Affinage

TNFSF11

Tumor necrosis factor ligand superfamily member 11 · UniProt O14788

Length
317 aa
Mass
35.5 kDa
Annotated
2026-06-10
100 papers in source corpus 25 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TNFSF11 (RANKL) is the essential, membrane-bound and soluble TNF-family cytokine that licenses osteoclast formation and broader developmental programs, established genetically by the complete absence of osteoclasts, lymph nodes, and normal lymphocyte differentiation in knockout mice (PMID:9950424). Expressed as a membrane-associated cytokine on osteoblasts and stromal cells, RANKL signals through cell-to-cell contact to RANK on hematopoietic osteoclast precursors, driving their differentiation in the presence of M-CSF; soluble RANKL generated by ectodomain shedding can act at a distance, and the decoy receptor OPG blocks the RANKL-RANK interaction (PMID:10080918, PMID:10976996, PMID:11278735). In situ analysis localizes RANKL to bone-surface osteoprogenitor cells adjacent to osteoclasts while OPG is enriched in osteocytes and bone-forming osteoblasts, defining a spatially partitioned regulatory circuit (PMID:39424806). Beyond differentiation, RANKL directly activates mature osteoclasts—rapidly inducing actin-ring formation and bone-surface erosion through RANK (PMID:10225954)—and acts as a survival factor by suppressing Fas-mediated apoptosis in an NF-κB-dependent, biphasic manner (PMID:15619676). Downstream of RANK, RANKL drives a transcriptional cascade centered on NFATc1 and c-Fos, modulated positively by FOXO1 (PMID:25694609) and restrained by MafB, which interferes with c-Fos, Mitf, and NFATc1 DNA binding (PMID:17158225); this program is amplified through epigenetic reprogramming, with RANKL inducing BATF-dependent superenhancers and an SE-eRNA at the NFATc1 locus (PMID:36513810). RANKL transcription itself is controlled by distal enhancers responsive to PTH and 1,25(OH)2D3 via VDR and CREB in osteoblasts (RL-D2) (PMID:26332516) and to TCR/MEK signaling via c-FOS in T cells (hTCCR) (PMID:25211367), and by TNFα through PGE2-driven NFATc1/CREB binding to the promoter (PMID:28245593). Osteoclastogenesis is counter-regulated by IFN-β (which suppresses c-Fos) and by T-cell-derived IFN-γ (which degrades TRAF6) (PMID:12110142). RANKL also operates well beyond bone, governing beige adipocyte differentiation and thermogenesis (PMID:32315212), Sertoli-cell-to-germ-cell signaling that restrains male fertility (PMID:33893301), and BRCA1/p53-driven mammary tumorigenesis through expansion of mammary stem and progenitor cells (PMID:27241552).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 High

    Establishing whether RANKL is genuinely required for osteoclast formation in vivo answered whether bone resorption depends on a single dedicated ligand and revealed its developmental breadth.

    Evidence Gene knockout mouse with skeletal, immunological, and lymph-node phenotyping

    PMID:9950424

    Open questions at the time
    • Does not resolve the receptor or signaling mechanism
    • Does not distinguish membrane-bound versus soluble ligand requirements
  2. 1999 High

    Defining how RANKL is presented to precursors and how it engages mature cells answered whether it acts via contact-dependent membrane signaling and direct activation through RANK.

    Evidence Osteoblast/precursor co-culture, spot-culture distinguishing membrane vs soluble forms, primary osteoclast bone-slice assays with anti-RANK and OPG blockade

    PMID:10080918 PMID:10225954 PMID:10976996

    Open questions at the time
    • Does not identify the intracellular signaling adapters
    • Does not define the sheddase generating soluble RANKL
  3. 2001 Medium

    Characterizing ectodomain shedding answered how the soluble RANKL form is produced, revealing at least two distinct metalloprotease activities separable from TACE/ADAM17.

    Evidence Pharmacological shedding assays with pervanadate/phorbol esters and TIMP-1/TIMP-2 sensitivity across cell types

    PMID:11278735

    Open questions at the time
    • No protease molecularly identified
    • Physiological contribution of soluble vs membrane RANKL in vivo unresolved
  4. 2002 High

    Mapping immune counter-regulation answered how T-cell signals brake osteoclastogenesis, identifying TRAF6 degradation by IFN-γ and c-Fos suppression by RANKL-induced IFN-β.

    Evidence IFN-knockout mice, NF-κB/JNK signaling biochemistry, gene expression and epistasis

    PMID:12110142

    Open questions at the time
    • Does not quantify relative contribution of the two IFN arms in disease
    • Mechanism of RANKL-induced IFN-β induction not fully dissected
  5. 2003 Medium

    Dissecting promoter and rescue requirements answered how RANKL transcription responds to vitamin D/glucocorticoids and whether local versus systemic delivery dictates site-specific skeletal function.

