Affinage

TNFRSF11A

Tumor necrosis factor receptor superfamily member 11A · UniProt Q9Y6Q6

Length
616 aa
Mass
66.0 kDa
Annotated
2026-04-28
100 papers in source corpus 26 papers cited in narrative 26 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNFRSF11A (RANK) is the obligate receptor for RANKL that drives osteoclast differentiation, bone resorption, mammary progenitor expansion, and dendritic cell survival through TRAF6-dependent activation of NF-κB, MAPK, and calcium signaling. The RANK extracellular domain binds trimeric RANKL as a monomer with high affinity (KD ~10⁻¹⁰ M), undergoing a CRD2-CRD3 hinge conformational change that triggers cytoplasmic recruitment of TRAF6 and assembly of a signaling complex containing Gab2 and PLCγ2, which is negatively regulated by the deubiquitinase CYLD (via TRAF6 deubiquitination), A20 (via ubiquitin-binding zinc finger domains recruited directly to the RANK complex), and STAC2 (which disrupts the Gab2/PLCγ2 complex) (PMID:9878548, PMID:20483727, PMID:19416721, PMID:16147974, PMID:18382763, PMID:36194667, PMID:29348675). In mammary epithelium, RANK signaling amplifies WNT responsiveness through R-spondin1 upregulation, expanding luminal progenitors; genetic RANK inactivation delays BRCA1-mutant mammary tumorigenesis (PMID:26095608, PMID:27241552). Loss-of-function TNFRSF11A mutations cause autosomal recessive osteoclast-poor osteopetrosis with hypogammaglobulinemia, while gain-of-function signal-peptide insertions cause familial expansile osteolysis and related hyperresorptive bone diseases through constitutive NF-κB activation (PMID:18606301, PMID:10615125, PMID:11771666).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1998 High

    Identification of RANK as the essential receptor transducing RANKL signals in osteoclast progenitors resolved how osteoclastogenic cytokine signaling is received at the cell surface, establishing RANK as the central receptor in bone resorption.

    Evidence Molecular cloning, soluble receptor and Fab blocking of ODF binding, and anti-RANK antibody stimulation of osteoclastogenesis in vitro

    PMID:9878548

    Open questions at the time
    • Downstream intracellular signaling adaptors not yet mapped
    • Role in non-bone tissues unknown
  2. 2000 High

    Discovery that heterozygous signal-peptide insertions in TNFRSF11A cause familial expansile osteolysis through constitutive NF-κB activation established the first gain-of-function disease mechanism for RANK and linked aberrant receptor processing to ligand-independent signaling.

    Evidence Patient sequencing, recombinant mutant RANK expression, NF-κB reporter assay; allelic ESH mutation identified in 2002

    PMID:10615125 PMID:11771666

    Open questions at the time
    • Precise mechanism by which uncleaved signal peptide activates signaling not resolved
    • Whether mutations promote receptor oligomerization or trafficking defects unclear
  3. 2002 Medium

    Demonstration that RANK-RANKL interaction sustains dendritic cell survival via Bcl-2 extended RANK function beyond bone biology to immune cell homeostasis.

    Evidence Soluble RANK blocking and exogenous TRANCE rescue of CD34+-derived dendritic cell viability with Bcl-2 quantification

    PMID:12393586

    Open questions at the time
    • Intracellular signaling pathway mediating DC survival through RANK not delineated
    • In vivo validation in DC-specific RANK KO not performed
  4. 2005 High

    Genetic epistasis using RANK-null and TRAF6-null mice confirmed TRAF6 as the indispensable cytoplasmic adaptor for RANK-mediated osteoclastogenesis, while revealing a RANK-independent TNF-α/TGF-β backup pathway.

    Evidence In vitro osteoclast differentiation from RANK-null and TRAF6-null hematopoietic precursors with TNF-α/TGF-β stimulation

    PMID:16147974

    Open questions at the time
    • In vivo relevance of the RANK-independent backup pathway unresolved at this point
    • Other TRAFs' individual contributions not dissected
  5. 2005 Medium

    Mapping of a RANK cytoplasmic self-assembly domain (residues 534–539) distinct from TRAF-binding sites showed that RANK can oligomerize and signal ligand-independently, providing a mechanism for how gain-of-function mutations may constitutively activate the receptor.

