Affinage

TNFSF11

Tumor necrosis factor ligand superfamily member 11 · UniProt O14788

Round 2 corrected
Length
317 aa
Mass
35.5 kDa
Annotated
2026-04-28
130 papers in source corpus 29 papers cited in narrative 29 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNFSF11 (RANKL) is a type II transmembrane TNF-family cytokine that functions as the essential, non-substitutable ligand for RANK-mediated osteoclast differentiation, activation, survival, and recycling, while also regulating dendritic cell survival, lymph node organogenesis, and mammary epithelial proliferation (PMID:9520411, PMID:9950424, PMID:33636130, PMID:20881963). Expressed predominantly by osteoblast-lineage cells, osteocytes, and activated T cells under the control of distal enhancers responsive to PTH/cAMP, vitamin D3, and TCR signaling, RANKL exists in membrane-bound and soluble forms generated by proteolytic shedding via TACE and MMP-7 (PMID:10224132, PMID:15894268, PMID:26332516, PMID:25211367). Upon binding RANK, it assembles a signaling complex involving TRAF6 and c-Src that activates NF-κB, JNK, Akt/PKB, and NFATc1 to drive osteoclast gene programs, with IFN-β–mediated negative feedback restraining differentiation (PMID:10635328, PMID:12110142). Loss-of-function mutations in human TNFSF11 cause autosomal recessive osteopetrosis characterized by absent osteoclasts, and RANKL–RANK signaling in RANK-expressing cancer cells promotes bone-tropic metastasis and BRCA1-mutation-driven mammary tumorigenesis (PMID:17632511, PMID:16572175, PMID:27241552).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Cloning of RANKL as a T-cell-expressed TNF-family ligand that activates JNK and regulates dendritic cell survival established the gene's identity and first biological functions outside bone.

    Evidence Expression cloning from activated T cells, JNK kinase assays, DC survival assays with dominant-negative TRAF2 transgenic mice

    PMID:9312132 PMID:9367155 PMID:9396779

    Open questions at the time
    • Role in bone metabolism not yet recognized
    • Receptor on osteoclast lineage not identified
    • In vivo relevance to immune or skeletal homeostasis untested
  2. 1998 High

    Identification of RANKL as the osteoblast/stromal-cell-derived osteoclast differentiation factor (ODF/OPGL) resolved the longstanding question of how osteoblasts communicate with osteoclast precursors, showing that RANKL alone replaces stromal cells, vitamin D3, and glucocorticoids for osteoclastogenesis and causes hypercalcemia in vivo.

    Evidence Expression cloning from stromal cDNA library, reconstituted osteoclastogenesis without stromal cells, OPG blocking, in vivo mouse injection

    PMID:9520411 PMID:9568710

    Open questions at the time
    • Whether RANKL is truly non-redundant in vivo required genetic proof
    • Downstream signaling cascade from RANK uncharacterized
    • Proteolytic processing and soluble form significance unknown
  3. 1999 High

    RANKL-knockout mice demonstrated absolute in vivo requirement for RANKL in osteoclast formation, tooth eruption, and lymph node organogenesis, while parallel biochemical studies delineated the RANK–TRAF6–c-Src–Akt signaling axis and identified TACE-mediated ectodomain shedding.

    Evidence RANKL-null mice (skeletal/immune phenotyping), co-IP and kinase assays in c-Src-deficient cells, in vitro TACE cleavage with N-terminal sequencing, osteoclast actin ring and resorption assays on bone slices

    PMID:10224132 PMID:10225954 PMID:10635328 PMID:9950424

    Open questions at the time
    • Structural basis of RANKL-RANK specificity unknown
    • Whether additional sheddases exist beyond TACE
    • Negative feedback mechanisms limiting osteoclastogenesis undefined
  4. 2001 High

    The crystal structure of the RANKL trimer revealed unique surface loops that determine RANK-binding specificity, while additional sheddase activities distinct from TACE were shown to operate in different cell types, complicating the picture of soluble RANKL generation.