    Evidence Promoter luciferase reporters with CpG methylation analysis; lymphocyte-promoter transgenic rescue of RANKL-null mice

    PMID:10209265 PMID:12952207

    Open questions at the time
    • Promoter elements not validated in vivo at endogenous locus
    • Does not explain tooth-eruption and growth-plate non-rescue mechanistically
  6. 2004 Medium

    Resolving the survival role answered whether RANKL controls osteoclast lifespan, showing biphasic NF-κB-dependent regulation of Fas.

    Evidence Reporter assays, EMSA with NF-κB site mutants, caspase-3 and apoptosis assays in osteoclasts

    PMID:15619676

    Open questions at the time
    • Switch governing the early-up/late-down biphasic response not defined
    • In vivo relevance to bone turnover not established here
  7. 2006 Medium

    Identifying MafB answered how the osteoclast transcriptional program is restrained, placing a brake on c-Fos/Mitf/NFATc1 DNA binding downstream of RANKL.

    Evidence Overexpression/RNAi in monocyte lineage cells, TRAP staining, DNA-binding interference assays

    PMID:17158225

    Open questions at the time
    • Upstream control of MafB downregulation by RANKL unresolved
    • Structural basis of transcription-factor interference not defined
  8. 2008 Medium

    Testing vascular effects answered whether RANKL acts on endothelium, showing it inhibits angiogenesis through mechanisms distinct from OPG-driven ERK/Akt activation.

    Evidence Rat aortic ring assay, HUVEC proliferation/apoptosis, ERK1/2 and Akt phosphorylation assays

    PMID:19105036

    Open questions at the time
    • Receptor and signaling pathway mediating anti-angiogenic effect unidentified
    • In vivo angiogenesis relevance not established
  9. 2014 Medium

    Adding a microRNA layer answered how RANKL fine-tunes late osteoclastogenesis, with miR-26a targeting CTGF to limit DC-STAMP-driven fusion.

    Evidence miRNA mimic/inhibitor transfection, TRAP/actin-ring/resorption assays, recombinant CTGF rescue

    PMID:25518928

    Open questions at the time
    • In vivo skeletal role of the miR-26a/CTGF axis untested
    • How RANKL induces miR-26a not defined
  10. 2015 High

    Mapping enhancers in osteoblasts and T cells answered how RANKL transcription is wired to hormonal and immune cues, defining RL-D2 (VDR/CREB, PTH-responsive) and the hTCCR (c-FOS, MEK/TCR-responsive), and FOXO1 as an intracellular RANKL effector.

    Evidence ChIP-seq/ChIP-chip, in vivo enhancer deletion (RL-D2−/−), hTCCR reporter and MEK inhibition; FOXO1 conditional KO and siRNA with osteoclast assays

    PMID:25211367 PMID:25694609 PMID:26332516

    Open questions at the time
    • Crosstalk between osteoblast and T-cell enhancers not addressed
    • FOXO1 mechanism of NFATc1 regulation only partly defined
  11. 2016 High

    Genome-wide epigenetic profiling answered how RANKL reprograms the osteoclast genome, identifying BATF-dependent superenhancers and an NFATc1 SE-eRNA as essential drivers.

    Evidence ChIP-seq, ATAC-seq, PRO-seq, BATF1/3 depletion, SE-eRNA knockdown, BET inhibition in human osteoclasts

    PMID:36513810

    Open questions at the time
    • Signaling linking RANK to BATF recruitment unresolved
    • Mechanism of SE-eRNA action on NFATc1 not defined
  12. 2016 High

    Probing the mammary axis answered whether RANK/RANKL drives BRCA1-mutant tumorigenesis, showing it expands cancer-prone stem and progenitor cells.

    Evidence Conditional mammary RANK KO (two models), pharmacological RANKL inhibition, murine and human BRCA1-carrier progenitor assays

    PMID:27241552

    Open questions at the time
    • Downstream effectors of RANK in progenitor expansion not identified
    • Does not establish RANKL source within the mammary niche
  13. 2020 Medium

    Testing adipose effects answered whether RANKL influences metabolism, showing it drives beige adipocyte differentiation and thermogenesis in precursors but not mature white adipocytes.

    Evidence OPG-KO mice, in vivo RANKL infusion with indirect calorimetry, SVF and 3T3-L1 differentiation assays

    PMID:32315212

    Open questions at the time
    • Receptor/signaling pathway in preadipocytes not defined
    • Whether RANKL acts cell-autonomously on precursors unresolved
  14. 2021 High

    Imaging osteoclast fate answered whether resorbing cells simply die, revealing RANKL-dependent fission into transcriptionally distinct osteomorphs that recycle.

