TNFRSF11B

Official Full Name

TNF receptor superfamily member 11b

Organism

Homo sapiens

GeneID

4982

Background

The protein encoded by this gene is a member of the TNF-receptor superfamily. This protein is an osteoblast-secreted decoy receptor that functions as a negative regulator of bone resorption. This protein specifically binds to its ligand, osteoprotegerin ligand, both of which are key extracellular regulators of osteoclast development. Studies of the mouse counterpart also suggest that this protein and its ligand play a role in lymph-node organogenesis and vascular calcification. Alternatively spliced transcript variants of this gene have been reported, but their full length nature has not been determined. [provided by RefSeq, Jul 2008]

Synonyms

OPG; TR1; OCIF; PDB5;

Protein Sequence

MNNLLCCALVFLDISIKWTTQETFPPKYLHYDEETSHQLLCDKCPPGTYLKQHCTAKWKTVCAPCPDHYYTDSWHTSDECLYCSPVCKELQYVKQECNRTHNRVCECKEGRYLEIEFCLKHRSCPPGFGVVQAGTPERNTVCKRCPDGFFSNETSSKAPCRKHTNCSVFGLLLTQKGNATHDNICSGNSESTQKCGIDVTLCEEAFFRFAVPTKFTPNWLSVLVDNLPGTKVNAESVERIKRQHSSQEQTFQLLKLWKHQNKDQDIVKKIIQDIDLCENSVQRHIGHANLTFEQLRSLMESLPGKKVGAEDIEKTIKACKPSDQILKLLSLWRIKNGDQDTLKGLMHALKHSKTYHFPKTVTQSLKKTIRFLHSFTMYKLYQKLFLEMIGNQVQSVKISCL

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Detailed Information

The TNFRSF11B gene, also known as osteoprotegerin (OPG), is located on human chromosome 8q24.12 and consists of five exons. It encodes a secreted glycoprotein of 401 amino acids with an approximate molecular weight of 60 kDa. The promoter region of TNFRSF11B contains regulatory elements responsive to RANKL, calcium, and estrogen. OPG is mainly secreted by osteoblasts, vascular smooth muscle cells, and endothelial cells, and circulates predominantly as a disulfide-linked homodimer. Structurally, OPG contains four cysteine-rich domains (D1–D4): D1–D3 mediate binding to its key ligand RANKL, whereas D4 participates in heparin binding, which influences OPG localization within the vascular wall.

Biological Functions and Molecular Mechanisms

The central function of OPG is to act as a decoy receptor for RANKL (Receptor Activator of NF-κB Ligand), thereby regulating bone remodeling and immune homeostasis:

Bone metabolism balance: RANKL normally binds to its functional receptor RANK on osteoclast precursors, activating NF-κB and NFATc1 signaling pathways to promote osteoclast differentiation and bone resorption. By competitively binding RANKL, OPG blocks this axis and maintains the balance between bone formation and resorption.

Inhibition of vascular calcification: In the vascular wall, OPG binds TRAIL (TNF-related apoptosis-inducing ligand) and prevents TRAIL-mediated apoptosis of vascular smooth muscle cells. Since apoptotic bodies serve as nucleation sites for hydroxyapatite deposition, OPG indirectly reduces vascular calcification by suppressing apoptosis.

Immune regulation and organogenesis: OPG knockout mice display disorganized lymphoid architecture due to uncontrolled RANKL signaling. More recent studies have also shown that OPG can directly bind BMP-2, inhibiting its osteogenic activity, which provides protection against heterotopic ossification.

Figure 1. Mechanisms of action of OPG and TRAIL in endothelial cells. (Montañez-Barragán A, et al., 2022)

Skeletal Disorders

Juvenile Paget disease (PDB5): Homozygous TNFRSF11B mutations reduce OPG affinity for RANKL, leading to severe juvenile-onset skeletal deformities and pathological fractures. Despite normal or elevated serum OPG levels, the protein is functionally deficient, resulting in excessive osteoclast activation.

Postmenopausal osteoporosis: Estrogen deficiency downregulates OPG expression, shifting the OPG/RANKL ratio in favor of bone resorption. Denosumab, a monoclonal antibody against RANKL and a functional OPG mimetic, reduces vertebral fracture risk by up to 70%.

Cardiovascular Disease

OPG exerts adual rolein atherosclerosis:

Protective:Low OPG levels correlate with higher coronary artery calcification scores, particularly in diabetic patients, and OPG polymorphisms (e.g.,rs2073618) have been associated with increased myocardial infarction risk.

Pathological:Excessive OPG expression in advanced plaques may promote plaque instability, partly through OPG-mediated induction ofmonocyte chemoattractant protein-1 (MCP-1).

Chronic Kidney Disease and Metabolic Disorders

In end-stage renal disease, serum OPG concentrations exceeding10 pmol/Lare independently associated with cardiovascular mortality. Hyperphosphatemia induces OPG secretion by vascular smooth muscle cells as a compensatory anti-calcification mechanism, but sustained overexpression paradoxically promotes mineral deposition. In type 2 diabetes, high glucose andadvanced glycation end products (AGEs)enhance OPG expression, and serum OPG levels correlate positively withcarotid intima-media thickness (cIMT), suggesting its utility as a biomarker of diabetic vasculopathy.

OPG Mimetics

Denosumab is the first clinically approved monoclonal antibody targeting RANKL and has been widely used in osteoporosis and giant cell tumors of bone. However, long-term use may lead to adverse effects such as osteonecrosis of the jaw (ONJ), and vertebral fracture risk rebounds upon discontinuation.

Gene Therapy Approaches

AAV-mediated OPG overexpression has demonstratedchondroprotective effects in canine models of osteoarthritis, though systemic elevation of OPG poses risks of impaired physiological bone remodeling.

Small-Molecule Modulators

Thiazolidinediones can upregulate OPG via PPARγ activation, but their cardiovascular side effects limit clinical use. Next-generation selective PPARγ modulators (SPPARMγ) are under development to circumvent these drawbacks.

Global multicenter studies, such as the FREEDOM trial, confirm that the OPG/RANKL signaling axis remains a central therapeutic target in both skeletal and vascular diseases. Emerging strategies that exploit tissue-specific delivery systems (e.g., bone-targeted peptide conjugates) hold promise for overcoming current therapeutic limitations.

Reference

Dutka M, Bobiński R, Wojakowski W, et al. Osteoprotegerin and RANKL-RANK-OPG-TRAIL signalling axis in heart failure and other cardiovascular diseases. Heart Fail Rev. 2022 Jul;27(4):1395-1411.
Montañez-Barragán A, Gómez-Barrera I, Sanchez-Niño MD, et al. Osteoprotegerin and kidney disease. J Nephrol. 2014 Dec;27(6):607-17.

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