Affinage

Showing TNFRSF11A — RANK is a alias.

TNFRSF11A

Tumor necrosis factor receptor superfamily member 11A · UniProt Q9Y6Q6

Length
616 aa
Mass
66.0 kDa
Annotated
2026-06-10
100 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: tie faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNFRSF11A (RANK) is a transmembrane TNF-receptor superfamily member that serves as the essential signaling receptor for the osteoclast differentiation factor RANKL on osteoclast progenitors, where ligand engagement drives osteoclastogenesis in the presence of M-CSF (PMID:9878548). Crystallographic analysis shows RANK presents four cysteine-rich domains and undergoes a hinge conformational change between CRD2 and CRD3 upon RANKL binding, forming a high-affinity continuous contact whose disruption abrogates osteoclast formation (PMID:20483727); this affinity sets the off-rate that tunes osteoclastogenic output in a biphasic manner, indicating the physiological interaction is not optimized for maximal signaling (PMID:25864714). Cytoplasmically, RANK recruits TRAF family members, of which TRAF6 is indispensable, to activate MAPKs and NF-κB/AP-1 and induce NFATc1, the master transcription factor that, together with PLCγ2-driven Ca2+ oscillation and c-Fos, directs osteoclast-specific gene expression and cell fusion (PMID:17633024, PMID:29047262). RANK can also self-assemble through a cytoplasmic oligomerization domain at residues 534–539, distinct from TRAF-binding sites, enabling ligand-independent osteoclastogenesis that still depends on TRAF6 (PMID:16234979). Signaling output is held in check by the CYLD deubiquitinase, which is recruited via p62 to restrain TRAF6 ubiquitination (PMID:18382763), and receptor expression itself is regulated by cell adhesion and TGF-β1 in osteoclast precursors (PMID:11573248, PMID:23139818). Activating signal-peptide insertion mutations cause familial expansile osteolysis and Paget's disease variants through enhanced NF-κB signaling (PMID:10615125, PMID:11771666), whereas loss-of-function mutations cause autosomal recessive osteoclast-poor osteopetrosis with hypogammaglobulinemia, also implicating RANK in B-cell function (PMID:18606301). Beyond bone, RANK amplifies WNT responsiveness via R-spondin1 to expand mammary progenitors (PMID:26095608) and promotes BRCA1/p53-driven mammary carcinogenesis (PMID:27241552), while exerting context-dependent roles including anti-inflammatory modulation of microglia (PMID:28402971) and tumor-suppressive pro-apoptotic activity when re-expressed in epigenetically silenced gliomas (PMID:22787434).

Mechanistic history

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

    Established the molecular identity of the receptor required for osteoclast formation, answering which surface receptor transduces the osteoclast differentiation signal.

    Evidence Molecular cloning with antibody agonism/antagonism and soluble-receptor competition in a macrophage-like cell line

    PMID:9878548

    Open questions at the time
    • Did not resolve the cytoplasmic signaling cascade
    • No structural basis for ligand binding
  2. 2000 High

    Linked TNFRSF11A directly to human skeletal disease, showing signal-peptide insertion mutations are gain-of-function and act through elevated NF-κB.

    Evidence Genetic linkage, sequencing, and NF-κB reporter assays of recombinant mutant RANK in families with familial expansile osteolysis/Paget's disease

    PMID:10615125

    Open questions at the time
    • Mechanism by which signal-peptide defects increase signaling not fully resolved
    • Did not address cell-type specificity of disease
  3. 2002 Medium

    Extended the allelic series of activating signal-peptide duplications to expansile skeletal hyperphosphatasia, reinforcing a unified gain-of-function mechanism.

    Evidence Comparative Sanger sequencing of TNFRSF11A in affected families

    PMID:11771666

    Open questions at the time
    • No independent in vitro functional confirmation in this study
    • Genotype-phenotype severity determinants unexplained
  4. 2004 Medium

    Showed RANK signaling functions in monocytes beyond differentiation, mediating chemotaxis through PI3K/Src pathways.

    Evidence FACS/RT-PCR for RANK with migration assays and pharmacological inhibitors in human monocytes

    PMID:15248232

    Open questions at the time
    • Single lab, pharmacological rather than genetic dissection
    • In vivo relevance of monocyte chemotaxis not established
  5. 2005 Medium

    Identified a cytoplasmic oligomerization domain (534–539) enabling ligand-independent osteoclastogenesis, distinguishing self-assembly from TRAF binding.

