{"gene":"TNFRSF11A","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":1998,"finding":"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.","method":"Molecular cloning, antibody agonism/antagonism assays, soluble receptor competition, osteoclastogenesis assay in macrophage-like cell line C7","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct receptor-ligand binding, functional agonist/antagonist experiments, replicated across multiple subsequent labs","pmids":["9878548"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Genetic linkage, Sanger sequencing, recombinant protein expression, NF-κB reporter assay","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutation identified in multiple families, functional NF-κB reporter assay confirmed gain-of-function mechanism, replicated in subsequent studies","pmids":["10615125"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Sanger sequencing of TNFRSF11A, comparative mutation analysis","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic identification in affected families with functional inference from prior NF-κB data; single-lab sequencing without independent in vitro functional confirmation in this paper","pmids":["11771666"],"is_preprint":false},{"year":2005,"finding":"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.","method":"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":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with deletion mutants, functional osteoclastogenesis rescue, single lab with multiple orthogonal methods","pmids":["16234979"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Biochemical interaction studies, genetic knock-out analysis (TRAF6-null mice), downstream signaling assays (reviewed mechanistic data)","journal":"Advances in experimental medicine and biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — TRAF6 requirement established by multiple labs using KO mice and binding studies; independently replicated","pmids":["17633024"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Genetic CYLD knockout mice, osteoclast differentiation assays, co-immunoprecipitation (CYLD-p62-TRAF6), ubiquitination assays, downstream signaling analysis","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse phenotype combined with reciprocal Co-IP and mechanistic ubiquitination assay in single rigorous study","pmids":["18382763"],"is_preprint":false},{"year":2008,"finding":"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.","method":"TNFRSF11A sequencing in ARO patients, in vitro osteoclast differentiation assay from patient monocytes, immunological B cell analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple unrelated families with homozygous TNFRSF11A mutations, functional osteoclast differentiation assay establishing cell-intrinsic defect, multiple orthogonal analyses","pmids":["18606301"],"is_preprint":false},{"year":2010,"finding":"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.","method":"X-ray crystallography (crystal structures of unliganded RANK and RANKL-RANK complex), mutagenesis, osteoclast formation assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus functional osteoclastogenesis assay in a single rigorous study","pmids":["20483727"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Genetic KO (TRANCE-null, RANK-null, TRAF6-null mice), in vitro osteoclast differentiation with TNF-α and TGF-β, negative epistasis","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — triple independent KO mouse models with in vitro differentiation assay, directly challenges the prior paradigm","pmids":["16147974"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Conditional/inducible Rank knockout mice, K/BxN serum-transfer arthritis model, in vitro osteoclast cultures, micro-CT, histology, qPCR","journal":"Arthritis & rheumatology","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible KO mice with rigorous histological and imaging endpoints, multiple genetic tools used","pmids":["27563728"],"is_preprint":false},{"year":2004,"finding":"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).","method":"RT-PCR and FACS for RANK expression, micropore filter migration assay, pharmacological signaling inhibitors, Western blot","journal":"Arthritis and rheumatism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct receptor expression confirmed, migration assay with multiple pathway inhibitors, single lab","pmids":["15248232"],"is_preprint":false},{"year":2001,"finding":"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.","method":"RT-PCR for RANK mRNA, flow cytometry for RANK protein, TRAP staining and multinucleated cell counting for osteoclast differentiation, dose-response experiments","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple readouts (mRNA, protein, functional differentiation), single lab, single cell line","pmids":["11573248"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Adherent vs. non-adherent culture, RT-PCR and Western blot for RANK, RANK/TRAF6 forced expression, echistatin treatment, NF-κB pathway analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (pharmacological, overexpression rescue, gene expression), single lab","pmids":["23139818"],"is_preprint":false},{"year":2015,"finding":"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.","method":"RANK knockout mouse mammary analysis, flow cytometry of mammary subpopulations, WNT pathway reporter assays, R-spondin1 rescue experiments, human breast tissue analysis","journal":"Stem cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with specific cellular phenotype, molecular pathway identification (R-spondin1/WNT), rescue experiment, human validation","pmids":["26095608"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Conditional mammary epithelium-specific RANK knockout mice, pharmacological RANKL inhibition, mammary stem cell assays, human BRCA1 carrier progenitor cell expansion assays","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — two mouse models, genetic and pharmacological approaches, human tissue validation, multiple orthogonal methods","pmids":["27241552"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Constitutively active RANK mouse model, flow cytometry of mammary subpopulations, histology, tumor formation assay","journal":"Stem cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mouse model with multiple cellular readouts, single lab","pmids":["23766243"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Site-directed mutagenesis, TF deletion/interference assays, animal bone metastasis models, co-culture experiments","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo metastasis rescue combined with molecular pathway dissection, single lab","pmids":["24478054"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Pyrosequencing for methylation, demethylating agent treatment, RANK overexpression in glioma cell lines, flow cytometry for apoptosis, focus formation assay, reporter assay","journal":"Neoplasia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods including epigenetic reversal and functional overexpression with apoptosis assay, single lab","pmids":["22787434"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Genetic association study, NF-κB luciferase reporter co-transfection assay with SQSTM1 and TNFRSF11A variants","journal":"Journal of bone and mineral research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional NF-κB assay in cell lines supporting genetic association, single lab","pmids":["21987421"],"is_preprint":false},{"year":2014,"finding":"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.","method":"TNFRSF11A sequencing, NF-κB luciferase reporter assay in cells expressing wild-type vs. mutant RANK, Luminex cytokine measurement","journal":"Arthritis & rheumatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional NF-κB reporter plus cytokine profiling, single family/lab","pmids":["24891336"],"is_preprint":false},{"year":2019,"finding":"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.","method":"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","journal":"Developmental neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CRISPR KO with functional inflammatory assays and primary cell validation, single lab","pmids":["28402971"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Review synthesizing genetic epistasis, kinase/adaptor knockout models, Ca2+ imaging, and transcription factor analysis from multiple labs","journal":"Molecules and cells","confidence":"High","confidence_rationale":"Tier 2 / Strong — established through independently replicated genetic and biochemical experiments across multiple labs; well-supported multi-stage signaling model","pmids":["29047262"],"is_preprint":false},{"year":2015,"finding":"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.","method":"Yeast surface display mutagenesis screen, recombinant RANKL mutant proteins, osteoclast differentiation assays, binding kinetics","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro reconstitution with binding kinetics and functional osteoclastogenesis, single lab","pmids":["25864714"],"is_preprint":false},{"year":2018,"finding":"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.","method":"mRNA/protein quantification in tissue and cell subpopulations, PR agonist treatment, RANK-Fc inhibitor treatment, murine xenograft model with tumor growth and Ki67 measurement","journal":"The Journal of clinical endocrinology and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo xenograft model combined with molecular pathway analysis, single lab","pmids":["29741640"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Extracellular vesicle isolation, RANK detection in EVs, functional bone formation assays (reviewed mechanistic data)","journal":"Extracellular vesicles and circulating nucleic acids","confidence":"Low","confidence_rationale":"Tier 3 / Weak — review paper citing primary data; mechanism cited but primary experimental detail not in this abstract","pmids":["33982033"],"is_preprint":false},{"year":2017,"finding":"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.","method":"ChIP/promoter binding assay, KLF5 overexpression/knockdown, TNFRSF11a knockdown (siRNA), in vivo xenograft and liver metastasis mouse models, RT-PCR, Western blot, p38 inhibitor","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding plus in vivo functional knockdown, single lab with multiple orthogonal methods","pmids":["29146991"],"is_preprint":false}],"current_model":"TNFRSF11A/RANK is a transmembrane TNF receptor superfamily member that, upon binding its ligand RANKL, recruits TRAF6 (and other TRAFs) to activate NF-κB, MAPKs (JNK, ERK, p38), and downstream NFATc1 transcription, driving osteoclast differentiation, activation, and survival; RANK self-assembles via its cytoplasmic domain (aa 534–539) to permit ligand-independent signaling, its expression is upregulated by cell adhesion, TGF-β, and TNF-α and downregulated by loss of adhesion, activating signal-peptide insertion mutations cause gain-of-function NF-κB signaling leading to familial expansile osteolysis/Paget's disease variants, while loss-of-function mutations cause osteoclast-poor osteopetrosis with immunodeficiency; beyond bone, RANK controls mammary progenitor expansion via R-spondin1/WNT signaling, drives progesterone/BRCA1-linked breast carcinogenesis, modulates microglial inflammatory responses, promotes leiomyoma and cervical cancer growth, and exhibits tumor-suppressive pro-apoptotic activity in gliomas where it is epigenetically silenced."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1998,"claim":"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","pmids":["9878548"],"confidence":"High","gaps":["Did not resolve the cytoplasmic signaling cascade","No structural basis for ligand binding"]},{"year":2000,"claim":"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","pmids":["10615125"],"confidence":"High","gaps":["Mechanism by which signal-peptide defects increase signaling not fully resolved","Did not address cell-type specificity of disease"]},{"year":2002,"claim":"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","pmids":["11771666"],"confidence":"Medium","gaps":["No independent in vitro functional confirmation in this study","Genotype-phenotype severity determinants unexplained"]},{"year":2004,"claim":"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","pmids":["15248232"],"confidence":"Medium","gaps":["Single lab, pharmacological rather than genetic dissection","In vivo relevance of monocyte chemotaxis not established"]},{"year":2005,"claim":"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","pmids":["16234979"],"confidence":"Medium","gaps":["Physiological role of ligand-independent assembly unclear","Single-lab study"]},{"year":2005,"claim":"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","pmids":["16147974"],"confidence":"High","gaps":["Physiological contribution of alternative pathway in vivo not quantified"]},{"year":2007,"claim":"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)","pmids":["17633024"],"confidence":"High","gaps":["Roles of the other four TRAFs not delineated","Reviewed rather than primary data"]},{"year":2008,"claim":"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","pmids":["18382763"],"confidence":"High","gaps":["How p62/CYLD recruitment is regulated dynamically unknown"]},{"year":2008,"claim":"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","pmids":["18606301"],"confidence":"High","gaps":["Mechanism of RANK action in B cells not resolved"]},{"year":2010,"claim":"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","pmids":["20483727"],"confidence":"High","gaps":["Structure of full-length receptor and transmembrane assembly not resolved"]},{"year":2015,"claim":"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","pmids":["25864714"],"confidence":"Medium","gaps":["In vivo consequences of affinity-tuned variants untested"]},{"year":2017,"claim":"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","pmids":["29047262"],"confidence":"High","gaps":["Quantitative thresholds for stage transitions not defined"]},{"year":2015,"claim":"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","pmids":["26095608"],"confidence":"High","gaps":["Direct link between RANK signaling and R-spondin1 transcription not detailed"]},{"year":2016,"claim":"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","pmids":["27241552"],"confidence":"High","gaps":["Cell of origin and timing of RANK-dependent transformation not fully defined"]},{"year":2016,"claim":"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","pmids":["27563728"],"confidence":"High","gaps":["Relative contribution of RANK-independent osteoclastogenesis in human arthritis unknown"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,7]},{"term_id":"GO:0048018","term_label":"receptor ligand activity","supporting_discovery_ids":[0,7,22]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,10]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,21]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[13,15]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,20]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,6,17]}],"complexes":[],"partners":["RANKL","TRAF6","CYLD","SQSTM1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y6Q6","full_name":"Tumor necrosis factor receptor superfamily member 11A","aliases":["Osteoclast differentiation factor receptor","ODFR","Receptor activator of NF-KB"],"length_aa":616,"mass_kda":66.0,"function":"Receptor for TNFSF11/RANKL/TRANCE/OPGL; essential for RANKL-mediated osteoclastogenesis (PubMed:9878548). Its interaction with EEIG1 promotes osteoclastogenesis via facilitating the transcription of NFATC1 and activation of PLCG2 (By similarity). Involved in the regulation of interactions between T-cells and dendritic cells (By similarity)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9Y6Q6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TNFRSF11A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TNFRSF11A","total_profiled":1310},"omim":[{"mim_id":"612301","title":"OSTEOPETROSIS, AUTOSOMAL