    Evidence X-ray crystallography at 2.6 Å with mutagenesis-coupled osteoclastogenesis, metalloprotease inhibitor profiling in multiple cell types

    PMID:11278735 PMID:11581298

    Open questions at the time
    • Co-crystal structure of RANKL-RANK complex not yet solved
    • Identity of non-TACE sheddases not determined
    • Relative contributions of membrane-bound vs soluble RANKL to physiology unclear
  5. 2002 High

    Identification of IFN-γ-mediated TRAF6 degradation and RANKL-induced IFN-β negative feedback established that RANKL signaling is self-limiting, explaining how the immune and skeletal systems restrain osteoclastogenesis.

    Evidence In vitro osteoclastogenesis with Western blot for TRAF6 degradation, NF-κB/JNK and c-Fos expression analysis

    PMID:12110142

    Open questions at the time
    • Quantitative contribution of IFN-β feedback vs IFN-γ to in vivo bone homeostasis unclear
    • Whether other negative regulators act at the same nodes not resolved
  6. 2005 High

    MMP-7 was identified as a pathologically relevant RANKL sheddase at the tumor-bone interface, directly linking proteolytic release of soluble RANKL to tumor-induced osteolysis.

    Evidence MMP-7 knockout mice with prostate tumor-bone model, in vitro MMP-7 cleavage of RANKL

    PMID:15894268

    Open questions at the time
    • Whether MMP-7 cleaves RANKL at the same site as TACE not resolved
    • Relative contribution of MMP-7 vs other sheddases in non-tumor settings unknown
  7. 2006 High

    RANKL was shown to act as a chemotactic cue directing RANK-expressing cancer cells to bone, while Wnt/β-catenin signaling was found to repress RANKL transcription in osteoblasts—expanding RANKL's roles from differentiation factor to metastasis mediator and linking its expression to anabolic skeletal pathways.

    Evidence In vitro migration assay and in vivo melanoma metastasis model with OPG neutralization; β-catenin overexpression and Wnt3a/LiCl treatment of osteoblast co-cultures with RANKL promoter reporters

    PMID:16522681 PMID:16572175

    Open questions at the time
    • Whether RANKL is sufficient or merely permissive for bone metastasis tropism
    • Full catalog of transcription factors controlling cell-type-specific RANKL expression incomplete
  8. 2007 High

    Human loss-of-function mutations in TNFSF11 were shown to cause autosomal recessive osteopetrosis, and patient monocytes formed osteoclasts when provided exogenous RANKL, proving RANKL is absolutely required for human osteoclastogenesis and that the defect lies in the microenvironment, not in precursor cells.

    Evidence Human genetic mutation identification, bone biopsy histology, failed HSC transplantation, ex vivo RANKL rescue of patient monocytes

    PMID:17632511

    Open questions at the time
    • Whether partial loss-of-function alleles produce milder human skeletal phenotypes unknown
    • Immune consequences (lymph node, DC) of human RANKL deficiency incompletely characterized
  9. 2010 High

    RANKL was established as the paracrine mediator of progestin-driven mammary epithelial proliferation and tumorigenesis, with regulatory T cells identified as a major RANKL source promoting pulmonary metastasis of mammary carcinoma.

    Evidence MMTV-RANK transgenic mice, pharmacological RANKL inhibition in mammary tumor models, Treg depletion and RANKL add-back in vivo

    PMID:20881963 PMID:21326202

    Open questions at the time
    • Whether RANKL drives mammary tumorigenesis independent of progesterone in humans not established
    • Molecular mechanism of RANKL-induced mammary progenitor expansion vs differentiation unclear
  10. 2016 High

    Dissection of distal enhancer elements (RL-D2) demonstrated how PTH/cAMP signaling controls RANKL expression in bone, while genetic RANK inactivation in mammary epithelium confirmed RANKL-RANK as a therapeutic target in BRCA1-associated breast cancer by restraining progenitor expansion.

