Affinage

TNFRSF11B

Tumor necrosis factor receptor superfamily member 11B · UniProt O00300

Round 2 corrected
Length
401 aa
Mass
46.0 kDa
Annotated
2026-04-28
130 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNFRSF11B (osteoprotegerin/OPG) is a secreted homodimeric decoy receptor of the TNF receptor superfamily that functions as a master negative regulator of osteoclastogenesis by sequestering RANKL and preventing its engagement with RANK on osteoclast precursors (PMID:9108485, PMID:9520411). OPG also binds TRAIL with nanomolar affinity and inhibits TRAIL-induced apoptosis, linking bone remodeling to cell survival signaling in both normal and cancer contexts (PMID:9603945, PMID:11912131). Homodimerization through C-terminal cysteine residues is required for full RANKL-binding activity, and OPG transcription is regulated by a PKA-CREB pathway downstream of PTH, by the transcriptional repressor TIEG/KLF10 acting through Sp-1 sites, by Wnt signaling, by promoter CpG methylation, and by mechanotransduction via Piezo1-NOTCH3 (PMID:15777670, PMID:12364326, PMID:20059964, PMID:18305214, PMID:35754337). Loss-of-function mutations in TNFRSF11B cause juvenile Paget's disease (idiopathic hyperphosphatasia) through unrestrained RANKL-driven osteoclastogenesis, and OPG-deficient mice additionally develop arterial calcification, establishing OPG as a critical regulator of both bone mass and vascular integrity (PMID:12124406, PMID:9573043).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1997 High

    The discovery that OPG is a secreted TNF receptor superfamily member that inhibits osteoclast differentiation in vitro and causes osteopetrosis when overexpressed in vivo established the existence of a soluble osteoclastogenesis inhibitor.

    Evidence Transgenic mouse overexpression, recombinant protein administration, and in vitro osteoclast differentiation assays; independently confirmed by purification from fibroblast conditioned medium

    PMID:9108485 PMID:9168977

    Open questions at the time
    • Identity of OPG's ligand was unknown
    • Mechanism of osteoclastogenesis inhibition (direct vs. indirect) was unresolved
    • Physiological relevance of endogenous OPG was not yet tested by loss-of-function
  2. 1998 High

    Identification of RANKL as the OPG ligand, and the demonstration that OPG binds TRAIL, established OPG as a dual decoy receptor integrating bone remodeling and apoptosis pathways.

    Evidence Expression cloning identified ODF/RANKL as OPG's osteoblast-expressed ligand; independent binding studies showed OPG binds TRAIL at ~3 nM and blocks TRAIL-induced apoptosis

    PMID:9492069 PMID:9520411 PMID:9603945

    Open questions at the time
    • Whether OPG-TRAIL interaction has physiological significance in vivo was unclear
    • Relative affinities and competitive dynamics between RANKL and TRAIL binding to OPG were not fully quantified
  3. 1998 High

    OPG knockout mice developing severe osteoporosis and arterial calcification demonstrated that endogenous OPG is essential for maintaining both bone mass and vascular integrity in vivo.

    Evidence OPG-/- mice with skeletal phenotyping and arterial histopathology

    PMID:9573043

    Open questions at the time
    • Mechanism of OPG-mediated vascular protection was unknown
    • Whether arterial calcification reflects direct OPG action on vascular cells or indirect bone-vascular coupling was unresolved
  4. 1998 High

    Beyond blocking osteoclast differentiation, OPG was shown to directly inhibit bone-resorbing activity of mature osteoclasts by disrupting F-actin ring formation, via a 140 kDa binding protein on the osteoclast surface, revealing a post-differentiation function.

    Evidence Isolated osteoclast bone resorption assay with F-actin staining and ligand-binding detection

    PMID:9790989

    Open questions at the time
    • Identity of the 140 kDa OPG-binding protein on osteoclasts was not determined
    • Whether this direct osteoclast effect is RANKL-dependent or independent was not resolved
  5. 2002 High

    Human genetic studies linked loss-of-function TNFRSF11B mutations to juvenile Paget's disease, with complete gene deletion causing undetectable serum OPG and elevated RANKL, providing definitive proof that OPG is the critical RANKL antagonist in human bone homeostasis.

