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

	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.

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).
	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.
	For details see: http://www.ncbi.nlm.nih.gov/sites/entrez?cmd=Retrieve&db=homologene&dopt=AlignmentScores&list_uids=1912

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

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