    Evidence In vivo enhancer deletion in mice with PTH challenge and microCT; conditional RANK knockout and pharmacological RANKL blockade in Brca1;p53 mammary cancer models plus human BRCA1-carrier tissue

    PMID:26332516 PMID:27241552

    Open questions at the time
    • Full enhancer landscape for RANKL in non-skeletal tissues (mammary, lymph node) not mapped
    • Clinical efficacy of RANKL inhibition for BRCA1-associated breast cancer prevention not yet demonstrated
  11. 2017 High

    The finding that TRAF6 E3 ubiquitin ligase activity is dispensable for RANKL-induced osteoclastogenesis revised the mechanistic model of RANK signaling, showing TRAF6 serves an essential scaffolding function independent of its catalytic activity.

    Evidence TRAF6 E3 ligase-inactive knockin mice with normal bone and osteoclastogenesis

    PMID:28404732

    Open questions at the time
    • Which TRAF6 domain mediates the E3-independent scaffolding for RANK signaling unknown
    • Whether other E3 ligases compensate at the RANK signalosome not investigated
  12. 2021 High

    Intravital imaging revealed that RANKL-stimulated osteoclasts undergo fission into 'osteomorphs' rather than exclusively apoptosing, expanding RANKL's role from osteoclast formation to osteoclast lifecycle regulation and recycling.

    Evidence Intravital imaging of osteoclast fission, RANKL inhibition blocking recycling, scRNA-seq and genetic deletion of osteomorph-specific genes

    PMID:33636130

    Open questions at the time
    • Signals that determine osteoclast fission vs apoptosis downstream of RANKL not identified
    • Whether osteomorphs contribute to bone-remodeling coupling signals unknown
  13. 2022 Medium

    Identification of a druggable binding site unique to soluble RANKL demonstrated that membrane-bound and soluble RANKL have conformational differences exploitable for selective inhibition, achieving anti-osteoporotic effects without immunosuppression in vivo.

    Evidence Molecular dynamics simulation, KD measurement, cell-based osteoclastogenesis assay, in vivo osteoporosis model with small molecule S3-15

    PMID:36097003

    Open questions at the time
    • Independent replication of selective soluble-RANKL inhibitor efficacy not yet reported
    • Structural validation of the proposed soluble-RANKL-specific binding pocket by co-crystallography absent
    • Long-term safety and specificity of soluble-RANKL-selective inhibition not characterized
  14. 2024 Medium

    High-resolution in situ hybridization across species resolved that osteoprogenitor cells at the bone surface—not mature osteoblasts or osteocytes—are the primary physiological RANKL source, and that OPG:Fc treatment paradoxically upregulates local RANKL, providing a mechanistic explanation for the denosumab rebound phenomenon.

    Evidence Multi-species in situ hybridization, OPG:Fc and PTH treatment of mice, scRNA-seq reanalysis

    PMID:39424806

    Open questions at the time
    • Whether the osteoprogenitor RANKL source dominance holds in pathological states (inflammation, cancer) not tested
    • Molecular mechanism of OPG:Fc-induced RANKL upregulation not delineated
    • Findings from single lab with limited human tissue validation

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the precise signals distinguishing osteoclast fission from apoptosis downstream of RANKL, the full cis-regulatory architecture governing tissue-specific RANKL expression, the structural basis for soluble versus membrane-bound RANKL conformational differences, and whether selective soluble-RANKL inhibition can achieve clinical benefit in humans.
  • No co-crystal structure of RANKL–RANK complex at high resolution available
  • Enhancer landscape of RANKL in mammary and lymphoid tissues unmapped
  • Osteomorph biology and its regulation by RANKL poorly understood

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 5 GO:0098631 cell adhesion mediator activity 1
Localization
GO:0005576 extracellular region 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-1643685 Disease 4 R-HSA-1266738 Developmental Biology 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 2
Partners
ADAM17CTNNB1MMP7SRCTNFRSF11ATNFRSF11BTRAF6