    Evidence Genomic deletion mapping, point mutation identification, serum OPG/sRANKL ELISA, and functional testing of mutant OPG in bone resorption assays

    PMID:12124406 PMID:12189164

    Open questions at the time
    • Full genotype-phenotype spectrum across different TNFRSF11B domains was incomplete
    • Whether heterozygous carriers have intermediate bone phenotypes was not established
  6. 2002 High

    The PTH-PKA-CREB pathway was identified as a major transcriptional regulator of the RANKL/OPG ratio, with PTH suppressing OPG through CREB-dependent mechanisms, explaining how hormonal signals modulate osteoclastogenesis via OPG.

    Evidence PKA inhibition, dominant-negative CREB/c-fos constructs, and reporter assays in osteoblastic cells; differentiation-stage analysis showed maximal OPG suppression in early osteoblasts

    PMID:12364326 PMID:14969393

    Open questions at the time
    • Direct CREB binding to the OPG promoter was not demonstrated by ChIP
    • Whether other PTH-responsive transcription factors contribute was unclear
  7. 2002 High

    OPG was found to function as a cancer cell survival factor by neutralizing TRAIL-induced apoptosis in prostate cancer, while myeloma cells actively degrade OPG via heparan sulfate-dependent internalization, revealing pathological exploitation of OPG in cancer.

    Evidence TRAIL apoptosis assays with RANKL competition in prostate cancer lines; OPG binding/internalization and degradation assays on myeloma cells

    PMID:11912131 PMID:12351414

    Open questions at the time
    • Whether OPG-mediated TRAIL neutralization is relevant to other cancer types in vivo was untested
    • Structural basis for OPG-heparan sulfate interaction was unknown
  8. 2005 High

    Truncation mutations removing the C-terminal domain abolished OPG homodimerization and reduced RANKL-binding capacity, establishing that C-terminal cysteine-mediated dimerization is required for full functional activity.

    Evidence Western blotting and ELISA of wild-type vs. truncated OPG after transient expression; confirmed by Balkan mutation analysis showing elevated monomeric OPG with impaired function in vivo

    PMID:15777670 PMID:17352649

    Open questions at the time
    • Crystal structure of the OPG homodimer was lacking
    • Precise stoichiometry of OPG-RANKL complex was not determined
  9. 2008 High

    Wnt signaling was identified as a positive regulator of OPG production in osteoblasts, with myeloma-derived DKK1 abolishing Wnt3a-induced OPG expression while enhancing RANKL, providing a molecular mechanism for myeloma bone disease.

    Evidence Recombinant DKK1 and Wnt3a treatment of osteoblasts, coculture with myeloma cells, and patient bone marrow sera analysis

    PMID:18305214

    Open questions at the time
    • Which specific Wnt pathway components (TCF/LEF binding sites) control OPG transcription was not mapped
    • Whether other Wnt antagonists similarly suppress OPG was untested
  10. 2010 High

    TIEG/KLF10 was shown to directly bind the OPG promoter at Sp-1 sites and repress transcription, identifying a specific transcription factor–promoter interaction that fine-tunes OPG levels in osteoblasts.

    Evidence ChIP assay demonstrating TIEG occupancy, luciferase reporter with deletion constructs, and site-directed mutagenesis of Sp-1 sites

    PMID:20059964

    Open questions at the time
    • Whether TIEG regulation of OPG operates in non-osteoblast lineages was unknown
    • Interaction with other Sp-1 site-binding factors was not examined
  11. 2014 Medium

    A gain-of-function read-through mutation in TNFRSF11B causing dominantly inherited early-onset osteoarthritis with chondrocalcinosis expanded the disease spectrum beyond loss-of-function bone disease, revealing that excessive OPG activity also has pathological consequences.

    Evidence Exome sequencing with linkage analysis, and functional bone resorption assay showing enhanced anti-resorptive activity of mutant OPG

    PMID:24743232

    Open questions at the time
    • Mechanism by which enhanced OPG activity causes chondrocalcinosis was not determined
    • Whether the extended C-terminal sequence gains new binding properties was untested
  12. 2020 Medium

    A RANKL-independent oncogenic function was identified in which TNFRSF11B directly binds GSK-3β, enhances its phosphorylation, and activates Wnt/β-catenin signaling in gastric cancer cells.