RECESSIVE 7; OPTB7","url":"https://www.omim.org/entry/612301"},{"mim_id":"610900","title":"CHARGED MULTIVESICULAR BODY PROTEIN 5; CHMP5","url":"https://www.omim.org/entry/610900"},{"mim_id":"607507","title":"PSORIATIC ARTHRITIS, SUSCEPTIBILITY TO","url":"https://www.omim.org/entry/607507"},{"mim_id":"607414","title":"FEZ FAMILY ZINC FINGER PROTEIN 2; FEZF2","url":"https://www.omim.org/entry/607414"},{"mim_id":"605018","title":"CYLD LYSINE-63 DEUBIQUITINASE; CYLD","url":"https://www.omim.org/entry/605018"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":28.5},{"tissue":"salivary gland","ntpm":23.7}],"url":"https://www.proteinatlas.org/search/TNFRSF11A"},"hgnc":{"alias_symbol":["RANK","CD265","FEO","ODFR","TRANCE-R"],"prev_symbol":["PDB2","LOH18CR1"]},"alphafold":{"accession":"Q9Y6Q6","domains":[{"cath_id":"2.10.50.10","chopping":"25-94_102-111","consensus_level":"medium","plddt":91.2676,"start":25,"end":111},{"cath_id":"2.10.50.10","chopping":"133-200","consensus_level":"medium","plddt":93.7687,"start":133,"end":200}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6Q6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6Q6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y6Q6-F1-predicted_aligned_error_v6.png","plddt_mean":58.91},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TNFRSF11A","jax_strain_url":"https://www.jax.org/strain/search?query=TNFRSF11A"},"sequence":{"accession":"Q9Y6Q6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y6Q6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y6Q6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y6Q6"}},"corpus_meta":[{"pmid":"18395508","id":"PMC_18395508","title":"Functions of RANKL/RANK/OPG in bone modeling and remodeling.","date":"2008","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/18395508","citation_count":1331,"is_preprint":false},{"pmid":"11713196","id":"PMC_11713196","title":"Minireview: the OPG/RANKL/RANK system.","date":"2001","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/11713196","citation_count":1050,"is_preprint":false},{"pmid":"16356770","id":"PMC_16356770","title":"RANKL-RANK signaling in osteoclastogenesis and bone disease.","date":"2005","source":"Trends in molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16356770","citation_count":935,"is_preprint":false},{"pmid":"17634140","id":"PMC_17634140","title":"Biology of RANK, RANKL, and osteoprotegerin.","date":"2007","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/17634140","citation_count":696,"is_preprint":false},{"pmid":"11861618","id":"PMC_11861618","title":"RANK-L and RANK: T cells, bone loss, and mammalian evolution.","date":"2001","source":"Annual review of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11861618","citation_count":637,"is_preprint":false},{"pmid":"9878548","id":"PMC_9878548","title":"RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis.","date":"1998","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/9878548","citation_count":574,"is_preprint":false},{"pmid":"29047262","id":"PMC_29047262","title":"Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation.","date":"2017","source":"Molecules and cells","url":"https://pubmed.ncbi.nlm.nih.gov/29047262","citation_count":503,"is_preprint":false},{"pmid":"25368616","id":"PMC_25368616","title":"Biology of the RANKL-RANK-OPG System in Immunity, Bone, and Beyond.","date":"2014","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/25368616","citation_count":492,"is_preprint":false},{"pmid":"20660011","id":"PMC_20660011","title":"Rank-rank hypergeometric overlap: identification of statistically significant overlap between gene-expression signatures.","date":"2010","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/20660011","citation_count":371,"is_preprint":false},{"pmid":"10615125","id":"PMC_10615125","title":"Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis.","date":"2000","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10615125","citation_count":343,"is_preprint":false},{"pmid":"19076348","id":"PMC_19076348","title":"RANK/RANKL: regulators of immune responses and bone physiology.","date":"2008","source":"Annals of the New York Academy of Sciences","url":"https://pubmed.ncbi.nlm.nih.gov/19076348","citation_count":309,"is_preprint":false},{"pmid":"16147974","id":"PMC_16147974","title":"Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis.","date":"2005","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16147974","citation_count":301,"is_preprint":false},{"pmid":"26684538","id":"PMC_26684538","title":"Bacterial ferrous iron transport: the Feo system.","date":"2015","source":"FEMS microbiology reviews","url":"https://pubmed.ncbi.nlm.nih.gov/26684538","citation_count":294,"is_preprint":false},{"pmid":"16718600","id":"PMC_16718600","title":"Feo--transport of ferrous iron into bacteria.","date":"2006","source":"Biometals : an international journal on the role of metal ions in biology, biochemistry, and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16718600","citation_count":273,"is_preprint":false},{"pmid":"17925190","id":"PMC_17925190","title":"The RANKL/RANK/OPG pathway.","date":"2007","source":"Current osteoporosis reports","url":"https://pubmed.ncbi.nlm.nih.gov/17925190","citation_count":259,"is_preprint":false},{"pmid":"18606301","id":"PMC_18606301","title":"Human osteoclast-poor osteopetrosis with hypogammaglobulinemia due to TNFRSF11A (RANK) mutations.","date":"2008","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18606301","citation_count":218,"is_preprint":false},{"pmid":"12424190","id":"PMC_12424190","title":"RANK ligand and osteoprotegerin in myeloma bone disease.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12424190","citation_count":207,"is_preprint":false},{"pmid":"15883214","id":"PMC_15883214","title":"Dysregulated osteoprotegerin/RANK ligand/RANK axis in clinical and experimental heart failure.","date":"2005","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/15883214","citation_count":203,"is_preprint":false},{"pmid":"19419454","id":"PMC_19419454","title":"RANK/RANKL/OPG during orthodontic tooth movement.","date":"2009","source":"Orthodontics & craniofacial research","url":"https://pubmed.ncbi.nlm.nih.gov/19419454","citation_count":201,"is_preprint":false},{"pmid":"17895323","id":"PMC_17895323","title":"CLINICAL Review #: the role of receptor activator of nuclear factor-kappaB (RANK)/RANK ligand/osteoprotegerin: clinical implications.","date":"2007","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/17895323","citation_count":196,"is_preprint":false},{"pmid":"16313338","id":"PMC_16313338","title":"Osteoclast precursors, RANKL/RANK, and immunology.","date":"2005","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/16313338","citation_count":187,"is_preprint":false},{"pmid":"15615494","id":"PMC_15615494","title":"The OPG/RANKL/RANK system in metabolic bone diseases.","date":"2004","source":"Journal of musculoskeletal & neuronal interactions","url":"https://pubmed.ncbi.nlm.nih.gov/15615494","citation_count":183,"is_preprint":false},{"pmid":"11306358","id":"PMC_11306358","title":"Osteoprotegerin and rank ligand expression in prostate cancer.","date":"2001","source":"Urology","url":"https://pubmed.ncbi.nlm.nih.gov/11306358","citation_count":175,"is_preprint":false},{"pmid":"33389131","id":"PMC_33389131","title":"Discovery of the RANKL/RANK/OPG system.","date":"2021","source":"Journal of bone and mineral metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/33389131","citation_count":169,"is_preprint":false},{"pmid":"12379618","id":"PMC_12379618","title":"Role of RANKL and RANK in bone loss and arthritis.","date":"2002","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/12379618","citation_count":162,"is_preprint":false},{"pmid":"18382763","id":"PMC_18382763","title":"Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice.","date":"2008","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/18382763","citation_count":162,"is_preprint":false},{"pmid":"22113597","id":"PMC_22113597","title":"Rank/Rankl/opg: literature review.","date":"2011","source":"Acta