to coronary artery disease to sporadic Paget bone disease

Variant & Polymorphism SNP , other	A163-G and T245-G were significantly more common among patients with vertebral fractures
	950 TC/1181 GC and 950 CC/1181 CC associated to an increased risk of coronary artery disease
	TG haplotype of T950C and G1181C polymorphisms in the OPG gene may be useful genetic markers for the prediction of periodontitis (Park 2008)
	G1181 allele, encoding lysine at codon 3 predisposing to the development of sporadic Paget bone disease
	Lys3Asn polymorphism increases susceptibility to hip fractures among older white women

Candidate gene
Marker	expression of TNFRSF11A, TNFSF11 and TNFRSF11B may be used as diagnostic markers to identify patients at high risk for aggressive Prostate carcinoma 6)
Therapy target
	System Type Disorder Pubmed cancer reproductive prostate effective suppression of Prostate carcinoma cell migration by TNFRSF11B via the blockage of TNFSF11 activity represents a potential therapeutic strategy for interfering with prostate tumor metastasis and progression to bone

ANIMAL & CELL MODELS

	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
	OCIF/OPG knockout mice are viable and fertile but exhibit severe osteoporosis due to enhanced osteoclastogenesis, and marked bone loss accompanied by destruction of growth plate and lack of trabecular bone in their femurs