    Evidence Co-immunoprecipitation of OPG with GSK-3β, nuclear β-catenin quantification, and in vitro/in vivo tumor assays

    PMID:32398963

    Open questions at the time
    • GSK-3β interaction awaits reciprocal validation and domain mapping
    • Whether this occurs in non-cancer cells is unknown
    • Mechanism by which a secreted protein accesses intracellular GSK-3β was not explained
  13. 2022 Medium

    Mechanotransduction inputs were connected to OPG regulation through the Piezo1-NOTCH3 axis in osteocytes, and RANKL-independent downstream effects of OPG overexpression in chondrocytes (driving osteoblast-like gene programs) were identified, broadening OPG's functional repertoire beyond RANKL sequestration.

    Evidence Fluid shear stress with Piezo1 blocker GsMTx4 in osteocyte cell line; lentiviral OPG overexpression in 3D primary chondrocyte culture with RT-qPCR for osteogenic markers

    PMID:33989379 PMID:35754337

    Open questions at the time
    • NOTCH3 pathway intermediates connecting Piezo1 to OPG transcription were not mapped
    • The receptor mediating RANKL-independent OPG signaling in chondrocytes is unknown
    • In vivo validation of the Piezo1-OPG axis in bone loading is lacking

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of OPG homodimerization and RANKL/TRAIL dual binding, the identity of the receptor mediating RANKL-independent OPG signaling in chondrocytes and vascular cells, and the mechanism by which secreted OPG accesses intracellular GSK-3β in cancer contexts.
  • No crystal structure of the OPG homodimer or OPG-RANKL complex exists
  • RANKL-independent OPG receptor in chondrocytes/vasculature is unidentified
  • GSK-3β interaction mechanism requires validation that OPG is internalized or acts before secretion

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 5 GO:0140313 molecular sequestering activity 3 GO:0048018 receptor ligand activity 2
Localization
GO:0005576 extracellular region 5 GO:0031012 extracellular matrix 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3
Partners
DKK1GSK3BKLF10PIEZO1TNFSF10TNFSF11