    Evidence Co-IP of tagged RANK constructs with deletion mutants, TRAF6 decoy inhibition, and bone marrow differentiation assays

    PMID:16234979

    Open questions at the time
    • Physiological role of ligand-independent assembly unclear
    • Single-lab study
  6. 2005 High

    Demonstrated that the RANK-TRAF6 axis is not absolutely required for osteoclast differentiation, revealing alternative TNF-α/TGF-β routes.

    Evidence In vitro differentiation of TRANCE-, RANK-, and TRAF6-null precursors with TNF-α plus TGF-β

    PMID:16147974

    Open questions at the time
    • Physiological contribution of alternative pathway in vivo not quantified
  7. 2007 High

    Defined TRAF6 as the indispensable adaptor among five RANK-interacting TRAFs, anchoring the cytoplasmic signaling output.

    Evidence Biochemical interaction studies and TRAF6-null mouse analysis (review of mechanistic data)

    PMID:17633024

    Open questions at the time
    • Roles of the other four TRAFs not delineated
    • Reviewed rather than primary data
  8. 2008 High

    Identified CYLD/p62 as a negative regulator restraining RANK signaling via TRAF6 deubiquitination, explaining tonic control of osteoclast precursors.

    Evidence CYLD knockout mice with osteoclast assays, CYLD-p62-TRAF6 Co-IP, and ubiquitination assays

    PMID:18382763

    Open questions at the time
    • How p62/CYLD recruitment is regulated dynamically unknown
  9. 2008 High

    Showed loss-of-function TNFRSF11A mutations cause osteoclast-poor osteopetrosis with immunodeficiency, defining the human null phenotype and a B-cell role.

    Evidence Sequencing in ARO families, patient monocyte differentiation assays, and B-cell immunological analysis

    PMID:18606301

    Open questions at the time
    • Mechanism of RANK action in B cells not resolved
  10. 2010 High

    Provided the structural basis of RANKL recognition, showing a CRD2-CRD3 hinge conformational change and continuous high-affinity contact required for function.

    Evidence X-ray crystallography of liganded/unliganded RANK with mutagenesis and osteoclast formation assays

    PMID:20483727

    Open questions at the time
    • Structure of full-length receptor and transmembrane assembly not resolved
  11. 2015 Medium

    Linked RANK affinity kinetics to signaling output, establishing a biphasic, off-rate-driven relationship and that physiological binding is sub-maximal.

    Evidence Yeast surface display mutagenesis of RANKL, binding kinetics, and osteoclast differentiation assays

    PMID:25864714

    Open questions at the time
    • In vivo consequences of affinity-tuned variants untested
  12. 2017 High

    Synthesized the multi-stage osteoclastogenic signaling model from TRAF6/NF-κB/AP-1 initiation through PLCγ2/Ca2+ amplification to NFATc1-driven gene induction.

    Evidence Review integrating genetic epistasis, kinase/adaptor knockouts, Ca2+ imaging, and transcription factor analysis

    PMID:29047262

    Open questions at the time
    • Quantitative thresholds for stage transitions not defined
  13. 2015 High

    Defined a non-bone role: RANK amplifies WNT responsiveness through R-spondin1 to expand mammary luminal progenitors under progesterone control.

    Evidence RANK knockout mouse mammary analysis, WNT reporters, R-spondin1 rescue, and human tissue validation

    PMID:26095608

    Open questions at the time
    • Direct link between RANK signaling and R-spondin1 transcription not detailed
  14. 2016 High

    Established RANK as a driver of BRCA1/p53-mutant mammary carcinogenesis, supporting RANKL blockade as a preventive strategy.

    Evidence Conditional RANK knockout and pharmacological RANKL inhibition in mouse models with human BRCA1 carrier progenitor assays

    PMID:27241552

    Open questions at the time
    • Cell of origin and timing of RANK-dependent transformation not fully defined
  15. 2016 High

    Demonstrated that bone erosion and osteoclast formation persist without RANK in inflammatory arthritis via a TNF/IL-6/DAP12/NFATc1 pathway.