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 TRANCE (RANKL/TNFSF11) was cloned as a type II membrane protein of 316 amino acids expressed on activated T cells; its ectodomain activated c-Jun N-terminal kinase (JNK) in T cells upon interaction with its receptor, and its expression was controlled by calcineurin-regulated transcription factors downstream of TCR stimulation. Somatic cell genetic cloning, recombinant protein production, JNK kinase assay, Northern blot, chromosomal mapping The Journal of biological chemistry High 9312132
1997 RANKL (TRANCE) was identified as the ligand for the receptor RANK on dendritic cells; RANKL augments dendritic cell ability to stimulate naive T-cell proliferation and increases survival of RANK+ T cells, establishing RANKL-RANK as a regulator of T cell–dendritic cell interactions. Direct expression cloning, mixed lymphocyte reaction, cell survival assays Nature High 9367155
1997 TRANCE (RANKL) acts as a dendritic cell-specific survival factor by signaling through TRANCE-R (RANK) in a TRAF2-dependent manner, upregulating Bcl-xL expression to inhibit apoptosis of bone marrow-derived and monocyte-derived dendritic cells. In vitro DC survival assay, dominant-negative TRAF2 transgenic mice, Bcl-xL Western blot The Journal of experimental medicine High 9396779
1998 RANKL (ODF/OPGL) was identified as the osteoblast/stromal cell membrane-bound ligand for OPG/OCIF, functioning as the osteoclast differentiation factor (ODF). Soluble ectodomain of ODF induced osteoclast-like cell formation from spleen cells in the absence of osteoblasts/stromal cells, and this was blocked by OPG. RANKL expression in osteoblasts/stromal cells was upregulated by bone-resorbing factors. Expression cloning from stromal cell cDNA library, in vitro osteoclastogenesis assay, OPG blocking experiment Proceedings of the National Academy of Sciences of the United States of America High 9520411
1998 RANKL (OPGL) is a TNF-related cytokine that replaces the requirement for stromal cells, vitamin D3, and glucocorticoids in osteoclastogenesis. It binds to a hematopoietic progenitor committed to the osteoclast lineage, stimulates rapid induction of osteoclast-specific genes, directly activates isolated mature osteoclasts in vitro, and causes systemic hypercalcemia when administered to mice in vivo. Its effects are blocked by OPG in vitro and in vivo. Recombinant protein production, in vitro osteoclastogenesis, gene expression analysis, in vivo mouse injection, OPG neutralization Cell High 9568710
1999 RANKL (OPGL) directly binds to and activates mature osteoclasts via RANK, inducing actin ring formation within 30 minutes—a cytoskeletal rearrangement required for bone resorption—and increases total bone surface erosion approximately 7-fold. Anti-RANK antibodies also induce actin ring formation, confirming RANK as the mediating receptor. OPG blocks these effects. Primary rat osteoclast culture on bone slices, scanning electron microscopy, actin ring immunofluorescence, antibody blocking The Journal of cell biology High 10225954
1999 RANKL-deficient (opgl-null) mice completely lack osteoclasts due to inability of osteoblasts to support osteoclastogenesis, show severe osteopetrosis, defective tooth eruption, defects in early T and B lymphocyte differentiation, and absence of all lymph nodes. This genetic evidence establishes RANKL as an essential osteoclast differentiation factor in vivo and a regulator of lymph node organogenesis. Gene knockout in mice, skeletal and immunological phenotyping, histology Nature High 9950424
1999 Activated T cells directly trigger osteoclastogenesis through RANKL expression; systemic T cell activation in vivo causes RANKL-mediated increases in osteoclastogenesis and bone loss. In a rat adjuvant arthritis model, OPG treatment blocking RANKL prevents bone and cartilage destruction but not inflammation, establishing that T-cell-derived RANKL drives pathological bone resorption. T cell activation in vivo, OPG treatment in rat adjuvant arthritis model, histology, bone density measurement Nature High 10580503