    Evidence Co-immunoprecipitation of FLAG/HA-tagged RANK deletion mutants, TRAF6 decoy peptide inhibition, osteoclast differentiation assay

    PMID:16234979

    Open questions at the time
    • Crystal structure of cytoplasmic domain oligomer not obtained
    • Self-assembly not validated with biophysical methods beyond co-IP
    • Physiological stoichiometry on cell surface not determined
  6. 2008 High

    Identification of CYLD as a negative regulator that deubiquitinates TRAF6 via p62-mediated recruitment to the RANK complex established the first checkpoint mechanism restraining RANK-driven osteoclastogenesis, with CYLD-null mice displaying severe osteoporosis.

    Evidence CYLD knockout mouse, co-IP of CYLD-p62-TRAF6, ubiquitination assays, osteoclast differentiation

    PMID:18382763

    Open questions at the time
    • Whether CYLD acts on other ubiquitin chain types beyond K63 at the RANK complex not fully resolved
    • Relative contributions of CYLD versus other DUBs not compared
  7. 2008 High

    Discovery that loss-of-function TNFRSF11A mutations cause autosomal recessive osteopetrosis with hypogammaglobulinemia proved that RANK is non-redundant for both osteoclast formation and B cell terminal differentiation in humans.

    Evidence Patient TNFRSF11A sequencing, failed in vitro osteoclast differentiation from patient monocytes, immunological phenotyping

    PMID:18606301

    Open questions at the time
    • Mechanism of RANK requirement for immunoglobulin-secreting B cells not elucidated
    • Thymic epithelial cell involvement in patients not assessed
  8. 2009 High

    Quantitative biophysical measurement of the RANK-RANKL interaction (KD ~1.09 × 10⁻¹⁰ M, monomeric RANK binding trimeric RANKL) provided the affinity benchmark needed to interpret how signaling strength relates to receptor occupancy.

    Evidence Recombinant protein SPR, gel filtration, and chemical cross-linking

    PMID:19416721

    Open questions at the time
    • On-cell binding parameters may differ from solution measurements
    • Effect of membrane context and pre-assembly not captured
  9. 2010 High

    Crystal structures of free RANK and the RANKL–RANK complex revealed a four-CRD architecture with a CRD2-CRD3 hinge conformational change upon ligand binding, providing the first atomic-resolution view of how RANKL engages its receptor.

    Evidence X-ray crystallography of unliganded and complexed RANK, site-directed mutagenesis with osteoclast formation assay

    PMID:20483727

    Open questions at the time
    • Full-length receptor structure including transmembrane and cytoplasmic domains unavailable
    • How extracellular conformational change transmits to cytoplasmic TRAF recruitment not structurally resolved
  10. 2013 Medium

    Constitutive RANK signaling in mammary epithelium expanded stem/progenitor populations and disrupted luminal commitment, establishing RANK as a driver of mammary cell fate and tumorigenesis beyond its skeletal role.

    Evidence Transgenic mouse model with constitutive RANK expression, FACS of mammary populations, histology

    PMID:23766243

    Open questions at the time
    • Downstream transcriptional program in mammary progenitors not fully mapped
    • Whether RANK acts cell-autonomously or via paracrine WNT not separated at this stage
  11. 2015 High

    Conditional RANK knockout in mammary epithelium revealed that RANK amplifies WNT signaling through R-spondin1, and exogenous R-spondin1 rescue demonstrated epistasis, placing RANK upstream of WNT in mammary progenitor expansion.

    Evidence Conditional RANK KO mouse, WNT reporter, R-spondin1 rescue, human breast tissue analysis

    PMID:26095608

    Open questions at the time
    • Direct transcriptional mechanism linking RANK signaling to R-spondin1 gene induction not identified
    • Whether this axis operates in human breast cancer in vivo unclear
  12. 2016 High

    Genetic RANK inactivation in mammary epithelium delayed BRCA1/p53-driven breast cancer onset and pharmacological RANKL inhibition suppressed human BRCA1-mutant progenitor expansion, establishing RANK as a therapeutic target in hereditary breast cancer.

    Evidence Two conditional RANK KO mouse models, pharmacological RANKL inhibition, human BRCA1-mutant tissue progenitor assays

    PMID:27241552

    Open questions at the time
    • Long-term efficacy of RANKL inhibition in breast cancer prevention trials not established
    • Whether RANK-independent compensatory pathways emerge over time not tested
  13. 2016 High

    Demonstration that RANK-independent osteoclastogenesis occurs in inflammatory arthritis via TNF/IL-6/DAP12 defined the limits of RANK's non-redundancy and explained clinical observations of bone erosion despite RANKL blockade.