    Evidence Intravital imaging, single-cell RNA-seq, RANKL inhibition, genetic deletion of osteomorph genes

    PMID:33636130

    Open questions at the time
    • Molecular trigger of fission versus apoptosis not defined
    • Functional contribution of osteomorph recycling to bone homeostasis incompletely quantified
  15. 2021 Medium

    Examining testis and cell-death pathways answered additional non-skeletal and metabolic roles: Sertoli-cell RANKL restrains male fertility via germ-cell RANK, and RANKL induces ferroptosis through ferritinophagy in normoxic osteoclasts.

    Evidence Sertoli-specific/global Rankl KO, OPG and denosumab treatment, seminal RANKL measurement; iron-homeostasis and autophagy-flux assays with HIF-1α inhibition in OVX model

    PMID:33893301 PMID:33895289

    Open questions at the time
    • Germ-cell signaling downstream of RANK in fertility not mapped
    • In vivo significance of RANKL-induced ferroptosis under physiological oxygen tension unresolved
  16. 2021 Low

    Proposing EV-borne reverse signaling addressed how resorption couples to formation, suggesting osteoclast EV RANK triggers RANKL reverse signaling in osteoblasts.

    Evidence EV isolation and functional assays on osteoblast bone formation (review summary)

    PMID:33982033

    Open questions at the time
    • Review-level summary lacking primary mechanistic detail
    • RANKL reverse-signaling pathway in osteoblasts not molecularly defined
    • In vivo contribution to coupling unestablished
  17. 2024 Medium

    Spatial localization answered which cells supply RANKL versus OPG, defining a division of labor between bone-surface osteoprogenitors and osteocytes in regulating osteoclastogenesis.

    Evidence In situ hybridization across species/sites, OPG:Fc and PTH treatment, scRNA-seq of bone marrow stroma

    PMID:39424806

    Open questions at the time
    • Mechanism coordinating the two cell populations not defined
    • Does not establish causal contribution of each source in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • The molecular identity of the RANKL sheddases, the receptor mediating its non-skeletal effects (angiogenesis, adipose browning), and the molecular basis of RANKL reverse signaling remain unresolved.
  • Sheddase enzymes not molecularly identified
  • Receptor for anti-angiogenic and beige-adipocyte effects unknown
  • Reverse-signaling pathway in osteoblasts uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0048018 receptor ligand activity 3 GO:0060089 molecular transducer activity 2
Localization
GO:0005576 extracellular region 2 GO:0005886 plasma membrane 2
Partners
TNFRSF11ATNFRSF11B