1999 TRANCE (RANKL) activates the antiapoptotic kinase Akt/PKB in osteoclasts through a signaling complex at TRANCE-R (RANK) that involves TRAF6 and c-Src. c-Src deficiency or Src-family kinase inhibitors block TRANCE-mediated PKB activation. TRAF6 and c-Src interact with each other and with TRANCE-R upon receptor engagement; TRAF6 enhances c-Src kinase activity, leading to tyrosine phosphorylation of c-Cbl. Co-immunoprecipitation, kinase assays, c-Src-deficient cells, pharmacological Src inhibitors Molecular cell High 10635328
1999 TRANCE (RANKL) is shed from the plasma membrane as a soluble form by a metalloprotease activity consistent with TACE (TNF-alpha converting enzyme) or a related metalloprotease-disintegrin. TACE can cleave immunoprecipitated TRANCE in vitro at the same site used in intact cells. Soluble TRANCE retains potent dendritic cell survival and osteoclastogenic activity. Metalloprotease cleavage assay, in vitro TACE cleavage of immunoprecipitated TRANCE and ectodomain/CD8 fusion protein, N-terminal sequencing of cleavage site The Journal of biological chemistry High 10224132
1999 Mouse RANKL/TRANCE/OPGL/ODF gene promoter contains inverted TATA- and CAAT-boxes, a Cbfa1/Osf2/AML3 binding domain, and repeated half-sites for vitamin D3 and glucocorticoid receptors at -935 and -640 bp respectively. Transient transfection showed that 1α,25(OH)2 VitD3 and dexamethasone increase promoter activity (~200% and ~178%), while CpG methylation in later-passage stromal cells correlates with loss of RANKL expression and osteoclastogenic support. Promoter cloning, transient transfection luciferase assay, genomic Southern blot, CpG methylation analysis Biochimica et biophysica acta Medium 10209265
2001 Crystal structure of murine RANKL ectodomain at 2.6 Å resolution reveals a homotrimeric TNF-family scaffold with four unique surface loops that distinguish it from other TNF family members. Mutagenesis of selected residues in these loops significantly modulates RANK activation as measured by in vitro osteoclastogenesis, establishing these loops as specificity determinants for RANKL-RANK interaction. X-ray crystallography (2.6 Å), site-directed mutagenesis, in vitro osteoclastogenesis assay The Journal of clinical investigation High 11581298
2001 RANKL ectodomain shedding in different cell types involves at least two distinct metalloprotease activities, both different from TACE: one is induced by the tyrosine phosphatase inhibitor pervanadate but not phorbol esters and is sensitive to TIMP-2 (consistent with a membrane-type MMP); the other is refractory to both stimuli. Cleavage site usage differs between these activities. Biochemical inhibitor profiling (TIMP-1, TIMP-2, phorbol ester, pervanadate), cleavage site mapping in multiple cell types The Journal of biological chemistry Medium 11278735
2002 IFN-γ produced by activated T cells inhibits RANKL-induced osteoclastogenesis by inducing rapid degradation of the RANK adapter protein TRAF6, thereby blocking NF-κB and JNK activation downstream of RANK. Separately, RANKL itself induces IFN-β (but not IFN-α) in osteoclast precursors, and IFN-β in turn inhibits osteoclast differentiation by interfering with RANKL-induced c-Fos expression—establishing a negative feedback loop. In vitro osteoclastogenesis, Western blot for TRAF6 degradation, NF-κB/JNK activation assays, IFN-β gene induction assay, c-Fos expression analysis Arthritis research High 12110142
2005 MMP-7 produced by osteoclasts at the tumor-bone interface processes membrane-bound RANKL to a soluble form that promotes osteoclast activation and tumor-induced osteolysis. MMP-7-deficient mice demonstrate reduced prostate tumor-induced osteolysis and RANKL processing, establishing MMP-7 as a sheddase for RANKL in pathological bone resorption. Microarray, in vitro MMP-7 cleavage of RANKL, MMP-7 knockout mice, in vivo tumor-bone model, osteolysis measurement Cancer cell High 15894268
2006 RANKL triggers migration of RANK-expressing human epithelial cancer cells and melanoma cells; in vivo neutralization of RANKL by OPG in a mouse melanoma metastasis model provides complete protection from paralysis and marked reduction in bone tumor burden but not in other organs, establishing RANKL as a directional migration cue for RANK+ cancer cells mediating tissue-specific bone metastasis. In vitro migration assay with recombinant RANKL, in vivo mouse melanoma metastasis model with OPG neutralization, tumor burden measurement Nature High 16572175