reumatologica portuguesa","url":"https://pubmed.ncbi.nlm.nih.gov/22113597","citation_count":142,"is_preprint":false},{"pmid":"25720990","id":"PMC_25720990","title":"The RANKL-RANK Story.","date":"2015","source":"Gerontology","url":"https://pubmed.ncbi.nlm.nih.gov/25720990","citation_count":139,"is_preprint":false},{"pmid":"27241552","id":"PMC_27241552","title":"RANKL/RANK control Brca1 mutation- .","date":"2016","source":"Cell research","url":"https://pubmed.ncbi.nlm.nih.gov/27241552","citation_count":139,"is_preprint":false},{"pmid":"27279652","id":"PMC_27279652","title":"RANK-RANKL signalling in cancer.","date":"2016","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/27279652","citation_count":134,"is_preprint":false},{"pmid":"11521937","id":"PMC_11521937","title":"The osteoclastogenic molecules RANKL and RANK are associated with periprosthetic osteolysis.","date":"2001","source":"The Journal of bone and joint surgery. British volume","url":"https://pubmed.ncbi.nlm.nih.gov/11521937","citation_count":130,"is_preprint":false},{"pmid":"11771666","id":"PMC_11771666","title":"Expansile skeletal hyperphosphatasia is caused by a 15-base pair tandem duplication in TNFRSF11A encoding RANK and is allelic to familial expansile osteolysis.","date":"2002","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/11771666","citation_count":126,"is_preprint":false},{"pmid":"17530461","id":"PMC_17530461","title":"RANKL, RANK, osteoprotegerin: key partners of osteoimmunology and vascular diseases.","date":"2007","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/17530461","citation_count":125,"is_preprint":false},{"pmid":"27563728","id":"PMC_27563728","title":"RANK-Independent Osteoclast Formation and Bone Erosion in Inflammatory Arthritis.","date":"2016","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/27563728","citation_count":119,"is_preprint":false},{"pmid":"21445556","id":"PMC_21445556","title":"RANKL/RANK-beyond bones.","date":"2011","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/21445556","citation_count":112,"is_preprint":false},{"pmid":"20483727","id":"PMC_20483727","title":"Structural and functional insights of RANKL-RANK interaction and signaling.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20483727","citation_count":108,"is_preprint":false},{"pmid":"14523602","id":"PMC_14523602","title":"Novel aspects on RANK ligand and osteoprotegerin in osteoporosis and vascular disease.","date":"2003","source":"Calcified tissue international","url":"https://pubmed.ncbi.nlm.nih.gov/14523602","citation_count":96,"is_preprint":false},{"pmid":"22440513","id":"PMC_22440513","title":"Role of RANK ligand and denosumab, a targeted RANK ligand inhibitor, in bone health and osteoporosis: a review of preclinical and clinical data.","date":"2012","source":"Clinical therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/22440513","citation_count":96,"is_preprint":false},{"pmid":"11573248","id":"PMC_11573248","title":"Regulation of osteoclastogenesis and RANK expression by TGF-beta1.","date":"2001","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11573248","citation_count":94,"is_preprint":false},{"pmid":"30232468","id":"PMC_30232468","title":"Roles of the RANKL-RANK axis in antitumour immunity - implications for therapy.","date":"2018","source":"Nature reviews. Clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30232468","citation_count":92,"is_preprint":false},{"pmid":"19762475","id":"PMC_19762475","title":"Modulation of OPG, RANK and RANKL by human chondrocytes and their implication during osteoarthritis.","date":"2009","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/19762475","citation_count":89,"is_preprint":false},{"pmid":"29241686","id":"PMC_29241686","title":"RANKL and RANK: From Mammalian Physiology to Cancer Treatment.","date":"2017","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29241686","citation_count":76,"is_preprint":false},{"pmid":"29953152","id":"PMC_29953152","title":"Toward a mechanistic understanding of Feo-mediated ferrous iron uptake.","date":"2018","source":"Metallomics : integrated biometal science","url":"https://pubmed.ncbi.nlm.nih.gov/29953152","citation_count":74,"is_preprint":false},{"pmid":"12548579","id":"PMC_12548579","title":"RANK-Fc: a therapeutic antagonist for RANK-L in myeloma.","date":"2003","source":"Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/12548579","citation_count":74,"is_preprint":false},{"pmid":"24478054","id":"PMC_24478054","title":"RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization.","date":"2014","source":"Endocrine-related cancer","url":"https://pubmed.ncbi.nlm.nih.gov/24478054","citation_count":74,"is_preprint":false},{"pmid":"20163972","id":"PMC_20163972","title":"RANK/RANKL/OPG role in distraction osteogenesis.","date":"2010","source":"Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics","url":"https://pubmed.ncbi.nlm.nih.gov/20163972","citation_count":72,"is_preprint":false},{"pmid":"12707582","id":"PMC_12707582","title":"RANKL and RANK as novel therapeutic targets for arthritis.","date":"2003","source":"Current opinion in rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/12707582","citation_count":71,"is_preprint":false},{"pmid":"21225243","id":"PMC_21225243","title":"Zoledronic acid inhibits RANK expression and migration of osteoclast precursors during osteoclastogenesis.","date":"2011","source":"Naunyn-Schmiedeberg's archives of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/21225243","citation_count":69,"is_preprint":false},{"pmid":"17633024","id":"PMC_17633024","title":"TRAFs in RANK signaling.","date":"2007","source":"Advances in experimental medicine and biology","url":"https://pubmed.ncbi.nlm.nih.gov/17633024","citation_count":66,"is_preprint":false},{"pmid":"26095608","id":"PMC_26095608","title":"RANK Signaling Amplifies WNT-Responsive Mammary Progenitors through R-SPONDIN1.","date":"2015","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/26095608","citation_count":65,"is_preprint":false},{"pmid":"15785827","id":"PMC_15785827","title":"RANK, RANKL and osteoprotegerin in arthritic bone loss.","date":"2005","source":"Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas","url":"https://pubmed.ncbi.nlm.nih.gov/15785827","citation_count":64,"is_preprint":false},{"pmid":"30093448","id":"PMC_30093448","title":"Role of the RANK/RANKL Pathway in Multiple Myeloma.","date":"2018","source":"Clinical cancer research : an official journal of the American Association for Cancer Research","url":"https://pubmed.ncbi.nlm.nih.gov/30093448","citation_count":63,"is_preprint":false},{"pmid":"32850393","id":"PMC_32850393","title":"Targeting the RANKL/RANK/OPG Axis for Cancer Therapy.","date":"2020","source":"Frontiers in oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32850393","citation_count":58,"is_preprint":false},{"pmid":"17174136","id":"PMC_17174136","title":"RANK ligand.","date":"2006","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17174136","citation_count":56,"is_preprint":false},{"pmid":"11351498","id":"PMC_11351498","title":"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.","date":"2001","source":"Calcified tissue international","url":"https://pubmed.ncbi.nlm.nih.gov/11351498","citation_count":56,"is_preprint":false},{"pmid":"29146991","id":"PMC_29146991","title":"KLF5 promotes cervical cancer proliferation, migration and invasion in a manner partly dependent on TNFRSF11a expression.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29146991","citation_count":54,"is_preprint":false},{"pmid":"34214174","id":"PMC_34214174","title":"Rank-in: enabling integrative analysis across microarray and RNA-seq for cancer.","date":"2021","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/34214174","citation_count":53,"is_preprint":false},{"pmid":"26749530","id":"PMC_26749530","title":"RANK as a therapeutic target in cancer.","date":"2016","source":"The FEBS journal","url":"https://pubmed.ncbi.nlm.nih.gov/26749530","citation_count":52,"is_preprint":false},{"pmid":"7737382","id":"PMC_7737382","title":"Oxygen-derived free radical (ODFR) action on hyaluronan (HA), on two HA ester derivatives, and on the metabolism of articular chondrocytes.","date":"1995","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/7737382","citation_count":51,"is_preprint":false},{"pmid":"24486161","id":"PMC_24486161","title":"RANKL/RANK - from bone physiology to breast cancer.","date":"2014","source":"Cytokine & growth factor reviews","url":"https://pubmed.ncbi.nlm.nih.gov/24486161","citation_count":50,"is_preprint":false},{"pmid":"34440747","id":"PMC_34440747","title":"The Roadmap of RANKL/RANK Pathway in Cancer.