    Evidence Inducible Rank knockout mice in serum-transfer arthritis with micro-CT, histology, and in vitro osteoclast cultures

    PMID:27563728

    Open questions at the time
    • Relative contribution of RANK-independent osteoclastogenesis in human arthritis unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RANK's distinct context-dependent outputs—osteoclastogenic, mammary-proliferative, tumor-suppressive in glioma, and anti-inflammatory in microglia—are mechanistically selected by cell type remains unresolved.
  • No unifying model for cell-type-specific RANK signaling output
  • Reverse signaling via osteoclast EV-borne RANK rests on low-confidence reviewed data (#24)

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 2 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 2
Pathway
R-HSA-1643685 Disease 3 R-HSA-1266738 Developmental Biology 2 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2
Partners
CYLDRANKLSQSTM1TRAF6

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 RANK (ODFR) was identified as the essential signaling receptor for osteoclast differentiation factor (ODF/RANKL) on osteoclast progenitors. A polyclonal antibody against the extracellular domain of RANK induced osteoclastogenesis in the presence of M-CSF, while soluble RANK and Fab fragments blocked ODF binding to RANK and blocked ODF-mediated osteoclastogenesis, establishing RANK as the functional receptor required for osteoclastogenesis. Molecular cloning, antibody agonism/antagonism assays, soluble receptor competition, osteoclastogenesis assay in macrophage-like cell line C7 Biochemical and biophysical research communications High 9878548
2000 Heterozygous insertion mutations in exon 1 of TNFRSF11A (18-bp or 27-bp duplications affecting the signal peptide of RANK) cause familial expansile osteolysis and familial Paget's disease of bone. Expression of mutant RANK proteins revealed perturbed expression levels, lack of normal signal peptide cleavage, and increased RANK-mediated NF-κB signaling in vitro, consistent with activating gain-of-function mutations. Genetic linkage, Sanger sequencing, recombinant protein expression, NF-κB reporter assay Nature genetics High 10615125
2002 Expansile skeletal hyperphosphatasia (ESH) is caused by a 15-bp tandem duplication (84dup15) in the signal peptide-encoding region of TNFRSF11A, allelic to the 18-bp duplication causing familial expansile osteolysis, establishing that both disorders result from activating mutations in RANK signal peptide leading to enhanced NF-κB signaling. Sanger sequencing of TNFRSF11A, comparative mutation analysis Journal of bone and mineral research Medium 11771666
2005 RANK self-assembles through its cytoplasmic domain at positions 534–539 (distinct from TRAF-binding domains), and overexpression of oligomeric RANK induces osteoclastogenesis in a ligand-independent manner. This ligand-independent osteoclastogenesis requires TRAF6 and the oligomerization domain at 534–539. Immunoprecipitation of FLAG- and HA-tagged RANK constructs in 293T cells, C-terminal deletion mutants, TRAF6 decoy peptide inhibition, bone marrow osteoclast differentiation assay Journal of bone and mineral research Medium 16234979
2007 RANK interacts with five TRAF family members, of which TRAF6 is indispensable for RANK signaling capability, linking RANKL-RANK cytoplasmic signaling to downstream NF-κB and other transcriptional programs required for osteoclastogenesis. Biochemical interaction studies, genetic knock-out analysis (TRAF6-null mice), downstream signaling assays (reviewed mechanistic data) Advances in experimental medicine and biology High 17633024
2008 CYLD deubiquitinase negatively regulates RANK signaling by inhibiting TRAF6 ubiquitination and downstream signaling events. CYLD physically interacts with the adaptor p62, which recruits CYLD to TRAF6. CYLD-deficient mice develop severe osteoporosis with hyperresponsive osteoclast precursors to RANKL-induced differentiation. Genetic CYLD knockout mice, osteoclast differentiation assays, co-immunoprecipitation (CYLD-p62-TRAF6), ubiquitination assays, downstream signaling analysis The Journal of clinical investigation High 18382763
2008 Loss-of-function mutations in TNFRSF11A cause autosomal recessive osteoclast-poor osteopetrosis with hypogammaglobulinemia. Monocytes from affected patients failed to differentiate into osteoclasts upon M-CSF and RANKL stimulation, confirming an osteoclast-intrinsic signaling defect. Immunological analysis revealed impairment in immunoglobulin-secreting B cells, establishing a role for RANK signaling in B cell function. TNFRSF11A sequencing in ARO patients, in vitro osteoclast differentiation assay from patient monocytes, immunological B cell analysis American journal of human genetics High 18606301
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 with CRD3. Upon RANKL binding, RANK undergoes a conformational change via a hinge between CRD2 and CRD3. The interaction is maintained by continuous (rather than patched) contact. Mutations reducing RANKL-RANK affinity significantly disrupted osteoclast formation, confirming the functional necessity of high-affinity continuous contact. X-ray crystallography (crystal structures of unliganded RANK and RANKL-RANK complex), mutagenesis, osteoclast formation assay Journal of immunology High 20483727