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 Osteoprotegerin (OPG/TNFRSF11B) was identified as a novel secreted glycoprotein member of the TNF receptor superfamily that inhibits osteoclast differentiation from precursor cells in a dose-dependent manner. Hepatic overexpression in transgenic mice caused osteopetrosis with decreased osteoclast numbers, and administration of recombinant OPG to normal mice replicated these effects. OPG also blocked ovariectomy-associated bone loss in rats. Transgenic mouse overexpression, recombinant protein administration in vivo, in vitro osteoclast differentiation assay Cell High 9108485
1997 OPG/OCIF was purified from human fibroblast conditioned medium as a heparin-binding glycoprotein existing as a monomer (~60 kDa) and homodimer (~120 kDa). It specifically inhibited osteoclastogenesis driven by three distinct signaling pathways (vitamin D3, PTH, IL-11) without inhibiting mature osteoclast bone-resorbing activity, establishing it as a specific inhibitor of osteoclast development rather than function. Protein purification, in vitro osteoclastogenesis assay with multiple stimuli Biochemical and biophysical research communications High 9168977
1998 OPG/OCIF was shown to inhibit osteoclastogenesis by binding to a high-affinity site on osteoblastic stromal cells (ST2 line), blocking the cell-to-cell signal required for osteoclast progenitor differentiation. A single class of high-affinity OPG-binding sites appeared on ST2 cells in response to 1,25-dihydroxyvitamin D3, and an antibody blocking OPG binding to these sites abolished OPG's biological activity. Binding assay on stromal cells, antibody blockade, osteoclastogenesis coculture assay Endocrinology High 9492069
1998 Osteoclast differentiation factor (ODF/RANKL) was identified as the ligand for OPG/OCIF by expression cloning from mouse stromal cell cDNA library. OPG abolished OCL formation induced by soluble ODF, establishing OPG as a decoy receptor that blocks RANKL-RANK signaling to prevent osteoclastogenesis. Expression cloning, recombinant protein functional assay, OPG neutralization of ODF activity Proceedings of the National Academy of Sciences of the United States of America High 9520411
1998 OPG-deficient mice develop early-onset osteoporosis with severe trabecular and cortical bone porosity and high fracture incidence, demonstrating OPG is a critical regulator of postnatal bone mass. Unexpectedly, OPG-/- mice also develop medial calcification of the aorta and renal arteries, revealing OPG's role in protecting large arteries from calcification. Knockout mouse generation, skeletal phenotyping, histology, arterial pathology assessment Genes & development High 9573043
1998 OPG was identified as a receptor for the cytotoxic ligand TRAIL, binding TRAIL with an affinity of ~3 nM. OPG-Fc inhibits TRAIL-induced apoptosis of Jurkat cells, and conversely TRAIL blocks OPG's anti-osteoclastogenic activity, revealing cross-regulatory mechanisms between bone remodeling and apoptosis pathways. Binding affinity measurement (Fc-fusion proteins), TRAIL-induced apoptosis assay, competitive inhibition The Journal of biological chemistry High 9603945
1998 OCIF/OPG directly inhibits bone-resorbing activity of isolated mature osteoclasts in an ODF-independent manner. An OPG-binding protein of 140 kDa was detected on the osteoclast plasma membrane. OPG did not affect cathepsin K or carbonic anhydrase II mRNA levels but reduced/disrupted F-actin ring formation in osteoclasts, a cytoskeletal structure required for bone resorption. Isolated osteoclast bone resorption assay, ligand binding on osteoclast membrane, F-actin staining Biochemical and biophysical research communications High 9790989
1999 Genetic deletion of OPGL (RANKL) in mice caused severe osteopetrosis and complete absence of osteoclasts, confirming OPG's ligand RANKL is an essential osteoclast differentiation factor in vivo and that the OPG/RANKL system is the dominant regulator of osteoclastogenesis. Gene knockout in mice, skeletal phenotyping, osteoclast enumeration Nature High 9950424