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 OPGL/RANKL/TRANCE knockout mice completely lack osteoclasts due to inability of osteoblasts to support osteoclastogenesis, demonstrating RANKL is an essential osteoclast differentiation factor in vivo. Knockout mice also lack all lymph nodes and exhibit defects in early T and B lymphocyte differentiation, establishing roles in lymph-node organogenesis and lymphocyte development. Gene knockout mouse model (opgl-deficient mice) with skeletal, immunological, and lymph-node phenotypic analysis Nature High 9950424
1999 OPGL/RANKL directly activates mature osteoclasts by binding specifically to RANK on their surface and rapidly (within 30 min) inducing actin ring formation, a cytoskeletal rearrangement that precedes bone resorption. OPGL increases total bone surface erosion ~7-fold. Anti-RANK antibodies also induce actin ring formation, confirming RANK mediates these effects. OPG blocks both actin ring formation and bone resorption. Primary rat osteoclast cultures on bone slices, scanning electron microscopy, in vivo Ca++ measurement, antibody blocking experiments The Journal of cell biology High 10225954
1999 RANKL/ODF is expressed as a membrane-associated cytokine on osteoblasts/stromal cells and signals to osteoclast precursors bearing RANK via cell-to-cell contact, inducing osteoclast differentiation in the presence of M-CSF. Membrane or matrix-associated forms of RANKL are required for osteoblast-supported osteoclastogenesis; soluble RANKL can act at a distance. Soluble OPG (decoy receptor) blocks RANKL-RANK interaction and inhibits osteoclastogenesis. Co-culture of osteoblasts/stromal cells and hematopoietic cells; spot-culture assay distinguishing membrane-bound vs. soluble forms; OPG and M-CSF neutralization Biochemical and biophysical research communications High 10080918 10976996
1999 The mouse RANKL/TNFSF11 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. Short-term treatment with 1α,25(OH)2 VitD3 or dexamethasone increased promoter-driven luciferase activity ~2-fold. CpG methylation in the promoter region correlates with loss of osteoclastogenesis support capacity in stromal cells. Promoter cloning, transient transfection luciferase reporter assay, genomic Southern blot, CpG methylation analysis Biochimica et biophysica acta Medium 10209265
2001 TRANCE/OPGL undergoes ectodomain shedding to generate a soluble form. At least two distinct sheddase activities operate in different cell types, both distinct from TNF-alpha convertase (TACE/ADAM17). One sheddase is induced by the tyrosine phosphatase inhibitor pervanadate but not phorbol esters and is sensitive to TIMP-2 but not TIMP-1, consistent with a membrane-type matrix metalloprotease. A second sheddase is refractory to both stimuli. Biochemical characterization of cleavage site usage, pharmacological inhibition/activation with pervanadate and phorbol esters, TIMP-1 and TIMP-2 sensitivity assays in different 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, resulting in strong inhibition of RANKL-induced NF-κB and JNK activation. Separately, RANKL induces IFN-β (but not IFN-α) gene expression in osteoclast precursor cells, and IFN-β strongly inhibits osteoclast differentiation by interfering with RANKL-induced expression of c-Fos. Both IFN-mediated mechanisms maintain bone resorption homeostasis in vivo. Genetic (IFN-KO mice, in vivo models), biochemical signaling assays (NF-κB, JNK activation), gene expression analysis, epistasis experiments Arthritis research High 12110142
2003 PTH upregulates RANKL mRNA in primary mouse bone marrow stromal osteoblasts with maximal sensitivity at late stages of osteoblast differentiation, while simultaneously inhibiting OPG gene expression at all stages. Changes in RANKL and OPG mRNA after PTH exposure are associated with increased osteoclastogenesis (increased TRACP+ cells in co-culture). PTH acts through at least protein kinase A pathway to regulate this balance. Quantitative real-time RT-PCR of RANKL and OPG mRNA at sequential differentiation stages, co-culture osteoclastogenesis assay with TRACP staining Journal of bone and mineral research Medium 14969393
2004 RANKL acts as a survival factor in mature osteoclasts by downregulating Fas expression and Fas-mediated apoptosis. During early osteoclastogenesis, RANKL upregulates Fas promoter activity via NF-κB binding sites. In differentiated mature osteoclasts, RANKL reduces Fas expression and protects from Fas-stimulated apoptosis. The regulation of Fas by RANKL is biphasic and NF-κB-dependent. Western blotting, RT-PCR, flow cytometry, nuclear staining, caspase-3 activity assay, luciferase reporter assay, EMSA with NF-κB site mutations Journal of bone and mineral research Medium 15619676