    Evidence Conditional RANK KO in K/BxN serum-transfer arthritis model, in vitro differentiation from RANK-null precursors, micro-CT

    PMID:27563728

    Open questions at the time
    • Relative quantitative contribution of RANK-dependent vs RANK-independent osteoclasts in human arthritis not measured
    • Whether RANK-independent osteoclasts are functionally equivalent not determined
  14. 2018 Medium

    Identification of STAC2 as a RANKL-inducible negative feedback inhibitor that disrupts the Gab2/PLCγ2 signaling complex at RANK added a second layer of intrinsic restraint distinct from the CYLD/A20 deubiquitination axis.

    Evidence Co-immunoprecipitation of STAC2-RANK, NF-κB/MAPK reporters, osteoclast differentiation assay

    PMID:29348675

    Open questions at the time
    • In vivo validation in STAC2-deficient mice not reported
    • Structural basis of STAC2 interaction with RANK not determined
  15. 2022 High

    Discovery that A20 is recruited to the RANK complex within minutes and restrains NF-κB via ubiquitin-binding ZnF4/7 domains (not its deubiquitinase activity) revealed a mechanistically distinct negative regulator and explained severe osteoporosis in osteoclast-specific A20 knockouts.

    Evidence Osteoclast-specific conditional A20 KO mouse, co-IP of RANK complex, ZnF domain mutants, NF-κB reporter

    PMID:36194667

    Open questions at the time
    • Structural basis of A20 recruitment to RANK complex not determined
    • Whether CYLD and A20 act redundantly or sequentially at the RANK complex not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RANK's extracellular conformational change upon RANKL binding is mechanically transmitted through the transmembrane domain to initiate cytoplasmic TRAF6 recruitment remains structurally unresolved, and no full-length RANK structure exists.
  • Full-length RANK structure including transmembrane and cytoplasmic domains not solved
  • Temporal order and cooperativity of TRAF6, CYLD, A20, and STAC2 assembly at the receptor not defined
  • Whether RANK's mammary WNT-amplifying function uses the same or distinct cytoplasmic signaling complexes as osteoclastogenesis unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 4
Localization
GO:0005886 plasma membrane 5
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2
Partners
CYLDGAB2PLCG2SQSTM1STAC2TNFAIP3TNFSF11TRAF6
Complex memberships
RANK-RANKL signaling complexRANK-TRAF6 complex