2002 A homozygous 3-bp in-frame deletion in exon 3 of TNFRSF11B (loss of aspartate residue) was found in patients with idiopathic hyperphosphatasia. Recombinant mutant OPG expressed in HEK cells was secreted but failed to suppress bone resorption in vitro, whereas wild-type OPG suppressed it, confirming this as an inactivating mutation affecting RANKL-binding function. Genetic sequencing, recombinant protein expression in HEK cells, in vitro bone resorption assay Human molecular genetics High 12189164
2002 Juvenile Paget's disease in two Navajo patients results from homozygous deletion of TNFRSF11B (~100 kb) at chromosome 8q24.2. Serum OPG was undetectable and soluble RANKL was markedly elevated, directly demonstrating that OPG deficiency causes uncontrolled RANKL-driven osteoclastogenesis and rapid bone turnover in humans. PCR and Southern blotting of genomic DNA, sequence-tagged site mapping, ELISA for serum OPG and sRANKL The New England journal of medicine High 12124406
2002 OPG is produced by prostate cancer cells and functions as a survival factor by inhibiting TRAIL-induced apoptosis. High endogenous OPG production correlated with resistance to TRAIL-induced apoptosis, and this protection was reversed by 100-fold molar excess of RANKL (which competes for OPG binding), establishing OPG as a cancer cell survival factor via TRAIL neutralization. TRAIL apoptosis assay, OPG ELISA, competitive inhibition with RANKL, multiple prostate cancer cell lines Cancer research High 11912131
2002 Multiple myeloma cells bind, internalize, and degrade OPG through a mechanism dependent on OPG interaction with heparan sulfates on myeloma cell surfaces, providing a mechanism for reduced OPG levels in myeloma bone marrow and contributing to myeloma-associated bone destruction. OPG binding and internalization assays on myeloma cells, heparan sulfate competition, degradation assays Blood High 12351414
2002 PTH stimulates RANKL gene transcription and mRNA stability while potently suppressing OPG mRNA in stromal/osteoblastic cells via protein kinase A (PKA) activation. The transcription factor CREB is required for PTH stimulation of RANKL; dominant-negative CREB and c-fos reduced PTH suppression of OPG, establishing a PKA-CREB pathway as the mechanism for PTH-mediated regulation of the RANKL/OPG axis. PKA inhibition, dominant-negative CREB/c-fos expression, luciferase reporter assay, mRNA stability assay The Journal of biological chemistry High 12364326
2003 Homozygous mutations in TNFRSF11B were found in affected members of six of nine families with idiopathic hyperphosphatasia. Four of six mutations occurred in the cysteine-rich ligand-binding domain, predicted to disrupt OPG-RANKL binding. Cysteine missense mutations causing major disruption of the ligand-binding region correlated with severe phenotype, while non-cysteine or C-terminal mutations caused milder phenotypes, establishing a genotype-phenotype relationship for TNFRSF11B domain function. Genomic DNA sequencing, clinical phenotype correlation Journal of bone and mineral research Medium 14672344
2003 PTH differentially regulates RANKL and OPG expression across osteoblast differentiation stages: PTH maximally inhibits OPG in early osteoblasts (day 14) and maximally upregulates RANKL in mature osteoblasts (days 21-28). PTH-induced changes in RANKL/OPG ratio at day 14 increased TRACP+ cell numbers 5.6-fold in coculture, demonstrating that stage-specific PTH regulation of RANKL and OPG has functional osteoclastogenic consequences. qRT-PCR at multiple osteoblast differentiation stages, osteoclast coculture assay with TRACP staining Journal of bone and mineral research High 14969393
2004 Local OPG gene transfer (via HVJ envelope vector carrying pcDNA3.1-mOPG) to the periodontal tissue of rats significantly inhibited osteoclastogenesis and reduced experimental orthodontic tooth movement, demonstrating that OPG protein produced locally can neutralize RANKL activity and block osteoclast-mediated bone resorption in vivo. In vivo gene transfer, OPG protein production confirmed in vitro, osteoclast enumeration, tooth movement measurement Journal of dental research High 15557398