2005 Hematopoietic precursors from TRANCE-, RANK-, or TRAF6-null mice can differentiate into osteoclasts in vitro when stimulated with TNF-α in the presence of TGF-β, demonstrating that the TRANCE-RANK-TRAF6 pathway is not absolutely required for osteoclast differentiation and that alternative routes exist. Genetic KO (TRANCE-null, RANK-null, TRAF6-null mice), in vitro osteoclast differentiation with TNF-α and TGF-β, negative epistasis The Journal of experimental medicine High 16147974
2016 Bone erosion and synovial osteoclast formation persisted in arthritic mice with inducible RANK deficiency, and TNF-α plus IL-6 induced RANK-independent osteoclastogenesis in vitro through a pathway dependent on IL-6R, NFATc1, DAP12, and cell proliferation but independent of RANK or RANKL, establishing that RANK is not absolutely required for osteoclastogenesis and bone erosion in inflammatory arthritis. Conditional/inducible Rank knockout mice, K/BxN serum-transfer arthritis model, in vitro osteoclast cultures, micro-CT, histology, qPCR Arthritis & rheumatology High 27563728
2004 RANK is expressed on the surface of human monocytes, and RANKL stimulates monocyte chemotaxis via RANK through activation of phosphatidylinositol 3-kinase, phosphodiesterase, and Src kinase. This chemotactic effect is inhibited by OPG (decoy receptor for RANKL). RT-PCR and FACS for RANK expression, micropore filter migration assay, pharmacological signaling inhibitors, Western blot Arthritis and rheumatism Medium 15248232
2001 TGF-β1 directly stimulates osteoclastic differentiation of RAW 264.7 preosteoclastic cells in the presence of M-CSF and RANKL, accompanied by upregulation of RANK mRNA and protein expression in a time- and dose-dependent manner, establishing that TGF-β1 regulates RANK expression and responsiveness in osteoclast precursors. RT-PCR for RANK mRNA, flow cytometry for RANK protein, TRAP staining and multinucleated cell counting for osteoclast differentiation, dose-response experiments Journal of cellular biochemistry Medium 11573248
2012 Cell adhesion signaling regulates RANK expression in osteoclast precursors. BMMs cultured under non-adherent conditions showed markedly reduced RANK expression and failed to respond to RANKL, while adherent conditions maintained high RANK expression. Forced RANK overexpression or TRAF6 overexpression rescued osteoclast differentiation under non-adherent conditions. RGD-disintegrin echistatin decreased RANK expression. Adherent vs. non-adherent culture, RT-PCR and Western blot for RANK, RANK/TRAF6 forced expression, echistatin treatment, NF-κB pathway analysis PloS one Medium 23139818
2015 RANK signaling in mammary luminal progenitors amplifies WNT responsiveness through R-spondin1. RANK-positive luminal progenitors with WNT pathway activation are expanded during the progesterone-high menstrual phase. Loss of RANK in mice prevents proliferation of hormone receptor-negative luminal progenitors and basal cells, loss of WNT activation, and suppression of lobuloalveologenesis. R-spondin1 is depleted in RANK-null progenitors and its exogenous addition rescues WNT response and mammary cell expansion. RANK knockout mouse mammary analysis, flow cytometry of mammary subpopulations, WNT pathway reporter assays, R-spondin1 rescue experiments, human breast tissue analysis Stem cell reports High 26095608
2016 Genetic inactivation of RANK in mammary epithelium markedly delayed onset, reduced incidence, and attenuated progression of Brca1;p53 mutation-driven mammary cancer in mice. RANK/RANKL blockade impaired proliferation and expansion of Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. Conditional mammary epithelium-specific RANK knockout mice, pharmacological RANKL inhibition, mammary stem cell assays, human BRCA1 carrier progenitor cell expansion assays Cell research High 27241552
2013 Constitutive RANK signaling in mammary epithelium expands luminal and basal mammary compartments including stem and luminal progenitor cell pools, interferes with generation of CD61+ and Sca1+ luminal cells and Elf5 expression, causes accumulation of K14+K8+ bipotent progenitors, and leads to formation of heterogeneous mammary tumors. Constitutively active RANK mouse model, flow cytometry of mammary subpopulations, histology, tumor formation assay Stem cells Medium 23766243
2014 RANK-mediated signaling in prostate cancer cells establishes a feed-forward loop involving induction of RANKL and c-Met, repression of androgen receptor (AR), and activation of transcription factors controlling EMT (Twist1, Slug, Zeb1/2), stem cell properties (Sox2, Myc, Oct3/4, Nanog), and neuroendocrine differentiation. Abrogating RANK or downstream c-Myc/Max or c-Met signaling minimized skeletal metastasis in mice. Site-directed mutagenesis, TF deletion/interference assays, animal bone metastasis models, co-culture experiments Endocrine-related cancer Medium 24478054