2006 Wnt signaling in osteoblasts transcriptionally represses RANKL (TNFSF11) gene expression through a β-catenin-dependent mechanism; overexpression of full-length but not transcriptionally inactive β-catenin inhibits RANKL promoter activity. Activation of Wnt signaling (LiCl or Wnt3a) in osteoblast-spleen cell co-cultures inhibits osteoclast formation without directly affecting osteoclast differentiation, survival, or activity in the absence of osteoblasts. Wnt3a and LiCl treatment of osteoblast/spleen cell co-cultures, β-catenin overexpression, RANKL promoter reporter assay, RANKL mRNA/protein measurement Journal of cell science Medium 16522681
2007 Loss-of-function mutations in the RANKL-encoding TNFSF11 gene cause autosomal recessive osteoclast-poor osteopetrosis in humans. Affected individuals lack osteoclasts in bone biopsies and cannot be cured by hematopoietic stem cell transplantation (confirming osteoclast precursors are not the primary defect), but exogenous RANKL induces functional osteoclast formation from their monocytes, demonstrating that RANKL is absolutely required for osteoclast differentiation in humans. Human genetics (mutation identification), bone biopsy histology, HSC transplantation outcome, exogenous RANKL rescue experiment on patient monocytes Nature genetics High 17632511
2010 RANK signaling in mammary carcinoma cells is required for pulmonary metastasis in Erbb2-transformed carcinoma; the major pro-metastatic RANKL source is tumour-infiltrating CD4+CD25+FOXP3+ regulatory T cells located adjacent to stromal cells. Exogenous RANKL stimulates pulmonary metastasis of RANK+ human breast cancer cells, and this dependence on T cells is replaceable by exogenous RANKL. In vivo mouse mammary tumor model, T cell depletion, exogenous RANKL administration, CD4+CD25+FOXP3+ T cell identification by flow cytometry and IHC Nature High 21326202
2010 RANKL is the paracrine mediator of progestin-induced mammary epithelial proliferation and a direct contributor to mammary tumorigenesis. MMTV-RANK transgenic mice show accelerated pre-neoplasias and increased mammary tumors after multiparity or hormone/carcinogen treatment, while pharmacological RANKL inhibition attenuates mammary tumor development in multiple models by reducing hormone-induced mammary epithelial proliferation and cyclin D1 levels. MMTV-RANK transgenic mice, pharmacological RANKL inhibition, MMTV-neu spontaneous tumor model, in vivo tumor assessment, cyclin D1 measurement Nature High 20881963
2011 Sclerostin produced by osteocytes dose-dependently upregulates RANKL mRNA and downregulates OPG mRNA in osteocyte-like cells, increasing osteoclastic resorption approximately 7-fold in co-cultures with splenocytes or PBMCs. This catabolic effect is abolished by OPG and sclerostin does not directly induce osteoclastogenesis from monocultures, establishing a RANKL-dependent mechanism by which osteocyte-derived sclerostin promotes bone resorption. Recombinant sclerostin treatment of osteocyte cultures, RANKL/OPG qPCR, co-culture osteoclastogenesis and resorption assay, OPG blocking PloS one High 21991382
2015 The human TNFSF11 locus contains a T cell control region (hTCCR) located between -170 and -220 kb upstream of the TSS that acts as a cell type-selective distal enhancer set for T cell-specific expression. ChIP-chip revealed histone acetylation enrichment and c-FOS recruitment to the hTCCR following TCR activation, and MEK1/2 signaling is required for RANKL induction in T cells. Both the RLD5a/b enhancer and hTCCR segments drove inducible reporter activity upon TCR stimulation. ChIP-chip, luciferase reporter assays, MEK1/2 inhibition (U0126), primary human T cells and Jurkat cells Journal of cellular biochemistry Medium 25211367