2006 MafB negatively regulates RANKL-induced osteoclast differentiation. RANKL reduces MafB expression during osteoclastogenesis. Overexpression of MafB inhibits formation of TRAP+ multinuclear osteoclasts and attenuates RANKL-induced NFATc1 and OSCAR gene expression. MafB proteins directly interfere with the DNA-binding ability of c-Fos, Mitf, and NFATc1, inhibiting their transactivation of NFATc1 and OSCAR. RNAi knockdown of MafB enhances osteoclastogenesis. Overexpression and RNAi knockdown in bone marrow-derived monocyte/macrophage lineage cells, TRAP staining, gene expression analysis, DNA-binding interference assays Blood Medium 17158225
2003 RANKL expression in skeletal tissue is regulated by a distal enhancer element (RL-D2) located 23 kb upstream of the Tnfsf11 TSS. Deletion of RL-D2 blunts PTH-induced RANKL expression in vivo and in primary stromal cells ex vivo, and leads to decreased osteoclast numbers and increased bone mineral density (high bone mass phenotype). VDR and CREB bind to this enhancer in osteoblastic cells. ChIP-seq, ChIP-chip, genomic enhancer deletion in mice (RL-D2−/− knockout), ex vivo stromal cell cultures with PTH/forskolin/1,25(OH)2D3, bone phenotype analysis Journal of bone and mineral research High 26332516
2015 Human TNFSF11 expression in T cells is regulated by a distal enhancer region (-170 to -220 kb upstream of TSS) designated the human T cell control region (hTCCR), which is conserved with the mouse TCCR. c-FOS is recruited to the hTCCR. MEK1/2 signaling is required for RANKL induction in T cells. Enhancer segments mediate robust inducible reporter activity following TCR activation. ChIP-chip (H3/H4 acetylation), MEK1/2 inhibition with U0126, luciferase reporter assay with hTCCR segments, Jurkat cells and primary human T cells Journal of cellular biochemistry Medium 25211367
2003 Genetic rescue of RANKL-null mice using a lymphocyte-specific promoter transgene restores osteoclasts and marrow spaces in long bone diaphyses but not in periosteum or jaws, demonstrating that local delivery of RANKL is required for many site-specific skeletal processes including tooth eruption, which was not rescued. The transgene had no effect on chondrodystrophy or growth plate defects, indicating distinct tissue requirements for RANKL. Transgenic rescue of RANKL knockout mice with lymphocyte-specific promoter, histological and TRAP staining of skeletal tissues Connective tissue research Medium 12952207
2008 RANKL inhibits angiogenesis: it potently inhibits basal and VEGF-induced microvessel formation in the rat aortic ring model, inhibits endothelial cell proliferation, and induces endothelial apoptosis. Signaling studies in HUVECs showed RANKL has no effect on ERK1/2 or Akt phosphorylation (in contrast to OPG which activates these pathways), indicating RANKL's anti-angiogenic effects operate through distinct mechanisms. Rat aortic ring angiogenesis assay, HUVEC proliferation and apoptosis assays, ERK1/2 and Akt phosphorylation signaling assays Angiogenesis Medium 19105036
2015 FOXO1 is induced by RANKL and translocates to the nucleus in osteoclast precursors. Lineage-specific deletion of FOXO1 (LyzM.Cre+ FOXO1L/L) reduces RANKL-induced osteoclast formation and activity by ~50% in vivo and in vitro. FOXO1 mediates RANKL effects by regulating NFATc1 nuclear localization/expression and downstream osteoclast genes (DC-STAMP, ATP6vod2, cathepsin K, integrin αv). FOXO1 deletion also reduces M-CSF-induced RANK expression and osteoclast precursor migration. Conditional knockout mice (LyzM.Cre+ FOXO1L/L), siRNA knockdown in RAW264.7, in vitro osteoclastogenesis, in vivo bone phenotype, gene expression analysis Journal of immunology Medium 25694609
2014 miR-26a is upregulated by RANKL at late stages of osteoclastogenesis. miR-26a mimic suppresses osteoclast formation, actin-ring formation, and bone resorption by targeting connective tissue growth factor/CCN2 (CTGF), which promotes osteoclast formation via DC-STAMP upregulation. Overexpression of miR-26a inhibitor enhances RANKL-induced osteoclastogenesis. Recombinant CTGF rescues the inhibitory effect of miR-26a. miRNA mimic/inhibitor transfection in osteoclast precursors, TRAP staining, actin-ring assay, bone resorption assay, gene expression analysis, rescue with recombinant CTGF Molecules and cells Medium 25518928
2016 RANKL-induced osteoclastogenesis involves an epigenetic reprogramming mechanism: RANKL induces formation of ~200 superenhancers (SEs) while suppressing ~148 SEs in human macrophages. RANKL-responsive SEs are enriched for BATF binding motifs; BATF1/3 depletion inhibits RANKL-induced osteoclast differentiation. RANKL also induces SE-associated enhancer RNAs (SE-eRNAs) at the NFATc1 locus; knockdown of SE-eRNA:NFATc1 diminishes NFATc1 expression and osteoclast differentiation. BET protein inhibition suppresses RANKL-responsive SEs and SE-eRNA:NFATc1 expression. ChIP-seq, ATAC-seq, nuclear RNA-seq, PRO-seq, BATF1/3 depletion, SE-eRNA knockdown, BET inhibitor treatment, human osteoclast differentiation assays Cellular & molecular immunology High 36513810