2012 TNFRSF11A/RANK is epigenetically silenced by promoter CpG methylation in gliomas. Demethylation with 5-aza-2'-deoxycytidine restored RANK mRNA expression. Overexpression of RANK in glioblastoma cell lines reduced focus formation and increased apoptotic activity, indicating a tumor-suppressive role via apoptosis-associated signaling pathways. Pyrosequencing for methylation, demethylating agent treatment, RANK overexpression in glioma cell lines, flow cytometry for apoptosis, focus formation assay, reporter assay Neoplasia Medium 22787434
2012 A nonsynonymous TNFRSF11A variant (V192A, T575C) is associated with increased severity of Paget's disease of bone. Co-transfection of mutated SQSTM1 with TNFRSF11A-A192 produced greater NF-κB activation than with wild-type TNFRSF11A-V192 in human cell lines, establishing synergistic NF-κB gain-of-function. Genetic association study, NF-κB luciferase reporter co-transfection assay with SQSTM1 and TNFRSF11A variants Journal of bone and mineral research Medium 21987421
2014 A heterozygous frameshift mutation in TNFRSF11A (p.Met416Cysfs*110) in patients with hereditary recurrent fever altered NF-κB signaling by the receptor (luciferase assay) and was associated with increased secretion of inflammatory cytokines (TNFα, IL-18, IL-1RA, IFN-γ), establishing RANK as a regulator of innate immune/inflammatory signaling beyond bone. TNFRSF11A sequencing, NF-κB luciferase reporter assay in cells expressing wild-type vs. mutant RANK, Luminex cytokine measurement Arthritis & rheumatology Medium 24891336
2019 RANK signaling in BV2 microglial cells attenuates TLR3/TLR4-mediated inflammatory activation. LPS treatment decreased RANK expression while increasing OPG. RANKL pretreatment decreased inducible nitric oxide synthase, COX-2, and TLR adaptor proteins MyD88 and TRIF. Effects were abolished in CRISPR/Cas9-generated RANK-knockout BV2 cells, confirming RANK-dependent anti-inflammatory modulation of microglial responses. CRISPR/Cas9 RANK knockout BV2 cells, RANKL pretreatment, LPS/Poly I:C stimulation, RT-PCR and protein expression analysis for inflammatory markers, primary microglia validation Developmental neuroscience Medium 28402971
2017 RANK signaling in early osteoclastogenesis recruits TRAF6 to activate MAPKs and NF-κB/AP-1, inducing NFATc1. In the intermediate stage, co-stimulatory signals activate PLCγ2-driven Ca2+ oscillation together with c-Fos/AP-1, enabling robust NFATc1 production. In the late stage, NFATc1 translocates to the nucleus to induce osteoclast-specific genes responsible for cell fusion and function. Review synthesizing genetic epistasis, kinase/adaptor knockout models, Ca2+ imaging, and transcription factor analysis from multiple labs Molecules and cells High 29047262
2015 RANKL variants with increased RANK-binding affinity (generated by yeast surface display screening) produce more robust downstream signaling and greater osteoclastogenic potential than wild-type RANKL. A biphasic relationship exists between RANKL/RANK affinity and osteoclastogenic capacity, driven by the kinetic off-rate. Physiological RANKL/RANK interaction is not optimized for maximal signaling. Yeast surface display mutagenesis screen, recombinant RANKL mutant proteins, osteoclast differentiation assays, binding kinetics Journal of cellular biochemistry Medium 25864714
2018 RANKL/RANK signaling promotes uterine leiomyoma growth. RANK expression is highest in leiomyoma stem cells (which lack progesterone receptor, PR), while RANKL is highest in PR-rich leiomyoma intermediate cells. PR agonist R5020 increased RANKL in these cells. RANK-Fc blocked RANKL-induced cyclin D1 expression and significantly decreased leiomyoma tumor growth in vivo in murine xenograft models. mRNA/protein quantification in tissue and cell subpopulations, PR agonist treatment, RANK-Fc inhibitor treatment, murine xenograft model with tumor growth and Ki67 measurement The Journal of clinical endocrinology and metabolism Medium 29741640
2021 RANK contained in extracellular vesicles (EVs) from osteoclasts can stimulate RANKL reverse signaling in osteoblasts, promoting bone formation and coupling bone resorption with bone formation. Extracellular vesicle isolation, RANK detection in EVs, functional bone formation assays (reviewed mechanistic data) Extracellular vesicles and circulating nucleic acids Low 33982033
2017 KLF5 transcription factor promotes TNFRSF11A (RANK) expression by directly binding to the TNFRSF11A gene, and promotes cervical cancer cell proliferation, migration, and invasiveness in a manner partly dependent on TNFRSF11a expression. In vivo TNFRSF11a knockdown suppressed tumorigenicity and liver metastatic potential. TNF-α induces KLF5 expression via the p38 signaling pathway. ChIP/promoter binding assay, KLF5 overexpression/knockdown, TNFRSF11a knockdown (siRNA), in vivo xenograft and liver metastasis mouse models, RT-PCR, Western blot, p38 inhibitor Scientific reports Medium 29146991