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 RANK (TNFRSF11A) was identified as the essential signaling receptor for osteoclast differentiation factor (ODF/RANKL) on osteoclast progenitors; soluble RANK and Fab antibody fragments blocked ODF binding to RANK and inhibited osteoclastogenesis, while anti-RANK polyclonal antibody stimulated osteoclastogenesis in the presence of M-CSF. Molecular cloning, receptor binding assay, antibody blocking, soluble receptor inhibition in osteoclast differentiation assay Biochemical and biophysical research communications High 9878548
2000 Heterozygous insertional duplications (18-bp and 27-bp) in exon 1 of TNFRSF11A affecting the RANK signal peptide cause familial expansile osteolysis; mutant RANK proteins showed perturbed expression levels, lack of normal signal peptide cleavage, and increased RANK-mediated NF-κB signaling in vitro, indicating gain-of-function activating mutations. Sequencing of patient samples, expression of recombinant mutant RANK proteins, NF-κB reporter assay Nature genetics High 10615125
2002 Expansile skeletal hyperphosphatasia (ESH) is caused by a 15-bp tandem duplication in the TNFRSF11A signal peptide, allelic to familial expansile osteolysis, and likely reflects increased NF-κB activity via activated RANK signaling. Molecular sequencing, genetic analysis Journal of bone and mineral research Medium 11771666
2005 TRAF6 is an indispensable signaling adaptor for RANK in osteoclastogenesis; however, osteoclast differentiation can occur via a TRANCE-RANK-TRAF6-independent pathway when hematopoietic precursors from RANK-null or TRAF6-null mice are stimulated with TNF-alpha plus TGF-beta in vitro. Genetic knockout mouse models, in vitro osteoclast differentiation assay with cytokine stimulation The Journal of experimental medicine High 16147974
2005 RANK self-assembles through its cytoplasmic domain at position 534-539 (distinct from TRAF binding domains) ligand-independently, and overexpression of oligomeric RANK induces osteoclastogenesis in a TRAF6-dependent manner without RANKL. Co-immunoprecipitation with FLAG/HA-tagged RANK constructs, C-terminal deletion mutants, osteoclast differentiation assay, TRAF6 decoy peptide inhibition Journal of bone and mineral research Medium 16234979
2007 RANK interacts with five members of the TRAF family (TRAF1, 2, 3, 5, 6), of which TRAF6 is indispensable for RANK signaling capability and links RANKL-RANK interaction to downstream NF-κB activation and osteoclastogenic transcriptional programs. Review of biochemical interaction studies, genetic experiments Advances in experimental medicine and biology Medium 17633024
2008 CYLD deubiquitinase negatively regulates RANK signaling by inhibiting TRAF6 ubiquitination, thereby suppressing downstream NF-κB and other signaling events; CYLD is recruited to TRAF6 through physical interaction with the adaptor p62, and CYLD deficiency leads to hyperresponsive RANKL-induced osteoclastogenesis and severe osteoporosis in mice. CYLD knockout mouse model, in vitro osteoclast differentiation assay, co-immunoprecipitation, ubiquitination assay The Journal of clinical investigation High 18382763
2008 Mutations in TNFRSF11A (RANK) cause autosomal recessive osteoclast-poor osteopetrosis with hypogammaglobulinemia; patient monocytes failed to differentiate into osteoclasts upon M-CSF and RANKL stimulation, establishing an osteoclast-intrinsic defect, and immunological analysis showed impairment of immunoglobulin-secreting B cells. TNFRSF11A sequencing in patients, in vitro osteoclast differentiation assay with patient monocytes, immunological phenotyping American journal of human genetics High 18606301
2008 RANKL stimulation of mature osteoclasts via RANK results in translocation of NF-κB to the nucleus and elevation of cytosolic and nuclear calcium levels, demonstrating functional RANK expression in mature (not only precursor) osteoclasts. Microisolation of pure osteoclast populations, RT-PCR, NF-κB nuclear translocation assay, calcium signaling measurement FEBS letters Medium 10606741