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/34440747","citation_count":49,"is_preprint":false},{"pmid":"30984193","id":"PMC_30984193","title":"The RANKL-RANK Axis: A Bone to Thymus Round Trip.","date":"2019","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/30984193","citation_count":49,"is_preprint":false},{"pmid":"26921922","id":"PMC_26921922","title":"Role of the RANK/RANKL pathway in breast cancer.","date":"2016","source":"Maturitas","url":"https://pubmed.ncbi.nlm.nih.gov/26921922","citation_count":48,"is_preprint":false},{"pmid":"16234979","id":"PMC_16234979","title":"Self-assembled RANK induces osteoclastogenesis ligand-independently.","date":"2005","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/16234979","citation_count":46,"is_preprint":false},{"pmid":"35845367","id":"PMC_35845367","title":"Empirical and philosophical problems with the subspecies rank.","date":"2022","source":"Ecology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/35845367","citation_count":45,"is_preprint":false},{"pmid":"23766243","id":"PMC_23766243","title":"Constitutive activation of RANK disrupts mammary cell fate leading to tumorigenesis.","date":"2013","source":"Stem cells (Dayton, Ohio)","url":"https://pubmed.ncbi.nlm.nih.gov/23766243","citation_count":44,"is_preprint":false},{"pmid":"27556008","id":"PMC_27556008","title":"RANK and RANK ligand expression in primary human osteosarcoma.","date":"2015","source":"Journal of bone oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27556008","citation_count":43,"is_preprint":false},{"pmid":"11914926","id":"PMC_11914926","title":"RANK ligand, RANK, and OPG expression in type II collagen-induced arthritis mouse.","date":"2002","source":"Histochemistry and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/11914926","citation_count":43,"is_preprint":false},{"pmid":"24398859","id":"PMC_24398859","title":"RANK-mediated signaling network and cancer metastasis.","date":"2014","source":"Cancer metastasis reviews","url":"https://pubmed.ncbi.nlm.nih.gov/24398859","citation_count":40,"is_preprint":false},{"pmid":"15248232","id":"PMC_15248232","title":"Expression and function of RANK in human monocyte chemotaxis.","date":"2004","source":"Arthritis and rheumatism","url":"https://pubmed.ncbi.nlm.nih.gov/15248232","citation_count":40,"is_preprint":false},{"pmid":"33982033","id":"PMC_33982033","title":"RANKL and RANK in extracellular vesicles: surprising new players in bone remodeling.","date":"2021","source":"Extracellular vesicles and circulating nucleic acids","url":"https://pubmed.ncbi.nlm.nih.gov/33982033","citation_count":36,"is_preprint":false},{"pmid":"15615493","id":"PMC_15615493","title":"Heritable disorders of the RANKL/OPG/RANK signaling pathway.","date":"2004","source":"Journal of musculoskeletal & neuronal interactions","url":"https://pubmed.ncbi.nlm.nih.gov/15615493","citation_count":35,"is_preprint":false},{"pmid":"15615495","id":"PMC_15615495","title":"RANK, RANKL and OPG in inflammatory arthritis and periprosthetic osteolysis.","date":"2004","source":"Journal of musculoskeletal & neuronal interactions","url":"https://pubmed.ncbi.nlm.nih.gov/15615495","citation_count":34,"is_preprint":false},{"pmid":"21087090","id":"PMC_21087090","title":"Physiology and pathophysiology of the RANKL/RANK system.","date":"2010","source":"Biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21087090","citation_count":34,"is_preprint":false},{"pmid":"20564239","id":"PMC_20564239","title":"Genetic variation in the TNFRSF11A gene encoding RANK is associated with susceptibility to Paget's disease of bone.","date":"2010","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/20564239","citation_count":34,"is_preprint":false},{"pmid":"33552088","id":"PMC_33552088","title":"RANK Signaling in the Differentiation and Regeneration of Thymic Epithelial Cells.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/33552088","citation_count":33,"is_preprint":false},{"pmid":"25864714","id":"PMC_25864714","title":"Correlating RANK ligand/RANK binding kinetics with osteoclast formation and function.","date":"2015","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25864714","citation_count":33,"is_preprint":false},{"pmid":"12210731","id":"PMC_12210731","title":"Detection and characterization of RANK ligand and osteoprotegerin in the thyroid gland.","date":"2002","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12210731","citation_count":33,"is_preprint":false},{"pmid":"25063546","id":"PMC_25063546","title":"Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK.","date":"2014","source":"Bone","url":"https://pubmed.ncbi.nlm.nih.gov/25063546","citation_count":32,"is_preprint":false},{"pmid":"15359989","id":"PMC_15359989","title":"The high rate of bone resorption in multiple myeloma is due to RANK (receptor activator of nuclear factor-kappaB) and RANK Ligand expression.","date":"2004","source":"Leukemia & lymphoma","url":"https://pubmed.ncbi.nlm.nih.gov/15359989","citation_count":32,"is_preprint":false},{"pmid":"18228207","id":"PMC_18228207","title":"Role of OPG/RANKL/RANK axis on the vasculature.","date":"2008","source":"Histology and histopathology","url":"https://pubmed.ncbi.nlm.nih.gov/18228207","citation_count":31,"is_preprint":false},{"pmid":"19995704","id":"PMC_19995704","title":"OPG/RANK/RANKL signaling system and its significance in nephrology.","date":"2009","source":"Folia histochemica et cytobiologica","url":"https://pubmed.ncbi.nlm.nih.gov/19995704","citation_count":29,"is_preprint":false},{"pmid":"22929916","id":"PMC_22929916","title":"Bone metastasis in breast cancer: the story of RANK-ligand.","date":"2012","source":"Journal of the Egyptian National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/22929916","citation_count":29,"is_preprint":false},{"pmid":"32971123","id":"PMC_32971123","title":"Ellagic acid blocks RANKL-RANK interaction and suppresses RANKL-induced osteoclastogenesis by inhibiting RANK signaling pathways.","date":"2020","source":"Chemico-biological interactions","url":"https://pubmed.ncbi.nlm.nih.gov/32971123","citation_count":28,"is_preprint":false},{"pmid":"30737962","id":"PMC_30737962","title":"An osteoclastogenesis system, the RANKL/RANK signalling pathway, contributes to aggravated allergic inflammation.","date":"2019","source":"British journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30737962","citation_count":28,"is_preprint":false},{"pmid":"22787434","id":"PMC_22787434","title":"RANK (TNFRSF11A) is epigenetically inactivated and induces apoptosis in gliomas.","date":"2012","source":"Neoplasia (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/22787434","citation_count":27,"is_preprint":false},{"pmid":"21987421","id":"PMC_21987421","title":"A nonsynonymous TNFRSF11A variation increases NFκB activity and the severity of Paget's disease.","date":"2012","source":"Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research","url":"https://pubmed.ncbi.nlm.nih.gov/21987421","citation_count":26,"is_preprint":false},{"pmid":"12923331","id":"PMC_12923331","title":"Expression of osteoprotegerin and RANK ligand in breast cancer bone metastasis.","date":"2003","source":"Journal of Korean medical science","url":"https://pubmed.ncbi.nlm.nih.gov/12923331","citation_count":26,"is_preprint":false},{"pmid":"28402971","id":"PMC_28402971","title":"Implicating Receptor Activator of NF-κB (RANK)/RANK Ligand Signalling in Microglial Responses to Toll-Like Receptor Stimuli.","date":"2017","source":"Developmental neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/28402971","citation_count":26,"is_preprint":false},{"pmid":"20531232","id":"PMC_20531232","title":"TNFRSF11A and TNFSF11 are associated with age at menarche and natural menopause in white women.","date":"2010","source":"Menopause (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/20531232","citation_count":25,"is_preprint":false},{"pmid":"18367263","id":"PMC_18367263","title":"OPG, RANK and RANK ligand expression in thyroid lesions.","date":"2008","source":"Regulatory peptides","url":"https://pubmed.ncbi.nlm.nih.gov/18367263","citation_count":25,"is_preprint":false},{"pmid":"28576140","id":"PMC_28576140","title":"RANK/RANKL/OPG system in the intervertebral disc.","date":"2017","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/28576140","citation_count":24,"is_preprint":false},{"pmid":"24147253","id":"PMC_24147253","title":"Role of RANKL/RANK in primary and secondary breast cancer.","date":"2013","source":"World journal of orthopedics","url":"https://pubmed.ncbi.nlm.nih.gov/24147253","citation_count":24,"is_preprint":false},{"pmid":"18928898","id":"PMC_18928898","title":"Expression of bone resorption regulators (RANK, RANKL, and OPG) in odontogenic tumors.","date":"2008","source":"Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics","url":"https://pubmed.ncbi.nlm.nih.gov/18928898","citation_count":24,"is_preprint":false},{"pmid":"24891336","id":"PMC_24891336","title":"Brief Report: Involvement of TNFRSF11A molecular defects in autoinflammatory disorders.","date":"2014","source":"Arthritis & rheumatology (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/24891336","citation_count":24,"is_preprint":false},{"pmid":"32544645","id":"PMC_32544645","title":"TNF-α stimulates the expression of RANK during orthodontic tooth movement.","date":"2020","source":"Archives of oral biology","url":"https://pubmed.ncbi.nlm.nih.gov/32544645","citation_count":24,"is_preprint":false},{"pmid":"37561047","id":"PMC_37561047","title":"PASSerRank: Prediction of allosteric sites with learning to rank.","date":"2023","source":"Journal of computational chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37561047","citation_count":24,"is_preprint":false},{"pmid":"29741640","id":"PMC_29741640","title":"RANKL/RANK Pathway and Its Inhibitor RANK-Fc in Uterine Leiomyoma Growth.","date":"2018","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/29741640","citation_count":23,"is_preprint":false},{"pmid":"17081156","id":"PMC_17081156","title":"Stress, social rank and leukocyte telomere length.","date":"2006","source":"Aging cell","url":"https://pubmed.ncbi.nlm.nih.gov/17081156","citation_count":23,"is_preprint":false},{"pmid":"23139818","id":"PMC_23139818","title":"Cell adhesion signaling regulates RANK expression in osteoclast precursors.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23139818","citation_count":22,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":47101,"output_tokens":6852,"usd":0.122041,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":16062,"output_tokens":4412,"usd":0.095305,"stage2_stop_reason":"end_turn"},"total_usd":0.217346,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Molecular cloning, antibody agonism/antagonism assays, soluble receptor competition, osteoclastogenesis assay in macrophage-like cell line C7\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct receptor-ligand binding, functional agonist/antagonist experiments, replicated across multiple subsequent labs\",\n      \"pmids\": [\"9878548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic linkage, Sanger sequencing, recombinant protein expression, NF-κB reporter assay\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutation identified in multiple families, functional NF-κB reporter assay confirmed gain-of-function mechanism, replicated in subsequent studies\",\n      \"pmids\": [\"10615125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Sanger sequencing of TNFRSF11A, comparative mutation analysis\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic identification in affected families with functional inference from prior NF-κB data; single-lab sequencing without independent in vitro functional confirmation in this paper\",\n      \"pmids\": [\"11771666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation of FLAG- and HA-tagged RANK constructs in 293T cells, C-terminal deletion mutants, TRAF6 decoy peptide inhibition, bone marrow osteoclast differentiation assay\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with deletion mutants, functional osteoclastogenesis rescue, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"16234979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Biochemical interaction studies, genetic knock-out analysis (TRAF6-null mice), downstream signaling assays (reviewed mechanistic data)\",\n      \"journal\": \"Advances in experimental medicine and biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — TRAF6 requirement established by multiple labs using KO mice and binding studies; independently replicated\",\n      \"pmids\": [\"17633024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic CYLD knockout mice, osteoclast differentiation assays, co-immunoprecipitation (CYLD-p62-TRAF6), ubiquitination assays, downstream signaling analysis\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse phenotype combined with reciprocal Co-IP and mechanistic ubiquitination assay in single rigorous study\",\n      \"pmids\": [\"18382763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"TNFRSF11A sequencing in ARO patients, in vitro osteoclast differentiation assay from patient monocytes, immunological B cell analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple unrelated families with homozygous TNFRSF11A mutations, functional osteoclast differentiation assay establishing cell-intrinsic defect, multiple orthogonal analyses\",\n      \"pmids\": [\"18606301\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography (crystal structures of unliganded RANK and RANKL-RANK complex), mutagenesis, osteoclast formation assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus functional osteoclastogenesis assay in a single rigorous study\",\n      \"pmids\": [\"20483727\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic KO (TRANCE-null, RANK-null, TRAF6-null mice), in vitro osteoclast differentiation with TNF-α and TGF-β, negative epistasis\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — triple independent KO mouse models with in vitro differentiation assay, directly challenges the prior paradigm\",\n      \"pmids\": [\"16147974\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional/inducible Rank knockout mice, K/BxN serum-transfer arthritis model, in vitro osteoclast cultures, micro-CT, histology, qPCR\",\n      \"journal\": \"Arthritis & rheumatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible KO mice with rigorous histological and imaging endpoints, multiple genetic tools used\",\n      \"pmids\": [\"27563728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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).