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 1331 18395508
2001 Minireview: the OPG/RANKL/RANK system. Endocrinology 1050 11713196
2005 RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends in molecular medicine 935 16356770
2007 Biology of RANK, RANKL, and osteoprotegerin. Arthritis research & therapy 696 17634140
2001 RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annual review of immunology 637 11861618
1998 RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochemical and biophysical research communications 574 9878548
2017 Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation. Molecules and cells 503 29047262
2014 Biology of the RANKL-RANK-OPG System in Immunity, Bone, and Beyond. Frontiers in immunology 492 25368616
2010 Rank-rank hypergeometric overlap: identification of statistically significant overlap between gene-expression signatures. Nucleic acids research 371 20660011
2000 Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nature genetics 343 10615125
2008 RANK/RANKL: regulators of immune responses and bone physiology. Annals of the New York Academy of Sciences 309 19076348
2005 Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis. The Journal of experimental medicine 301 16147974
2015 Bacterial ferrous iron transport: the Feo system. FEMS microbiology reviews 294 26684538
2006 Feo--transport of ferrous iron into bacteria. Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine 273 16718600
2007 The RANKL/RANK/OPG pathway. Current osteoporosis reports 259 17925190
2008 Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations. American journal of human genetics 218 18606301
2002 RANK ligand and osteoprotegerin in myeloma bone disease. Blood 207 12424190
2005 Dysregulated osteoprotegerin/RANK ligand/RANK axis in clinical and experimental heart failure. Circulation 203 15883214
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 196 17895323
2005 Osteoclast precursors, RANKL/RANK, and immunology. Immunological reviews 187 16313338
2004 The OPG/RANKL/RANK system in metabolic bone diseases. Journal of musculoskeletal & neuronal interactions 183 15615494
2001 Osteoprotegerin and rank ligand expression in prostate cancer. Urology 175 11306358
2021 Discovery of the RANKL/RANK/OPG system. Journal of bone and mineral metabolism 169 33389131
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 162 12379618
2011 Rank/Rankl/opg: literature review. Acta reumatologica portuguesa 142 22113597
2016 RANKL/RANK control Brca1 mutation- . Cell research 139 27241552
2015 The RANKL-RANK Story. Gerontology 139 25720990
2016 RANK-RANKL signalling in cancer. Bioscience reports 134 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) 108 20483727
2012 Role of RANK ligand and denosumab, a targeted RANK ligand inhibitor, in bone health and osteoporosis: a review of preclinical and clinical data. Clinical therapeutics 96 22440513
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 92 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
2018 Toward a mechanistic understanding of Feo-mediated ferrous iron uptake. Metallomics : integrated biometal science 74 29953152
2014 RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization. Endocrine-related cancer 74 24478054
2003 RANK-Fc: a therapeutic antagonist for RANK-L in myeloma. Cancer 74 12548579
2010 RANK/RANKL/OPG role in distraction osteogenesis. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics 72 20163972
2003 RANKL and RANK as novel therapeutic targets for arthritis. Current opinion in rheumatology 71 12707582
2011 Zoledronic acid inhibits RANK expression and migration of osteoclast precursors during osteoclastogenesis. Naunyn-Schmiedeberg's archives of pharmacology 69 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
2005 RANK, RANKL and osteoprotegerin in arthritic bone loss. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 64 15785827
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
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