2016 Deletion of the distal Tnfsf11 RL-D2 enhancer (23 kb upstream of TSS) in mice significantly blunts PTH-induced RANKL expression in vivo, reduces skeletal RANKL expression, decreases osteoclast numbers, and produces a progressive high bone mass phenotype. Ex vivo, RL-D2-/- stromal cells show decreased RANKL induction by forskolin and 1,25(OH)2D3. CREB binding at RL-D2 is induced by PTH/cAMP signaling. ChIP-seq, enhancer deletion in mice, in vivo PTH challenge, ex vivo stromal cell culture, bone phenotyping by microCT Journal of bone and mineral research High 26332516
2016 Genetic inactivation of RANK in mammary epithelium or long-term pharmacological RANKL inhibition markedly delays onset, reduces incidence, and attenuates Brca1;p53 mutation-driven mammary cancer in mice. RANKL/RANK blockade impairs proliferation of murine Brca1;p53 mutant mammary stem cells and progenitors from human BRCA1 mutation carriers, placing RANKL-RANK signaling upstream of progenitor expansion in BRCA1-associated breast cancer. Conditional RANK knockout in mammary epithelium, pharmacological RANKL blockade, mammary stem cell and progenitor proliferation assays, human BRCA1-carrier tissue ex vivo Cell research High 27241552
2016 LOX does not substitute for RANKL in osteoclastogenesis. LOX fails to generate TRAP+ osteoclasts or resorption pits from RANKL-deficient or RANK-deficient cells; in wild-type cells, LOX synergizes with RANKL only by stimulating RANKL expression in bone marrow stromal cells via ROS production. LOX injection does not rescue the RANKL-deficient osteopetrotic phenotype in vivo. RANKL/RANK-deficient mouse cells, LOX treatment, TRAP staining, resorption pit assay, in vivo LOX injection into RANKL-KO mice, ROS measurement Journal of bone and mineral research High 27606829
2017 TRAF6 E3 ligase activity is not absolutely required for RANKL-induced osteoclastogenesis; RANKL-induced signaling in macrophages and bone marrow-to-osteoclast differentiation is normal in knockin mice expressing E3 ligase-inactive TRAF6[L74H], explaining the normal bone structure and teeth in these mice (unlike TRAF6 KO mice). This reveals that essential roles of TRAF6 in RANKL signaling are independent of its E3 ubiquitin ligase activity. TRAF6 E3 ligase-inactive knockin mice, osteoclastogenesis assay, bone phenotyping, macrophage RANKL signaling assays Proceedings of the National Academy of Sciences of the United States of America High 28404732
2021 RANKL-stimulated osteoclasts do not exclusively undergo apoptosis after resorption; by intravital imaging, RANKL-stimulated osteoclasts undergo fission into daughter cells called osteomorphs. Inhibiting RANKL blocks this cellular recycling and causes osteomorph accumulation, establishing RANKL as a regulator of osteoclast recycling/fission in addition to differentiation. Intravital imaging, RANKL inhibition, single-cell RNA sequencing, genetic deletion of osteomorph-specific genes in mice Cell High 33636130
2022 A druggable binding site on soluble RANKL (distinct from the membrane RANKL-RANK interface) was identified by molecular dynamics simulations; small molecule S3-15 selectively inhibits soluble RANKL-RANK interaction without interfering with membrane RANKL-RANK interaction, demonstrating conformational/functional differences between soluble and membrane-bound RANKL forms. S3-15 shows anti-osteoporotic effects in vivo without immunosuppression. Molecular dynamics simulation, in vitro binding assay (KD measurement), cell-based osteoclastogenesis assay, in vivo osteoporosis model, in silico and in vitro binding model validation Nature communications Medium 36097003
2024 In situ hybridization across species and skeletal sites reveals that under physiological conditions RANKL (Tnfsf11) is expressed mainly by osteoprogenitor bone surface cells proximate to osteoclasts, while OPG is expressed mainly by osteocytes and bone-forming osteoblasts. OPG:Fc treatment increases RANKL mRNA in trabecular bone surface cells and decreases OPG in bone surface cells/osteocytes, creating localized osteoclastogenic activation sites—explaining the denosumab rebound effect mechanistically. In situ hybridization across species and skeletal sites, OPG:Fc and PTH treatment of mice, single-cell RNA sequencing (public data reanalysis), co-expression analysis (Mmp13/Tnfsf11) Bone research Medium 39424806