2004 OPG and RANK show expression in both internal and external enamel epithelium and dental papilla mesenchyme during murine odontogenesis, while RANKL is expressed in pre-osteogenic mesenchymal cells near developing tooth germs. Addition of exogenous OPG to tooth primordia explant cultures delayed tooth development and reduced mineralization, establishing a functional role for OPG in coordinating odontogenesis and osteogenesis. In situ hybridization/expression analysis during odontogenesis, OPG addition to organ culture explants Journal of dental research Medium 14981127
2004 RANKL stimulates matrix calcification, nodule formation, alkaline phosphatase activity, and expression of osteocalcin in cultured human aortic valve myofibroblasts, and increases DNA binding of cbfa-1. OPG expression is significantly lower in calcific aortic stenosis than controls, suggesting the RANKL-OPG pathway regulates valvular calcification by promoting osteoblast-like transition of valve cells. Immunohistochemistry on human valves, RANKL stimulation of cultured myofibroblasts, alkaline phosphatase assay, cbfa-1 DNA binding assay Journal of molecular and cellular cardiology Medium 14734048
2005 A truncating TNFRSF11B mutation (homozygous insertion/deletion in exon 5) predicts protein truncation at amino acid 325. Western blotting and ELISA after transient overexpression showed the mutant protein lacks homodimerization (C-terminal domain required for this) and has decreased RANKL-binding capacity, demonstrating that the C-terminal domain of OPG is required for homodimerization and full functional RANKL antagonism. Western blotting, ELISA, transient overexpression of wild-type vs. truncated OPG Bone High 15777670
2007 The TNFRSF11B 'Balkan' mutation (966_969delTGACinsCTT) deletes 79 C-terminal amino acids including a cysteine residue necessary for homodimerization. Despite elevated circulating immunoreactive OPG, the truncated monomer cannot form homodimers, and soluble RANKL is persistently elevated, demonstrating that OPG homodimerization via C-terminal cysteine is required for effective RANKL inhibition in vivo. TNFRSF11B sequencing, serum OPG and sRANKL ELISA, structural prediction of homodimerization requirement Journal of bone and mineral research Medium 17352649
2008 IL-6 and PGE2 produced by mechanically loaded osteoblasts induce a decrease in OPG expression (but not RANKL), and IL-6 neutralizing antibodies and piroxicam block this OPG decrease, establishing that mechanical compression-induced IL-6 and PGE2 downregulate OPG to increase the RANKL/OPG ratio in osteoblasts. Compression model of primary osteoblasts, neutralizing antibodies, COX inhibitor, real-time PCR, ELISA Osteoarthritis and cartilage Medium 18974013
2009 OPG binds membranous RANKL on cells and undergoes internalization through the clathrin pathway prior to proteasomal and/or lysosomal degradation. This OPG internalization process reduces the half-life of RANKL, revealing a reciprocal mechanism by which OPG-RANKL binding leads to co-degradation of both molecules. Internalization assay, clathrin pathway inhibition, degradation assays The Keio journal of medicine Medium 19398882
2009 OPG-Fc (OPG without the heparin-binding domain) treatment of OA chondrocytes significantly stimulated MMP-13 and PAR-2 production, revealing that OPG has RANKL-independent signaling in chondrocytes that promotes catabolic factor expression, a pathway distinct from its role in bone remodeling. OPG-Fc treatment of primary human OA chondrocytes, cytokine measurement by ELISA, flow cytometry for RANK/RANKL Rheumatology (Oxford, England) Medium 19762475
2009 DNA methylation silences OPG expression in cancer cells: OPG promoter CpG dinucleotides are highly methylated in OPG-silenced cancer cell lines, with reduced H3K4me3 and increased H3K27me3 at the OPG gene. Recombinant OPG reduced cancer cell growth through apoptosis, establishing epigenetic repression as a mechanism of OPG silencing in carcinoma. Bisulfite sequencing, ChIP for histone modifications, recombinant OPG apoptosis assay, cDNA microarray Journal of cellular biochemistry Medium 19565568