2017 TNFα increases RANKL expression in osteoblastic cells via PGE2-dependent activation of NFATc1 and CREB. TNFα stimulates COX2, increasing PGE2 production, which activates NFAT transcriptional activity and drives NFATc1 and CREB binding to the RANKL promoter. Mutations in the NFAT-binding element or CRE-like element in the RANKL promoter suppress TNFα/PGE2-induced RANKL promoter activity. PGE2 receptor antagonists block TNFα-induced RANKL expression. Luciferase reporter assay with RANKL promoter mutants, ChIP, NFAT inhibitors, COX inhibitor, PGE2 receptor antagonists, in C2C12 and primary calvarial cells International journal of molecular sciences Medium 28245593
2020 RANKL induces beige adipocyte differentiation in preadipocytes. RANKL treatment of stromal vascular fraction (SVF) cells or 3T3-L1 preadipocytes induces multilocular morphology and increased expression of beige adipocyte marker genes. Infusion of RANKL increases respiratory rates in subcutaneous white adipose tissue and increases whole body oxygen consumption. Mature white adipocytes do not respond to RANKL-induced browning. OPG-/- mice show spontaneous sWAT browning. OPG knockout mouse model, RANKL infusion in vivo (indirect calorimetry), SVF cell differentiation assays, 3T3-L1 cell assays, histology, gene expression analysis American journal of physiology. Endocrinology and metabolism Medium 32315212
2021 RANKL-stimulated osteoclasts undergo cell fission into daughter cells called osteomorphs rather than exclusively undergoing apoptosis. Inhibiting RANKL blocked this cellular recycling and caused osteomorph accumulation. Osteomorphs are transcriptionally distinct from osteoclasts and macrophages by single-cell RNA sequencing and express non-canonical osteoclast genes associated with bone phenotypes when deleted. Intravital imaging, single-cell RNA sequencing, RANKL inhibition experiments, genetic deletion of osteomorph genes in mice Cell High 33636130
2021 RANKL is highly expressed in Sertoli cells of the testis and signals through RANK expressed on germ cells, with OPG expressed in germ and peritubular cells. Mice with global or Sertoli-specific genetic suppression of Rankl have increased sperm counts and male fertility. OPG treatment increases wild-type mouse sperm counts. RANKL levels in seminal fluid are elevated and distinguish infertile from fertile men. Sertoli cell-specific and global Rankl knockout mice, OPG pharmacological treatment, seminal fluid RANKL measurement, immunohistochemistry for RANK/RANKL/OPG localization, human clinical intervention with denosumab Nature communications Medium 33893301
2021 Under normoxia, RANKL stimulation induces ferroptosis in osteoclasts through an iron-starvation response (increased transferrin receptor 1, decreased ferritin) and activation of ferritinophagy via FTH-NCOA4 complex autophagosome degradation. This process is blocked under hypoxia, where HIF-1α inhibits autophagosome formation and autophagy flux, thereby reducing ferritinophagy. Aconitase activity reduction links RANKL stimulation to iron-starvation response. In vitro osteoclast differentiation under normoxia/hypoxia, iron homeostasis assays, autophagy flux measurement, HIF-1α inhibitor (2ME2) in vivo OVX model, FTH-NCOA4 interaction analysis Free radical biology & medicine Medium 33895289
2016 Genetic inactivation of RANK in mammary epithelium markedly delayed onset and reduced incidence of Brca1;p53 mutation-driven mammary cancer. Long-term pharmacological RANKL inhibition abolished BRCA1 mutation-driven pre-neoplastic lesions in mice. RANK/RANKL blockade impaired proliferation and expansion of both murine Brca1;p53 mutant mammary stem cells and mammary progenitors from human BRCA1 mutation carriers. Conditional RANK knockout in mammary epithelium (two mouse models), pharmacological RANKL inhibition, mammary stem/progenitor cell proliferation assays, human BRCA1 carrier progenitor assays Cell research High 27241552
2024 In situ hybridization revealed that RANKL (Tnfsf11) is expressed mainly by bone surface osteoprogenitor cells (co-expressing Mmp13, Limch1, Wif1) proximate to osteoclasts, while OPG is expressed mainly by osteocytes and bone-forming osteoblasts. OPG:Fc treatment increased RANKL mRNA in trabecular bone surface cells while decreasing OPG mRNA in both bone surface cells and osteocytes. PTH treatment had a similar but more pronounced effect. These findings suggest bone surface cells and osteocytes conjointly regulate osteoclastogenesis activation. In situ hybridization across multiple species and skeletal sites, OPG:Fc and PTH treatment of mice, scRNA-seq analysis of murine bone marrow stromal cells Bone research Medium 39424806
2021 RANKL and RANK are present as functional components in extracellular vesicles (EVs). RANK in EVs from osteoclasts can stimulate a RANKL reverse signaling pathway in osteoblasts that promotes bone formation, serving to couple bone resorption with bone formation. Extracellular vesicle isolation, functional assays of RANK-containing EVs on osteoblast bone formation Extracellular vesicles and circulating nucleic acids Low 33982033

