TNFSF11 Gene

HGNC Family	Tumor necrosis factor (ligand) superfamily (TNFSF), CD molecules (CD)
Name	tumor necrosis factor (ligand) superfamily, member 11
Description	This gene encodes a member of the tumor necrosis factor (TNF) cytokine family which is a ligand for osteoprotegerin and functions as a key factor for osteoclast differentiation and activation. This protein was shown to be a dentritic cell survival factor and is involved in the regulation of T cell-dependent immune response. T cell activation was reported to induce expression of this gene and lead to an increase of osteoclastogenesis and bone loss. This protein was shown to activate antiapoptotic kinase AKT/PKB through a signaling complex involving SRC kinase and tumor necrosis factor receptor-associated factor (TRAF) 6, which indicated this protein may have a role in the regulation of cell apoptosis. Targeted disruption of the related gene in mice led to severe osteopetrosis and a lack of osteoclasts. The deficient mice exhibited defects in early differentiation of T and B lymphocytes, and failed to form lobulo-alveolar mammary structures during pregnancy. Two alternatively spliced transcript variants have been found. [provided by RefSeq, Jul 2008]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTNFSF11 (also known as RANKL) is a master regulator of bone remodeling and osteoclastogenesis. Secreted by osteoblasts and stromal cells, TNFSF11 binds to its receptor RANK on osteoclast precursors to stimulate their differentiation, activation, and survival, a process essential for both normal skeletal maintenance and pathological bone resorption. Multiple studies have demonstrated that TNFSF11‐mediated signaling proceeds via diverse pathways—including p38 MAP kinase, PKA–CREB, and TRAF6-dependent cascades—and is modulated by factors such as Wnt and parathyroid hormone. Mutations in TNFSF11 cause severe osteoclast deficits and osteopetrosis, and regulated ectodomain shedding by metalloproteinases further fine‐tunes local osteoclastogenesis. In addition, inflammatory mediators (for example, reactive oxygen species and cytokines like GM-CSF) and immune cell–derived signals (from T cells and B cells) regulate TNFSF11 expression to coordinate cross-talk between the skeletal and immune systems."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical role in bone, TNFSF11 contributes significantly to cancer development and metastasis. In breast and other cancers, TNFSF11 not only drives osteoclast-mediated bone destruction but also mediates tumor cell migration and niche formation within the bone microenvironment. Aberrant progesterone signaling, particularly in BRCA1-mutation carriers, appears to act via TNFSF11–RANK activation in luminal progenitor cells, thereby promoting mammary tumorigenesis and metastatic spread. In addition, studies have linked TNFSF11 overexpression in atherosclerotic plaques to the aggressive behavior of certain tumors and suggested its potential as a therapeutic target in cancer prevention."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn vascular biology, TNFSF11 plays multifaceted roles that extend to the regulation of calcification and angiogenesis. Expression of TNFSF11 in vascular cells has been implicated in the pathogenesis of calcific aortic stenosis and atherosclerosis, where a disturbance in the balance between TNFSF11 and its decoy receptor osteoprotegerin promotes vascular calcification. Moreover, TNFSF11 can directly stimulate angiogenic processes through activation of key kinases, linking bone–vascular interactions and underscoring its importance in vascular remodeling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "30"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTNFSF11 also exerts important effects in immune regulation and inflammatory joint diseases. Its production by activated T cells, B cells, neutrophils, and other immune components links inflammatory stimuli to enhanced osteoclastogenesis, as seen in rheumatoid arthritis and other autoimmune conditions. TNFSF11 thereby modulates osteoimmunological responses that drive inflammatory bone loss by integrating signals from Th17 and IFN-γ–producing immune cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "31", "end_ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, emerging evidence indicates that TNFSF11 signaling influences skeletal muscle function and mesenchymal stem cell fate. Inhibition of TNFSF11 using agents such as denosumab not only improves bone mass but also enhances muscle strength, suggesting that TNFSF11 is part of a broader musculoskeletal regulatory network. In addition, by affecting the balance between osteogenic and adipogenic differentiation of mesenchymal stem cells, TNFSF11 may contribute to the overall maintenance of musculoskeletal health."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "34", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Brendan F Boyce, Lianping Xing "}, {"type": "b", "children": [{"type": "t", "text": "Biology of RANK, RANKL, and osteoprotegerin."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Arthritis Res Ther (2007)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1186/ar2165"}], "href": "https://doi.org/10.1186/ar2165"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17634140"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17634140"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Eva Gonzalez-Suarez, Allison P Jacob, Jon Jones, et al. 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Synonyms	OPTB2, TRANCE, CD254, OPGL, RANKL, HRANKL2, TNLG6B
Proteins	TNF11_HUMAN
NCBI Gene ID	8600
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

TNFSF11 has 8,623 functional associations with biological entities spanning 8 categories (molecular profile, organism, functional term, phrase or reference, chemical, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 117 datasets.

Click the + buttons to view associations for TNFSF11 from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

TNFSF11 Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by TNFSF11 gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of TNFSF11 gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of TNFSF11 gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of TNFSF11 gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	Biocarta Pathways	pathways involving TNFSF11 protein from the Biocarta Pathways dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of TNFSF11 gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of TNFSF11 gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of TNFSF11 gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of TNFSF11 gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of TNFSF11 gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of TNFSF11 gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Gene Mutation Profiles	cell lines with TNFSF11 gene mutations from the CCLE Cell Line Gene Mutation Profiles dataset.
	CellMarker Gene-Cell Type Associations	cell types associated with TNFSF11 gene from the CellMarker Gene-Cell Type Associations dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of TNFSF11 gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of TNFSF11 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of TNFSF11 gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	ClinVar Gene-Phenotype Associations	phenotypes associated with TNFSF11 gene from the curated ClinVar Gene-Phenotype Associations dataset.
	ClinVar Gene-Phenotype Associations 2025	phenotypes associated with TNFSF11 gene from the curated ClinVar Gene-Phenotype Associations 2025 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of TNFSF11 gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing TNFSF11 protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with TNFSF11 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with TNFSF11 protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of TNFSF11 gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with TNFSF11 gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with TNFSF11 gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with TNFSF11 gene/protein from the curated CTD Gene-Disease Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by TNFSF11 gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores	diseases involving TNFSF11 gene from the DISEASES Curated Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Curated Gene-Disease Association Evidence Scores 2025	diseases involving TNFSF11 gene from the DISEASES Curated Gene-Disease Association Evidence Scores 2025 dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with TNFSF11 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with TNFSF11 gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with TNFSF11 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with TNFSF11 gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with TNFSF11 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with TNFSF11 gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	DrugBank Drug Targets	interacting drugs for TNFSF11 protein from the curated DrugBank Drug Targets dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at TNFSF11 gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of TNFSF11 gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of TNFSF11 gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing TNFSF11 from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.