2009 The extracellular domain of RANK binds RANKL as a monomer, while RANKL exists as a trimer; the binding affinity (KD ~1.09 × 10⁻¹⁰ M) was measured by surface plasmon resonance, establishing the high-affinity nature of the RANK-RANKL interaction. Recombinant protein expression and purification, gel filtration, chemical cross-linking, surface plasmon resonance Archives of biochemistry and biophysics High 19416721
2010 Crystal structures of unliganded RANK and the RANKL-RANK complex revealed that RANK has four full cysteine-rich domains (CRDs), with CRD4 stabilized by a sodium ion and a rigid linkage to CRD3; upon RANKL binding, RANK undergoes a hinge movement between CRD2 and CRD3 to form continuous close contact with RANKL. Mutations reducing RANK-RANKL affinity significantly disrupted osteoclast formation. X-ray crystallography of RANK alone and in complex with RANKL, site-directed mutagenesis, osteoclast formation assay Journal of immunology High 20483727
2004 RANK is expressed by monocytes and RANKL stimulates monocyte chemotaxis via RANK through activation of phosphatidylinositol 3-kinase, phosphodiesterase, and Src kinase pathways; chemotaxis was blocked by osteoprotegerin (decoy receptor for RANKL). Micropore filter migration assay, signaling enzyme inhibitors, Western blotting, RT-PCR, flow cytometry Arthritis and rheumatism Medium 15248232
2014 miR-503 directly targets RANK mRNA (TNFRSF11A) and inhibits RANKL-induced osteoclastogenesis; overexpression of miR-503 reduced RANK protein levels and inhibited osteoclast differentiation in CD14+ PBMCs and in vivo in ovariectomized mice. miRNA target validation, overexpression/knockdown in primary cells and in vivo (antagomir/agomir), osteoclast differentiation assay, RANK protein quantification Journal of bone and mineral research Medium 23821519
2015 RANK signaling in luminal mammary progenitors amplifies WNT responsiveness through upregulation of R-spondin1; loss of RANK prevents proliferation of hormone receptor-negative luminal progenitors and basal cells, suppresses WNT activation, and impairs lobuloalveologenesis. Exogenous R-spondin1 rescues key aspects of RANK deficiency. Conditional RANK knockout mouse model, human breast tissue analysis, WNT pathway reporter, exogenous R-spondin1 rescue experiment Stem cell reports High 26095608
2013 Constitutive RANK signaling in mammary epithelial cells expands luminal and basal mammary compartments including mammary stem and progenitor cell pools, impairs normal luminal cell commitment, accumulates K14+K8+ bipotent cells, and leads to formation of heterogeneous mammary tumors. Transgenic mouse model with constitutive RANK expression, FACS analysis of mammary cell populations, histology Stem cells Medium 23766243
2016 Genetic inactivation of RANK in mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer; RANK/RANKL blockade impaired proliferation and expansion of Brca1;p53 mutant mammary stem cells and progenitors from human BRCA1 mutation carriers. Conditional RANK knockout in two mouse models, pharmacological RANKL inhibition, in vitro progenitor proliferation assay with human BRCA1-mutant tissue Cell research High 27241552
2016 RANK-independent osteoclastogenesis and bone erosion can occur in inflammatory arthritis via a TNF/IL-6-dependent pathway requiring IL-6R, NFATc1, DNAX-activation protein 12 (DAP12), and cell proliferation but not RANKL or RANK; arthritic mice with inducible RANK deficiency still exhibited bone erosion and synovial osteoclasts. Conditional RANK knockout mouse model, K/BxN serum-transfer arthritis model, in vitro osteoclast differentiation from RANK-null precursors, micro-CT, histology Arthritis & rheumatology High 27563728
2018 STAC2 is a RANKL-inducible protein that physically interacts with RANK and negatively regulates osteoclast formation by inhibiting formation of the RANK signaling complex (containing Gab2 and PLCγ2) and suppressing NF-κB, MAPK activation, and Btk/Tec-mediated PLCγ2 phosphorylation. Co-immunoprecipitation, overexpression, NF-κB and MAPK reporter assays, osteoclast differentiation assay Cell death and differentiation Medium 29348675