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 2616 9950424
2001 Minireview: the OPG/RANKL/RANK system. Endocrinology 1050 11713196
2005 RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends in molecular medicine 935 16356770
2007 Biology of RANK, RANKL, and osteoprotegerin. Arthritis research & therapy 696 17634140
2020 Osteoclast differentiation by RANKL and OPG signaling pathways. Journal of bone and mineral metabolism 536 33079279
1999 The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. The Journal of cell biology 534 10225954
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
2021 Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell 297 33636130
2011 The RANKL-OPG system in clinical periodontology. Journal of clinical periodontology 266 22092994
2003 PTH differentially regulates expression of RANKL and OPG. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 264 14969393
2007 The RANKL/RANK/OPG pathway. Current osteoporosis reports 259 17925190
2005 Role of RANKL in physiological and pathological bone resorption and therapeutics targeting the RANKL-RANK signaling system. Immunological reviews 256 16313339
2006 MafB negatively regulates RANKL-mediated osteoclast differentiation. Blood 221 17158225
2005 Osteoprotegerin and RANKL regulate bone resorption, density, geometry and strength. Current opinion in pharmacology 214 16188502
2009 RANK/RANKL/OPG during orthodontic tooth movement. Orthodontics & craniofacial research 201 19419454
2005 Osteoclast precursors, RANKL/RANK, and immunology. Immunological reviews 187 16313338
2011 Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats. Journal of cellular biochemistry 183 21618594
2004 The OPG/RANKL/RANK system in metabolic bone diseases. Journal of musculoskeletal & neuronal interactions 183 15615494
2021 Discovery of the RANKL/RANK/OPG system. Journal of bone and mineral metabolism 169 33389131
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 162 12379618
2015 RANKL/OPG; Critical role in bone physiology. Reviews in endocrine & metabolic disorders 161 25557611
2021 Hypoxia inhibits RANKL-induced ferritinophagy and protects osteoclasts from ferroptosis. Free radical biology & medicine 152 33895289
2011 Rank/Rankl/opg: literature review. Acta reumatologica portuguesa 142 22113597
2016 RANKL/RANK control Brca1 mutation- . Cell research 139 27241552
2015 The RANKL-RANK Story. Gerontology 139 25720990
2016 RANK-RANKL signalling in cancer. Bioscience reports 134 27279652
2009 Action of RANKL and OPG for osteoclastogenesis. Critical reviews in eukaryotic gene expression 133 19191757
2001 The osteoclastogenic molecules RANKL and RANK are associated with periprosthetic osteolysis. The Journal of bone and joint surgery. British volume 130 11521937
2002 Signaling crosstalk between RANKL and interferons in osteoclast differentiation. Arthritis research 127 12110142
2010 Do RANKL inhibitors (denosumab) affect inflammation and immunity? Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 125 20571772
2007 RANKL, RANK, osteoprotegerin: key partners of osteoimmunology and vascular diseases. Cellular and molecular life sciences : CMLS 125 17530461
1999 Promoter structure of mouse RANKL/TRANCE/OPGL/ODF gene. Biochimica et biophysica acta 119 10209265
2011 RANKL/RANK-beyond bones. Journal of molecular medicine (Berlin, Germany) 112 21445556
2001 Biochemical and pharmacological criteria define two shedding activities for TRANCE/OPGL that are distinct from the tumor necrosis factor alpha convertase. The Journal of biological chemistry 107 11278735
2011 Regulatory mechanism of osteoclastogenesis by RANKL and Wnt signals. Frontiers in bioscience (Landmark edition) 105 21196156
2007 Clinical development of anti-RANKL therapy. Arthritis research & therapy 102 17634146
2022 RANKL biology. Bone 96 35181574
2020 RANKL and osteoimmunology in periodontitis. Journal of bone and mineral metabolism 90 33070252
2009 Denosumab: anti-RANKL antibody. Current osteoporosis reports 89 19239825
2022 Artemisinin relieves osteoarthritis by activating mitochondrial autophagy through reducing TNFSF11 expression and inhibiting PI3K/AKT/mTOR signaling in cartilage. Cellular & molecular biology letters 87 35902802
2016 Proinflammatory M1 Macrophages Inhibit RANKL-Induced Osteoclastogenesis. Infection and immunity 86 27456834
2014 The immune system, bone and RANKL. Archives of biochemistry and biophysics 79 24929185
2017 RANKL and RANK: From Mammalian Physiology to Cancer Treatment. Trends in cell biology 76 29241686
2014 Effects of RANKL-Targeted Therapy in Immunity and Cancer. Frontiers in oncology 76 24432249
2015 RANKL blockade prevents and treats aggressive osteosarcomas. Science translational medicine 74 26659571
2003 RANK-Fc: a therapeutic antagonist for RANK-L in myeloma. Cancer 74 12548579
2019 RANKL-independent modulation of osteoclastogenesis. Journal of oral biosciences 73 30929797
2010 RANK/RANKL/OPG role in distraction osteogenesis. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics 72 20163972
2008 Osteoprotegerin and RANKL differentially regulate angiogenesis and endothelial cell function. Angiogenesis 72 19105036
2003 RANKL and RANK as novel therapeutic targets for arthritis. Current opinion in rheumatology 71 12707582
2022 RANKL-responsive epigenetic mechanism reprograms macrophages into bone-resorbing osteoclasts. Cellular & molecular immunology 66 36513810
2014 MicroRNA-26a regulates RANKL-induced osteoclast formation. Molecules and cells 64 25518928
2005 RANK, RANKL and osteoprotegerin in arthritic bone loss. Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas 64 15785827
2000 Importance of membrane- or matrix-associated forms of M-CSF and RANKL/ODF in osteoclastogenesis supported by SaOS-4/3 cells expressing recombinant PTH/PTHrP receptors. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 63 10976996