2001 Mutation screening of the TNFRSF11A gene encoding receptor activator of NF kappa B (RANK) in familial and sporadic Paget's disease of bone and osteosarcoma. Calcified tissue international 56 11351498
2017 KLF5 promotes cervical cancer proliferation, migration and invasion in a manner partly dependent on TNFRSF11a expression. Scientific reports 54 29146991
2021 Rank-in: enabling integrative analysis across microarray and RNA-seq for cancer. Nucleic acids research 53 34214174
2016 RANK as a therapeutic target in cancer. The FEBS journal 52 26749530
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
2014 RANKL/RANK - from bone physiology to breast cancer. Cytokine & growth factor reviews 50 24486161
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
2016 Role of the RANK/RANKL pathway in breast cancer. Maturitas 48 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 46 16234979
2022 Empirical and philosophical problems with the subspecies rank. Ecology and evolution 45 35845367
2013 Constitutive activation of RANK disrupts mammary cell fate leading to tumorigenesis. Stem cells (Dayton, Ohio) 44 23766243
2015 RANK and RANK ligand expression in primary human osteosarcoma. Journal of bone oncology 43 27556008
2002 RANK ligand, RANK, and OPG expression in type II collagen-induced arthritis mouse. Histochemistry and cell biology 43 11914926
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 36 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
2021 RANK Signaling in the Differentiation and Regeneration of Thymic Epithelial Cells. Frontiers in immunology 33 33552088
2015 Correlating RANK ligand/RANK binding kinetics with osteoclast formation and function. Journal of cellular biochemistry 33 25864714
2002 Detection and characterization of RANK ligand and osteoprotegerin in the thyroid gland. Journal of cellular biochemistry 33 12210731
2014 Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK. Bone 32 25063546
2004 The high rate of bone resorption in multiple myeloma is due to RANK (receptor activator of nuclear factor-kappaB) and RANK Ligand expression. Leukemia & lymphoma 32 15359989
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
2020 Ellagic acid blocks RANKL-RANK interaction and suppresses RANKL-induced osteoclastogenesis by inhibiting RANK signaling pathways. Chemico-biological interactions 28 32971123
2019 An osteoclastogenesis system, the RANKL/RANK signalling pathway, contributes to aggravated allergic inflammation. British journal of pharmacology 28 30737962
2012 RANK (TNFRSF11A) is epigenetically inactivated and induces apoptosis in gliomas. Neoplasia (New York, N.Y.) 27 22787434
2017 Implicating Receptor Activator of NF-κB (RANK)/RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli. Developmental neuroscience 26 28402971
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
2010 TNFRSF11A and TNFSF11 are associated with age at menarche and natural menopause in white women. Menopause (New York, N.Y.) 25 20531232
2008 OPG, RANK and RANK ligand expression in thyroid lesions. Regulatory peptides 25 18367263
2023 PASSerRank: Prediction of allosteric sites with learning to rank. Journal of computational chemistry 24 37561047
2020 TNF-α stimulates the expression of RANK during orthodontic tooth movement. Archives of oral biology 24 32544645
2017 RANK/RANKL/OPG system in the intervertebral disc. Arthritis research & therapy 24 28576140
2014 Brief Report: Involvement of TNFRSF11A molecular defects in autoinflammatory disorders. Arthritis & rheumatology (Hoboken, N.J.) 24 24891336
2013 Role of RANKL/RANK in primary and secondary breast cancer. World journal of orthopedics 24 24147253
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
2018 RANKL/RANK Pathway and Its Inhibitor RANK-Fc in Uterine Leiomyoma Growth. The Journal of clinical endocrinology and metabolism 23 29741640
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

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