Source papers

Stage 0 corpus · 130 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 4243 9568710
1998 Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proceedings of the National Academy of Sciences of the United States of America 3272 9520411
1999 OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 2612 9950424
2010 Genome-wide meta-analysis increases to 71 the number of confirmed Crohn's disease susceptibility loci. Nature genetics 2036 21102463
1997 A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Nature 1763 9367155
2002 Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. Proceedings of the National Academy of Sciences of the United States of America 1479 12477932
1999 Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 1450 10580503
2015 The BioPlex Network: A Systematic Exploration of the Human Interactome. Cell 1118 26186194
2017 Architecture of the human interactome defines protein communities and disease networks. Nature 1085 28514442
2001 Minireview: the OPG/RANKL/RANK system. Endocrinology 1046 11713196
2005 RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends in molecular medicine 930 16356770
2020 A reference map of the human binary protein interactome. Nature 849 32296183
1997 TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. The Journal of biological chemistry 822 9312132
2021 Dual proteome-scale networks reveal cell-specific remodeling of the human interactome. Cell 705 33961781
2007 Biology of RANK, RANKL, and osteoprotegerin. Arthritis research & therapy 689 17634140
1997 TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. The Journal of experimental medicine 673 9396779
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2006 Regulation of cancer cell migration and bone metastasis by RANKL. Nature 634 16572175
2008 Genome-scale RNAi screen for host factors required for HIV replication. Cell host & microbe 627 18976975
2011 Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 545 21326202
1999 The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. The Journal of cell biology 533 10225954
2020 Osteoclast differentiation by RANKL and OPG signaling pathways. Journal of bone and mineral metabolism 514 33079279
1999 TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Molecular cell 502 10635328
2008 Multiple genetic loci for bone mineral density and fractures. The New England journal of medicine 485 18445777
2010 RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 480 20881963
2004 The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome research 438 15489334
2011 Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PloS one 386 21991382
2004 Regulation of vascular calcification by osteoclast regulatory factors RANKL and osteoprotegerin. Circulation research 383 15564564
1999 A new member of tumor necrosis factor ligand family, ODF/OPGL/TRANCE/RANKL, regulates osteoclast differentiation and function. Biochemical and biophysical research communications 366 10080918
2004 Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1. The Journal of biological chemistry 351 15304486
1999 Evidence for a role of a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival. The Journal of biological chemistry 326 10224132
2021 Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell 288 33636130
2007 Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Nature genetics 279 17632511
2005 MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer cell 278 15894268
1998 Osteoclast differentiation factor (ODF) induces osteoclast-like cell formation in human peripheral blood mononuclear cell cultures. Biochemical and biophysical research communications 278 9600092
2008 New sequence variants associated with bone mineral density. Nature genetics 274 19079262
2003 PTH differentially regulates expression of RANKL and OPG. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 262 14969393
2011 A directed protein interaction network for investigating intracellular signal transduction. Science signaling 258 21900206
2007 The RANKL/RANK/OPG pathway. Current osteoporosis reports 256 17925190
2006 Wnt signalling in osteoblasts regulates expression of the receptor activator of NFkappaB ligand and inhibits osteoclastogenesis in vitro. Journal of cell science 256 16522681
2012 New insights into osteoclastogenic signaling mechanisms. Trends in endocrinology and metabolism: TEM 252 22705116
2006 MafB negatively regulates RANKL-mediated osteoclast differentiation. Blood 220 17158225
2005 Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Current opinion in pharmacology 212 16188502
2005 Osteoclast precursors, RANKL/RANK, and immunology. Immunological reviews 185 16313338
2004 The OPG/RANKL/RANK system in metabolic bone diseases. Journal of musculoskeletal & neuronal interactions 182 15615494
1999 TRANCE is a TNF family member that regulates dendritic cell and osteoclast function. Journal of leukocyte biology 166 10380891
2002 Role of RANKL and RANK in bone loss and arthritis. Annals of the rheumatic diseases 160 12379618
2021 Discovery of the RANKL/RANK/OPG system. Journal of bone and mineral metabolism 158 33389131
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