2015 RANKL variants with higher affinity for RANK produce more robust downstream signaling and greater osteoclastogenic potential; the relationship between RANKL-RANK affinity and osteoclastogenesis is biphasic and driven entirely by the kinetic off-rate, indicating that physiological RANKL-RANK interaction is not optimized for maximal signaling. Yeast surface display, random mutagenesis library screening, surface plasmon resonance binding kinetics, in vitro osteoclast differentiation assay Journal of cellular biochemistry Medium 25864714
2022 A20 is rapidly recruited to the RANK receptor complex within minutes of RANKL binding and restrains NF-κB activation; this inhibition is independent of A20's deubiquitinating activity but requires its zinc finger (ZnF) 4 and 7 ubiquitin-binding functions. Osteoclast-specific A20 knockout mice develop severe osteoporosis with hyperresponsive RANKL-induced osteoclastogenesis. Osteoclast-specific conditional A20 knockout mouse, in vitro osteoclast differentiation, co-immunoprecipitation of RANK complex, domain-specific mutants, NF-κB reporter assay EMBO reports High 36194667
2012 TNFRSF11A (RANK) promoter is epigenetically silenced by CpG methylation in gliomas; demethylation with 5-aza-2'-deoxycytidine restores RANK expression, and RANK overexpression in glioblastoma cells reduces focus formation and increases apoptosis through activation of apoptosis-regulatory signaling pathways. Pyrosequencing methylation analysis, demethylating agent treatment, RANK overexpression, focus formation assay, flow cytometry for apoptosis, reporter assay Neoplasia Medium 22787434
2014 A frameshift mutation (p.Met416Cysfs*110) in TNFRSF11A causes hereditary recurrent fever with increased secretion of inflammatory cytokines (TNFα, IL-18, IL-1Ra, IFN-γ) and altered NF-κB signaling; a chromosomal duplication of TNFRSF11A also causes hereditary recurrent fever, implicating RANK in innate immune regulation and fever. Array-CGH, sequencing, serum cytokine multiplex measurement (Luminex), NF-κB luciferase reporter assay with wild-type and mutant RANK Arthritis & rheumatology Medium 24891336
2018 A novel splice-site mutation (c.616+3A>G) in TNFRSF11A causing exon 6 skipping and frameshift leads to dysosteosclerosis (autosomal recessive sclerosing bone disease), expanding the phenotypic spectrum of TNFRSF11A loss-of-function mutations. Whole-exome sequencing, exon trapping assay to demonstrate exon skipping Journal of human genetics Medium 29568001
2012 Cell adhesion signaling regulates RANK expression in osteoclast precursors; BMMs under adherent conditions express high RANK and differentiate efficiently into osteoclasts in response to RANKL, while non-adherent conditions reduce RANK expression and impair RANKL-mediated NF-κB signaling. Forced RANK or TRAF6 overexpression rescues osteoclastogenesis under non-adherent conditions. Adherent vs. non-adherent culture system, RT-PCR, Western blot, RGD-disintegrin inhibition, forced RANK/TRAF6 overexpression, osteoclast differentiation assay PloS one Medium 23139818
2001 TGF-β1 directly stimulates osteoclast differentiation of pre-osteoclastic RAW 264.7 cells in the presence of M-CSF and RANKL, and dose- and time-dependently increases RANK mRNA and protein expression in these cells. Osteoclast differentiation assay (TRAP staining), RT-PCR, flow cytometry with fluorescent RANKL probe Journal of cellular biochemistry Medium 11573248
2002 TRANCE (RANKL)-RANK interaction sustains the longevity of interstitial dendritic cells (derived from CD34+ progenitors) that co-express TRANCE and RANK; soluble RANK reduces viability and Bcl-2 expression of these cells, while CD1a+ DCs expressing only RANK are rescued from cell death by exogenous TRANCE or by TRANCE-expressing DCs. CD34+ progenitor culture, flow cytometry, soluble RANK treatment, viability assay, Bcl-2 expression analysis Blood Medium 12393586