2010 TGFβ-inducible early gene-1 (TIEG/KLF10) directly binds to the OPG promoter and represses its transcription in osteoblasts. Transient ChIP assays showed TIEG occupancy at the OPG promoter, and site-directed mutagenesis identified two Sp-1 binding sites within a 200 bp region as required for TIEG-mediated repression, explaining why TIEG KO osteoblasts have increased OPG and reduced osteoclastogenesis support. ChIP assay, luciferase reporter with OPG promoter deletion constructs, site-directed mutagenesis, TIEG KO osteoblasts Biochemical and biophysical research communications High 20059964
2014 A heterozygous read-through mutation (c.1205A>T; p.Stop402Leu) in TNFRSF11B was identified in a family with dominantly inherited early-onset osteoarthritis with chondrocalcinosis. The mutant OPG showed enhanced capacity to inhibit osteoclastogenesis and bone resorption in a bone resorption cell-based assay, establishing this as a gain-of-function mutation in TNFRSF11B that causes OA. Exome sequencing, linkage analysis, bone resorption cell-based assay comparing wild-type vs. mutant OPG Annals of the rheumatic diseases Medium 24743232
2018 DNA methylation inversely regulates OPG and RANKL expression in osteoporotic bone: OPG promoter CpG methylation is higher and OPG expression lower in osteoporotic fracture bone, while RANKL promoter methylation is lower and RANKL expression higher, demonstrating that promoter methylation is a major epigenetic switch controlling the RANKL/OPG ratio in bone pathophysiology. Bisulfite sequencing of promoter CpG islands, qRT-PCR of OPG and RANKL in bone biopsies International journal of medical sciences Medium 30443169
2020 TNFRSF11B overexpression in gastric cancer cells promotes proliferation, migration, invasion, and tumorigenesis. Mechanistically, TNFRSF11B directly binds GSK-3β (detected by co-immunoprecipitation), upregulates GSK-3β phosphorylation, and consequently increases nuclear β-catenin and downstream Wnt/β-catenin target gene expression, identifying a non-canonical RANKL-independent oncogenic signaling role for TNFRSF11B. Co-immunoprecipitation, immunofluorescence for nuclear β-catenin, Western blotting, in vitro and in vivo tumor assays International journal of biological sciences Medium 32398963
2022 TNFRSF11B overexpression in primary human articular chondrocytes (3D chondrogenic model) strongly upregulates MMP13, COL2A1, COL1A1, RUNX2, ASPN, OGN, and BMP6 (9-fold), while RANK and RANKL expression remained unchanged, indicating TNFRSF11B drives chondrocyte-to-osteoblast transition in OA cartilage through previously unknown downstream pathways independent of the OPG/RANK/RANKL triad. Lentiviral overexpression in primary chondrocytes, 3D chondrogenic culture, RT-qPCR, immunohistochemistry, ELISA, Alcian blue staining Rheumatology (Oxford, England) Medium 33989379
2022 Fluid shear stress (FSS) promotes OPG expression and inhibits RANKL expression in MLO-Y4 osteocytes via Piezo1 mechanosensitive ion channel and NOTCH3 signaling. Blocking Piezo1 with GsMTx4 reversed FSS effects on OPG and RANKL, establishing a Piezo1-NOTCH3 pathway as a mechanotransduction mechanism regulating OPG production. Fluid shear stress apparatus, Piezo1 blocker (GsMTx4), RT-PCR and protein expression in osteocyte cell line Channels (Austin, Tex.) Medium 35754337
2008 OPG and TRAIL co-localize at sites of vascular calcification in Mönckeberg's sclerosis and atherosclerosis, with OPG expressed surrounding calcified areas in medial and neointimal layers where apoptosis also occurs, suggesting OPG is expressed at vascular calcification sites to regulate both apoptosis (via TRAIL) and osteoclast-like differentiation. Immunohistochemistry, in situ hybridization, in situ ligation apoptosis assay on human arterial specimens The Journal of clinical endocrinology and metabolism Medium 15292354
2008 Myeloma-derived DKK1 (a Wnt inhibitor) abolishes Wnt3a-induced OPG mRNA and protein production by mouse and human osteoblasts, while simultaneously enhancing RANKL expression, providing a molecular mechanism by which myeloma cells disrupt the Wnt-regulated OPG/RANKL balance to promote osteoclastogenesis and bone lesions. Recombinant DKK1 treatment, coculture of osteoblasts with MM cells, Wnt3a stimulation, OPG/RANKL mRNA and protein measurement, bone marrow sera from MM patients Blood High 18305214