\",\n      \"method\": \"RT-PCR and FACS for RANK expression, micropore filter migration assay, pharmacological signaling inhibitors, Western blot\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct receptor expression confirmed, migration assay with multiple pathway inhibitors, single lab\",\n      \"pmids\": [\"15248232\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"RT-PCR for RANK mRNA, flow cytometry for RANK protein, TRAP staining and multinucleated cell counting for osteoclast differentiation, dose-response experiments\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple readouts (mRNA, protein, functional differentiation), single lab, single cell line\",\n      \"pmids\": [\"11573248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Adherent vs. non-adherent culture, RT-PCR and Western blot for RANK, RANK/TRAF6 forced expression, echistatin treatment, NF-κB pathway analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (pharmacological, overexpression rescue, gene expression), single lab\",\n      \"pmids\": [\"23139818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"RANK knockout mouse mammary analysis, flow cytometry of mammary subpopulations, WNT pathway reporter assays, R-spondin1 rescue experiments, human breast tissue analysis\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with specific cellular phenotype, molecular pathway identification (R-spondin1/WNT), rescue experiment, human validation\",\n      \"pmids\": [\"26095608\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional mammary epithelium-specific RANK knockout mice, pharmacological RANKL inhibition, mammary stem cell assays, human BRCA1 carrier progenitor cell expansion assays\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two mouse models, genetic and pharmacological approaches, human tissue validation, multiple orthogonal methods\",\n      \"pmids\": [\"27241552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Constitutively active RANK mouse model, flow cytometry of mammary subpopulations, histology, tumor formation assay\",\n      \"journal\": \"Stem cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse model with multiple cellular readouts, single lab\",\n      \"pmids\": [\"23766243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Site-directed mutagenesis, TF deletion/interference assays, animal bone metastasis models, co-culture experiments\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo metastasis rescue combined with molecular pathway dissection, single lab\",\n      \"pmids\": [\"24478054\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Pyrosequencing for methylation, demethylating agent treatment, RANK overexpression in glioma cell lines, flow cytometry for apoptosis, focus formation assay, reporter assay\",\n      \"journal\": \"Neoplasia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods including epigenetic reversal and functional overexpression with apoptosis assay, single lab\",\n      \"pmids\": [\"22787434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic association study, NF-κB luciferase reporter co-transfection assay with SQSTM1 and TNFRSF11A variants\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional NF-κB assay in cell lines supporting genetic association, single lab\",\n      \"pmids\": [\"21987421\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"TNFRSF11A sequencing, NF-κB luciferase reporter assay in cells expressing wild-type vs. mutant RANK, Luminex cytokine measurement\",\n      \"journal\": \"Arthritis & rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional NF-κB reporter plus cytokine profiling, single family/lab\",\n      \"pmids\": [\"24891336\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Developmental neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CRISPR KO with functional inflammatory assays and primary cell validation, single lab\",\n      \"pmids\": [\"28402971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Review synthesizing genetic epistasis, kinase/adaptor knockout models, Ca2+ imaging, and transcription factor analysis from multiple labs\",\n      \"journal\": \"Molecules and cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — established through independently replicated genetic and biochemical experiments across multiple labs; well-supported multi-stage signaling model\",\n      \"pmids\": [\"29047262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast surface display mutagenesis screen, recombinant RANKL mutant proteins, osteoclast differentiation assays, binding kinetics\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro reconstitution with binding kinetics and functional osteoclastogenesis, single lab\",\n      \"pmids\": [\"25864714\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"mRNA/protein quantification in tissue and cell subpopulations, PR agonist treatment, RANK-Fc inhibitor treatment, murine xenograft model with tumor growth and Ki67 measurement\",\n      \"journal\": \"The Journal of clinical endocrinology and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo xenograft model combined with molecular pathway analysis, single lab\",\n      \"pmids\": [\"29741640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Extracellular vesicle isolation, RANK detection in EVs, functional bone formation assays (reviewed mechanistic data)\",\n      \"journal\": \"Extracellular vesicles and circulating nucleic acids\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — review paper citing primary data; mechanism cited but primary experimental detail not in this abstract\",\n      \"pmids\": [\"33982033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"ChIP/promoter binding assay, KLF5 overexpression/knockdown, TNFRSF11a knockdown (siRNA), in vivo xenograft and liver metastasis mouse models, RT-PCR, Western blot, p38 inhibitor\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding plus in vivo functional knockdown, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"29146991\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TNFRSF11A/RANK is a transmembrane TNF receptor superfamily member that, upon binding its ligand RANKL, recruits TRAF6 (and other TRAFs) to activate NF-κB, MAPKs (JNK, ERK, p38), and downstream NFATc1 transcription, driving osteoclast differentiation, activation, and survival; RANK self-assembles via its cytoplasmic domain (aa 534–539) to permit ligand-independent signaling, its expression is upregulated by cell adhesion, TGF-β, and TNF-α and downregulated by loss of adhesion, activating signal-peptide insertion mutations cause gain-of-function NF-κB signaling leading to familial expansile osteolysis/Paget's disease variants, while loss-of-function mutations cause osteoclast-poor osteopetrosis with immunodeficiency; beyond bone, RANK controls mammary progenitor expansion via R-spondin1/WNT signaling, drives progesterone/BRCA1-linked breast carcinogenesis, modulates microglial inflammatory responses, promotes leiomyoma and cervical cancer growth, and exhibits tumor-suppressive pro-apoptotic activity in gliomas where it is epigenetically silenced.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0]. 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 [#7]; this affinity sets the off-rate that tunes osteoclastogenic output in a biphasic manner, indicating the physiological interaction is not optimized for maximal signaling [#22]. Cytoplasmically, RANK recruits TRAF family members, of which TRAF6 is indispensable, to activate MAPKs and NF-\\u03baB/AP-1 and induce NFATc1, the master transcription factor that, together with PLC\\u03b32-driven Ca2+ oscillation and c-Fos, directs osteoclast-specific gene expression and cell fusion [#4, #21]. RANK can also self-assemble through a cytoplasmic oligomerization domain at residues 534\\u2013539, distinct from TRAF-binding sites, enabling ligand-independent osteoclastogenesis that still depends on TRAF6 [#3]. Signaling output is held in check by the CYLD deubiquitinase, which is recruited via p62 to restrain TRAF6 ubiquitination [#5], and receptor expression itself is regulated by cell adhesion and TGF-\\u03b21 in osteoclast precursors [#11, #12]. Activating signal-peptide insertion mutations cause familial expansile osteolysis and Paget's disease variants through enhanced NF-\\u03baB signaling [#1, #2], whereas loss-of-function mutations cause autosomal recessive osteoclast-poor osteopetrosis with hypogammaglobulinemia, also implicating RANK in B-cell function [#6]. Beyond bone, RANK amplifies WNT responsiveness via R-spondin1 to expand mammary progenitors [#13] and promotes BRCA1/p53-driven mammary carcinogenesis [#14], while exerting context-dependent roles including anti-inflammatory modulation of microglia [#20] and tumor-suppressive pro-apoptotic activity when re-expressed in epigenetically silenced gliomas [#17].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established the molecular identity of the receptor required for osteoclast formation, answering which surface receptor transduces the osteoclast differentiation signal.