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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
2005 RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends in molecular medicine 930 16356770
2007 Biology of RANK, RANKL, and osteoprotegerin. Arthritis research & therapy 689 17634140
1998 RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochemical and biophysical research communications 573 9878548
2017 Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation. Molecules and cells 496 29047262
2014 Biology of the RANKL-RANK-OPG System in Immunity, Bone, and Beyond. Frontiers in immunology 487 25368616
2000 Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nature genetics 341 10615125
2008 RANK/RANKL: regulators of immune responses and bone physiology. Annals of the New York Academy of Sciences 308 19076348
2005 Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis. The Journal of experimental medicine 299 16147974
2015 Bacterial ferrous iron transport: the Feo system. FEMS microbiology reviews 285 26684538
2007 The RANKL/RANK/OPG pathway. Current osteoporosis reports 256 17925190
2008 Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. American journal of human genetics 215 18606301
2005 Dysregulated osteoprotegerin/RANK ligand/RANK axis in clinical and experimental heart failure. Circulation 203 15883214
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
2005 Osteoclast precursors, RANKL/RANK, and immunology. Immunological reviews 185 16313338
2004 The OPG/RANKL/RANK system in metabolic bone diseases. Journal of musculoskeletal & neuronal interactions 182 15615494
2001 Osteoprotegerin and rank ligand expression in prostate cancer. Urology 175 11306358
2014 MiR-503 regulates osteoclastogenesis via targeting RANK. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 173 23821519
2008 Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice. The Journal of clinical investigation 162 18382763
2002 Role of RANKL and RANK in bone loss and arthritis. Annals of the rheumatic diseases 160 12379618
2021 Discovery of the RANKL/RANK/OPG system. Journal of bone and mineral metabolism 158 33389131
2011 Receptor activator of NF-kB (RANK) expression in primary tumors associates with bone metastasis occurrence in breast cancer patients. PloS one 146 21559440
2011 Rank/Rankl/opg: literature review. Acta reumatologica portuguesa 141 22113597
2016 RANKL/RANK control Brca1 mutation- . Cell research 138 27241552
2015 The RANKL-RANK Story. Gerontology 138 25720990
2016 RANK-RANKL signalling in cancer. Bioscience reports 133 27279652
2001 The osteoclastogenic molecules RANKL and RANK are associated with periprosthetic osteolysis. The Journal of bone and joint surgery. British volume 130 11521937
2002 Expansile skeletal hyperphosphatasia is caused by a 15-base pair tandem duplication in TNFRSF11A encoding RANK and is allelic to familial expansile osteolysis. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 126 11771666
2007 RANKL, RANK, osteoprotegerin: key partners of osteoimmunology and vascular diseases. Cellular and molecular life sciences : CMLS 125 17530461
2016 RANK-Independent Osteoclast Formation and Bone Erosion in Inflammatory Arthritis. Arthritis & rheumatology (Hoboken, N.J.) 119 27563728
2011 RANKL/RANK-beyond bones. Journal of molecular medicine (Berlin, Germany) 112 21445556
2010 Structural and functional insights of RANKL-RANK interaction and signaling. Journal of immunology (Baltimore, Md. : 1950) 103 20483727
2003 Novel aspects on RANK ligand and osteoprotegerin in osteoporosis and vascular disease. Calcified tissue international 96 14523602
2001 Regulation of osteoclastogenesis and RANK expression by TGF-beta1. Journal of cellular biochemistry 94 11573248
2018 Roles of the RANKL-RANK axis in antitumour immunity - implications for therapy. Nature reviews. Clinical oncology 91 30232468
2009 Modulation of OPG, RANK and RANKL by human chondrocytes and their implication during osteoarthritis. Rheumatology (Oxford, England) 89 19762475
2017 RANKL and RANK: From Mammalian Physiology to Cancer Treatment. Trends in cell biology 76 29241686
2003 RANK-Fc: a therapeutic antagonist for RANK-L in myeloma. Cancer 74 12548579
2018 Toward a mechanistic understanding of Feo-mediated ferrous iron uptake. Metallomics : integrated biometal science 72 29953152
2003 RANKL and RANK as novel therapeutic targets for arthritis. Current opinion in rheumatology 71 12707582
2002 Long-lived immature dendritic cells mediated by TRANCE-RANK interaction. Blood 71 12393586
2011 Zoledronic acid inhibits RANK expression and migration of osteoclast precursors during osteoclastogenesis. Naunyn-Schmiedeberg's archives of pharmacology 68 21225243
2007 TRAFs in RANK signaling. Advances in experimental medicine and biology 66 17633024
2015 RANK Signaling Amplifies WNT-Responsive Mammary Progenitors through R-SPONDIN1. Stem cell reports 65 26095608
1999 Expression of functional RANK on mature rat and human osteoclasts. FEBS letters 65 10606741
2018 Role of the RANK/RANKL Pathway in Multiple Myeloma. Clinical cancer research : an official journal of the American Association for Cancer Research 63 30093448
2004 Opg, Rank, and Rankl in tooth development: co-ordination of odontogenesis and osteogenesis. Journal of dental research 61 14981127
2020 Targeting the RANKL/RANK/OPG Axis for Cancer Therapy. Frontiers in oncology 58 32850393
2006 RANK ligand. The international journal of biochemistry & cell biology 56 17174136
2017 KLF5 promotes cervical cancer proliferation, migration and invasion in a manner partly dependent on TNFRSF11a expression. Scientific reports 53 29146991
2021 Rank-in: enabling integrative analysis across microarray and RNA-seq for cancer. Nucleic acids research 51 34214174