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 3964 9108485
1998 Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proceedings of the National Academy of Sciences of the United States of America 3272 9520411
1999 OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 2612 9950424
1998 osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes & development 1928 9573043
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
2008 Functions of RANKL/RANK/OPG in bone modeling and remodeling. Archives of biochemistry and biophysics 1318 18395508
2001 Minireview: the OPG/RANKL/RANK system. Endocrinology 1046 11713196
1998 Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin (OPG): a mechanism by which OPG/OCIF inhibits osteoclastogenesis in vitro. Endocrinology 982 9492069
1998 Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. The Journal of biological chemistry 974 9603945
2012 Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture. Nature genetics 958 22504420
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2007 Biology of RANK, RANKL, and osteoprotegerin. Arthritis research & therapy 691 17634140
1997 Isolation of a novel cytokine from human fibroblasts that specifically inhibits osteoclastogenesis. Biochemical and biophysical research communications 619 9168977
2009 Twenty bone-mineral-density loci identified by large-scale meta-analysis of genome-wide association studies. Nature genetics 552 19801982
2004 The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine & growth factor reviews 531 15561602
2008 Bone mineral density, osteoporosis, and osteoporotic fractures: a genome-wide association study. Lancet (London, England) 522 18455228
2012 Bench to bedside: elucidation of the OPG-RANK-RANKL pathway and the development of denosumab. Nature reviews. Drug discovery 521 22543469
2020 Osteoclast differentiation by RANKL and OPG signaling pathways. Journal of bone and mineral metabolism 514 33079279
1994 Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides. Gene 492 8125298
2014 Biology of the RANKL-RANK-OPG System in Immunity, Bone, and Beyond. Frontiers in immunology 487 25368616
2008 Multiple genetic loci for bone mineral density and fractures. The New England journal of medicine 485 18445777
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2005 Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes. Genome research 409 16344560
2004 Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circulation research 383 15564564
2002 Osteoprotegerin deficiency and juvenile Paget's disease. The New England journal of medicine 296 12124406
2011 The RANKL-OPG system in clinical periodontology. Journal of clinical periodontology 265 22092994
2003 PTH differentially regulates expression of RANKL and OPG. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 262 14969393
2011 A genome-wide meta-analysis of six type 1 diabetes cohorts identifies multiple associated loci. PLoS genetics 260 21980299
2007 The RANKL/RANK/OPG pathway. Current osteoporosis reports 256 17925190
2012 New insights into osteoclastogenic signaling mechanisms. Trends in endocrinology and metabolism: TEM 252 22705116
1997 Characterization 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. Gene 238 9434163
2004 Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulate aortic valve calcification. Journal of molecular and cellular cardiology 225 14734048
2002 Osteoprotegerin (OPG) is a survival factor for human prostate cancer cells. Cancer research 222 11912131
2009 RANK/RANKL/OPG during orthodontic tooth movement. Orthodontics & craniofacial research 201 19419454
2007 CLINICAL Review #: the role of receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin: clinical implications. The Journal of clinical endocrinology and metabolism 195 17895323
2014 Tr1 cells and the counter-regulation of immunity: natural mechanisms and therapeutic applications. Current topics in microbiology and immunology 192 25004813
2004 RANKL/RANK/OPG: new therapeutic targets in bone tumours and associated osteolysis. Biochimica et biophysica acta 192 15363860
2002 Osteoprotegerin is bound, internalized, and degraded by multiple myeloma cells. Blood 189 12351414
2004 Following a TRAIL: update on a ligand and its five receptors. Cell research 187 15538968
2008 Myeloma-derived Dickkopf-1 disrupts Wnt-regulated osteoprotegerin and RANKL production by osteoblasts: a potential mechanism underlying osteolytic bone lesions in multiple myeloma. Blood 185 18305214
2002 Parathyroid hormone stimulates receptor activator of NFkappa B ligand and inhibits osteoprotegerin expression via protein kinase A activation of cAMP-response element-binding protein. The Journal of biological chemistry 177 12364326
2004 Localization of osteoprotegerin, tumor necrosis factor-related apoptosis-inducing ligand, and receptor activator of nuclear factor-kappaB ligand in Mönckeberg's sclerosis and atherosclerosis. The Journal of clinical endocrinology and metabolism 169 15292354
2002 A mutation in the gene TNFRSF11B encoding osteoprotegerin causes an idiopathic hyperphosphatasia phenotype. Human molecular genetics 165 12189164
2021 Discovery of the RANKL/RANK/OPG system. Journal of bone and mineral metabolism 158 33389131
2003 Expression of RANKL and OPG mRNA in periodontal disease: possible involvement in bone destruction. International journal of molecular medicine 158 12469211
2011 Rank/Rankl/opg: literature review. Acta reumatologica portuguesa 141 22113597
2011 Type 1 regulatory T cells (Tr1) in autoimmunity. Seminars in immunology 132 21840222
2009 Action of RANKL and OPG for osteoclastogenesis. Critical reviews in eukaryotic gene expression 130 19191757
2011 Induction of regulatory Tr1 cells and inhibition of T(H)17 cells by IL-27. Seminars in immunology 129 21893418
1983 RNA polymerase pausing and transcript release at the lambda tR1 terminator in vitro. The Journal of biological chemistry 109 6308007
2004 Local OPG gene transfer to periodontal tissue inhibits orthodontic tooth movement. Journal of dental research 108 15557398
2006 Mechanisms of disease: roles of OPG, RANKL and RANK in the pathophysiology of skeletal metastasis. Nature clinical practice. Oncology 106 16407878
2008 Mechanical loading highly increases IL-6 production and decreases OPG expression by osteoblasts. Osteoarthritis and cartilage 105 18974013
2008 IL-10 suppressor activity and ex vivo Tr1 cell function are impaired in multiple sclerosis. European journal of immunology 100 18200504
2008 Pathophysiological roles of osteoprotegerin (OPG). European journal of cell biology 97 18707795
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