\",\n      \"evidence\": \"Molecular cloning with antibody agonism/antagonism and soluble-receptor competition in a macrophage-like cell line\",\n      \"pmids\": [\"9878548\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the cytoplasmic signaling cascade\", \"No structural basis for ligand binding\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Linked TNFRSF11A directly to human skeletal disease, showing signal-peptide insertion mutations are gain-of-function and act through elevated NF-\\u03baB.\",\n      \"evidence\": \"Genetic linkage, sequencing, and NF-\\u03baB reporter assays of recombinant mutant RANK in families with familial expansile osteolysis/Paget's disease\",\n      \"pmids\": [\"10615125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which signal-peptide defects increase signaling not fully resolved\", \"Did not address cell-type specificity of disease\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Extended the allelic series of activating signal-peptide duplications to expansile skeletal hyperphosphatasia, reinforcing a unified gain-of-function mechanism.\",\n      \"evidence\": \"Comparative Sanger sequencing of TNFRSF11A in affected families\",\n      \"pmids\": [\"11771666\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No independent in vitro functional confirmation in this study\", \"Genotype-phenotype severity determinants unexplained\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed RANK signaling functions in monocytes beyond differentiation, mediating chemotaxis through PI3K/Src pathways.\",\n      \"evidence\": \"FACS/RT-PCR for RANK with migration assays and pharmacological inhibitors in human monocytes\",\n      \"pmids\": [\"15248232\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, pharmacological rather than genetic dissection\", \"In vivo relevance of monocyte chemotaxis not established\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified a cytoplasmic oligomerization domain (534\\u2013539) enabling ligand-independent osteoclastogenesis, distinguishing self-assembly from TRAF binding.\",\n      \"evidence\": \"Co-IP of tagged RANK constructs with deletion mutants, TRAF6 decoy inhibition, and bone marrow differentiation assays\",\n      \"pmids\": [\"16234979\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological role of ligand-independent assembly unclear\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that the RANK-TRAF6 axis is not absolutely required for osteoclast differentiation, revealing alternative TNF-\\u03b1/TGF-\\u03b2 routes.\",\n      \"evidence\": \"In vitro differentiation of TRANCE-, RANK-, and TRAF6-null precursors with TNF-\\u03b1 plus TGF-\\u03b2\",\n      \"pmids\": [\"16147974\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological contribution of alternative pathway in vivo not quantified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined TRAF6 as the indispensable adaptor among five RANK-interacting TRAFs, anchoring the cytoplasmic signaling output.\",\n      \"evidence\": \"Biochemical interaction studies and TRAF6-null mouse analysis (review of mechanistic data)\",\n      \"pmids\": [\"17633024\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Roles of the other four TRAFs not delineated\", \"Reviewed rather than primary data\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified CYLD/p62 as a negative regulator restraining RANK signaling via TRAF6 deubiquitination, explaining tonic control of osteoclast precursors.\",\n      \"evidence\": \"CYLD knockout mice with osteoclast assays, CYLD-p62-TRAF6 Co-IP, and ubiquitination assays\",\n      \"pmids\": [\"18382763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How p62/CYLD recruitment is regulated dynamically unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Showed loss-of-function TNFRSF11A mutations cause osteoclast-poor osteopetrosis with immunodeficiency, defining the human null phenotype and a B-cell role.\",\n      \"evidence\": \"Sequencing in ARO families, patient monocyte differentiation assays, and B-cell immunological analysis\",\n      \"pmids\": [\"18606301\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of RANK action in B cells not resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Provided the structural basis of RANKL recognition, showing a CRD2-CRD3 hinge conformational change and continuous high-affinity contact required for function.\",\n      \"evidence\": \"X-ray crystallography of liganded/unliganded RANK with mutagenesis and osteoclast formation assays\",\n      \"pmids\": [\"20483727\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of full-length receptor and transmembrane assembly not resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Linked RANK affinity kinetics to signaling output, establishing a biphasic, off-rate-driven relationship and that physiological binding is sub-maximal.\",\n      \"evidence\": \"Yeast surface display mutagenesis of RANKL, binding kinetics, and osteoclast differentiation assays\",\n      \"pmids\": [\"25864714\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo consequences of affinity-tuned variants untested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Synthesized the multi-stage osteoclastogenic signaling model from TRAF6/NF-\\u03baB/AP-1 initiation through PLC\\u03b32/Ca2+ amplification to NFATc1-driven gene induction.\",\n      \"evidence\": \"Review integrating genetic epistasis, kinase/adaptor knockouts, Ca2+ imaging, and transcription factor analysis\",\n      \"pmids\": [\"29047262\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative thresholds for stage transitions not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined a non-bone role: RANK amplifies WNT responsiveness through R-spondin1 to expand mammary luminal progenitors under progesterone control.\",\n      \"evidence\": \"RANK knockout mouse mammary analysis, WNT reporters, R-spondin1 rescue, and human tissue validation\",\n      \"pmids\": [\"26095608\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct link between RANK signaling and R-spondin1 transcription not detailed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Established RANK as a driver of BRCA1/p53-mutant mammary carcinogenesis, supporting RANKL blockade as a preventive strategy.\",\n      \"evidence\": \"Conditional RANK knockout and pharmacological RANKL inhibition in mouse models with human BRCA1 carrier progenitor assays\",\n      \"pmids\": [\"27241552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell of origin and timing of RANK-dependent transformation not fully defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated that bone erosion and osteoclast formation persist without RANK in inflammatory arthritis via a TNF/IL-6/DAP12/NFATc1 pathway.\",\n      \"evidence\": \"Inducible Rank knockout mice in serum-transfer arthritis with micro-CT, histology, and in vitro osteoclast cultures\",\n      \"pmids\": [\"27563728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of RANK-independent osteoclastogenesis in human arthritis unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How RANK's distinct context-dependent outputs\\u2014osteoclastogenic, mammary-proliferative, tumor-suppressive in glioma, and anti-inflammatory in microglia\\u2014are mechanistically selected by cell type remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model for cell-type-specific RANK signaling output\", \"Reverse signaling via osteoclast EV-borne RANK rests on low-confidence reviewed data (#24)\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 7]},\n      {\"term_id\": \"GO:0048018\", \"supporting_discovery_ids\": [0, 7, 22]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [13, 15]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 20]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 6, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RANKL\", \"TRAF6\", \"CYLD\", \"SQSTM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}