2015 Genome-Wide Association Study of Late-Onset Myasthenia Gravis: Confirmation of TNFRSF11A and Identification of ZBTB10 and Three Distinct HLA Associations. Molecular medicine (Cambridge, Mass.) 51 26562150
1995 Oxygen-derived free radical (ODFR) action on hyaluronan (HA), on two HA ester derivatives, and on the metabolism of articular chondrocytes. Experimental cell research 51 7737382
2021 The Roadmap of RANKL/RANK Pathway in Cancer. Cells 49 34440747
2019 The RANKL-RANK Axis: A Bone to Thymus Round Trip. Frontiers in immunology 49 30984193
2019 Measuring rank robustness in scored protein interaction networks. BMC bioinformatics 47 31462221
2016 Role of the RANK/RANKL pathway in breast cancer. Maturitas 47 26921922
2005 Self-assembled RANK induces osteoclastogenesis ligand-independently. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 45 16234979
2013 Constitutive activation of RANK disrupts mammary cell fate leading to tumorigenesis. Stem cells (Dayton, Ohio) 43 23766243
2022 Empirical and philosophical problems with the subspecies rank. Ecology and evolution 41 35845367
2014 RANK-mediated signaling network and cancer metastasis. Cancer metastasis reviews 40 24398859
2004 Expression and function of RANK in human monocyte chemotaxis. Arthritis and rheumatism 40 15248232
2021 RANKL and RANK in extracellular vesicles: surprising new players in bone remodeling. Extracellular vesicles and circulating nucleic acids 35 33982033
2004 Heritable disorders of the RANKL/OPG/RANK signaling pathway. Journal of musculoskeletal & neuronal interactions 35 15615493
2010 Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 34 20564239
2010 Physiology and pathophysiology of the RANKL/RANK system. Biological chemistry 34 21087090
2004 RANK, RANKL and OPG in inflammatory arthritis and periprosthetic osteolysis. Journal of musculoskeletal & neuronal interactions 34 15615495
2015 Correlating RANK ligand/RANK binding kinetics with osteoclast formation and function. Journal of cellular biochemistry 33 25864714
2021 RANK Signaling in the Differentiation and Regeneration of Thymic Epithelial Cells. Frontiers in immunology 32 33552088
2014 Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK. Bone 32 25063546
2002 Detection and characterization of RANK ligand and osteoprotegerin in the thyroid gland. Journal of cellular biochemistry 32 12210731
2008 Role of OPG/RANKL/RANK axis on the vasculature. Histology and histopathology 31 18228207
2012 Bone metastasis in breast cancer: the story of RANK-ligand. Journal of the Egyptian National Cancer Institute 29 22929916
2009 OPG/RANK/RANKL signaling system and its significance in nephrology. Folia histochemica et cytobiologica 29 19995704
2008 Circulating osteoprotegerin and soluble RANK ligand in systemic sclerosis. The Journal of rheumatology 29 18843778
2019 An osteoclastogenesis system, the RANKL/RANK signalling pathway, contributes to aggravated allergic inflammation. British journal of pharmacology 28 30737962
2017 NOTCH1 Mutations in Aortic Stenosis: Association with Osteoprotegerin/RANK/RANKL. BioMed research international 28 28246602
2009 The affinity of human RANK binding to its ligand RANKL. Archives of biochemistry and biophysics 28 19416721
2020 Ellagic acid blocks RANKL-RANK interaction and suppresses RANKL-induced osteoclastogenesis by inhibiting RANK signaling pathways. Chemico-biological interactions 27 32971123
2018 STAC2 negatively regulates osteoclast formation by targeting the RANK signaling complex. Cell death and differentiation 27 29348675
2012 RANK (TNFRSF11A) is epigenetically inactivated and induces apoptosis in gliomas. Neoplasia (New York, N.Y.) 27 22787434
2011 Inferring disease and gene set associations with rank coherence in networks. Bioinformatics (Oxford, England) 27 21824970
2012 A nonsynonymous TNFRSF11A variation increases NFκB activity and the severity of Paget's disease. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 26 21987421
2003 Expression of osteoprotegerin and RANK ligand in breast cancer bone metastasis. Journal of Korean medical science 26 12923331
2020 TNF-α stimulates the expression of RANK during orthodontic tooth movement. Archives of oral biology 24 32544645
2013 Role of RANKL/RANK in primary and secondary breast cancer. World journal of orthopedics 24 24147253
2010 TNFRSF11A and TNFSF11 are associated with age at menarche and natural menopause in white women. Menopause (New York, N.Y.) 24 20531232
2008 Expression of bone resorption regulators (RANK, RANKL, and OPG) in odontogenic tumors. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics 24 18928898
2014 Brief Report: Involvement of TNFRSF11A molecular defects in autoinflammatory disorders. Arthritis & rheumatology (Hoboken, N.J.) 23 24891336
2006 Stress, social rank and leukocyte telomere length. Aging cell 23 17081156
2012 Cell adhesion signaling regulates RANK expression in osteoclast precursors. PloS one 22 23139818
2023 PASSerRank: Prediction of allosteric sites with learning to rank. Journal of computational chemistry 21 37561047
2021 Uncertainty in denoising of MRSI using low-rank methods. Magnetic resonance in medicine 21 34545962
2011 Role of RANK-RANKL-OPG axis in cranial suture homeostasis. The Journal of craniofacial surgery 21 21415639
2001 Osteoprotegerin, RANK, RANKL. Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia 21 12426773
2022 Disentangling the Evolutionary History of Feo, the Major Ferrous Iron Transport System in Bacteria. mBio 20 35012344
2018 Dysosteosclerosis is also caused by TNFRSF11A mutation. Journal of human genetics 20 29568001
2016 Pioglitazone affects the OPG/RANKL/RANK system and increase osteoclastogenesis. Molecular medicine reports 20 27430581
2022 A20 controls RANK-dependent osteoclast formation and bone physiology. EMBO reports 19 36194667