2014 RANKL expression in periodontal disease: where does RANKL come from? BioMed research international 62 24719884
2016 Denosumab: targeting the RANKL pathway to treat rheumatoid arthritis. Expert opinion on biological therapy 60 27871200
2020 Targeting the RANKL/RANK/OPG Axis for Cancer Therapy. Frontiers in oncology 58 32850393
2014 Targeting RANKL in metastasis. BoneKEy reports 58 24795813
2007 Role of RANKL inhibition in osteoporosis. Arthritis research & therapy 57 17634142
2011 Relationship between serum RANKL and RANKL in bone. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 56 21850548
2014 Regulatory mechanisms of RANKL presentation to osteoclast precursors. Current osteoporosis reports 54 24477414
2004 RANKL regulates Fas expression and Fas-mediated apoptosis in osteoclasts. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 54 15619676
2020 RANKL as a target for the treatment of osteoporosis. Journal of bone and mineral metabolism 53 33057808
2003 The role of RANKL (TRANCE/TNFSF11), a tumor necrosis factor family member, in skeletal development: effects of gene knockout and transgenic rescue. Connective tissue research 53 12952207
2006 Leptin effect on RANKL and OPG expression in MC3T3-E1 osteoblasts. Journal of cellular biochemistry 52 16479591
2014 RANKL/RANK - from bone physiology to breast cancer. Cytokine & growth factor reviews 50 24486161
2013 AG490 inhibits NFATc1 expression and STAT3 activation during RANKL induced osteoclastogenesis. Biochemical and biophysical research communications 50 23665018
2021 The Roadmap of RANKL/RANK Pathway in Cancer. Cells 49 34440747
2019 The RANKL-RANK Axis: A Bone to Thymus Round Trip. Frontiers in immunology 49 30984193
2024 Mapping RANKL- and OPG-expressing cells in bone tissue: the bone surface cells as activators of osteoclastogenesis and promoters of the denosumab rebound effect. Bone research 48 39424806
2018 RANKL Triggers Treg-Mediated Immunoregulation in Inflammatory Osteolysis. Journal of dental research 45 29499125
2019 (-)-Epigallocatechin-3-Gallate Decreases Osteoclastogenesis via Modulation of RANKL and Osteoprotegrin. Molecules (Basel, Switzerland) 43 30609798
2021 RANKL regulates male reproductive function. Nature communications 41 33893301
2011 The expression of RANKL and OPG in the various grades of osteoarthritic cartilage. Rheumatology international 41 21259010
2018 CCL4 enhances preosteoclast migration and its receptor CCR5 downregulation by RANKL promotes osteoclastogenesis. Cell death & disease 39 29717113
2004 Expression of parathyroid hormone-related protein (PTHrP), osteoclast differentiation factor (ODF)/receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoclastogenesis inhibitory factor (OCIF)/osteoprotegerin (OPG) in ameloblastomas. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology 39 14675140
2020 RANKL as a therapeutic target of rheumatoid arthritis. Journal of bone and mineral metabolism 38 33070253
2021 RANKL and RANK in extracellular vesicles: surprising new players in bone remodeling. Extracellular vesicles and circulating nucleic acids 36 33982033
2016 Expression of osteoprotegerin and its ligands, RANKL and TRAIL, in rheumatoid arthritis. Scientific reports 36 27403809
2001 Receptor activator of nuclear factor kappa B ligand (RANKL): another link between breast and bone. Trends in endocrinology and metabolism: TEM 36 11137033
2021 The hidden secrets of soluble RANKL in bone biology. Cytokine 34 33994070
2010 Physiology and pathophysiology of the RANKL/RANK system. Biological chemistry 34 21087090
2004 RANK, RANKL and OPG in inflammatory arthritis and periprosthetic osteolysis. Journal of musculoskeletal & neuronal interactions 34 15615495
2011 Reduced osteoclastogenesis and RANKL expression in marrow from women taking alendronate. Calcified tissue international 32 21327765
2015 FOXO1 mediates RANKL-induced osteoclast formation and activity. Journal of immunology (Baltimore, Md. : 1950) 31 25694609
2013 Endotoxins potentiate COX-2 and RANKL expression in compressed PDL cells. Clinical oral investigations 30 23392729
2016 RANKL system in vascular and valve calcification with aging. Inflammation and regeneration 29 29259683
2015 Transcriptional regulation of the human TNFSF11 gene in T cells via a cell type-selective set of distal enhancers. Journal of cellular biochemistry 29 25211367
2011 The RANKL pathway and denosumab. Rheumatic diseases clinics of North America 29 22023901
2020 Ellagic acid blocks RANKL-RANK interaction and suppresses RANKL-induced osteoclastogenesis by inhibiting RANK signaling pathways. Chemico-biological interactions 28 32971123
2016 Deletion of the Distal Tnfsf11 RL-D2 Enhancer That Contributes to PTH-Mediated RANKL Expression in Osteoblast Lineage Cells Results in a High Bone Mass Phenotype in Mice. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 28 26332516
2016 Can we prevent BRCA1-associated breast cancer by RANKL inhibition? Breast cancer research and treatment 28 27783278
2017 Unexpected Bone Formation Produced by RANKL Blockade. Trends in endocrinology and metabolism: TEM 27 28733136
2006 Association of TNFSF11 gene promoter polymorphisms with bone mineral density in postmenopausal women. Maturitas 27 16730419
2010 TNFRSF11A and TNFSF11 are associated with age at menarche and natural menopause in white women. Menopause (New York, N.Y.) 25 20531232
2021 RANKL/OPG ratio regulates odontoclastogenesis in damaged dental pulp. Scientific reports 24 33633362
2020 RANKL induces beige adipocyte differentiation in preadipocytes. American journal of physiology. Endocrinology and metabolism 24 32315212
2017 TNFα Increases RANKL Expression via PGE₂-Induced Activation of NFATc1. International journal of molecular sciences 24 28245593
2017 RANK/RANKL/OPG system in the intervertebral disc. Arthritis research & therapy 24 28576140

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