TNFSF11

Summary

TNFSF11 (TNF superfamily member 11, HGNC:11926) is a protein-coding gene on chromosome 13q14.11, encoding Tumor necrosis factor ligand superfamily member 11 (O14788). Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK.

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 dendritic 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.

Source: NCBI Gene 8600 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive osteopetrosis 2 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 29
• Clinical variants (ClinVar): 138 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 66
• Druggable target: yes
• MANE Select transcript: NM_003701

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11926
Approved symbol	TNFSF11
Name	TNF superfamily member 11
Location	13q14.11
Locus type	gene with protein product
Status	Approved
Aliases	TRANCE, RANKL, OPGL, ODF, CD254
Ensembl gene	ENSG00000120659
Ensembl biotype	protein_coding
OMIM	602642
Entrez	8600

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000358545, ENST00000398795

RefSeq mRNA: 2 — MANE Select: NM_003701 NM_003701, NM_033012

CCDS: CCDS9384, CCDS9385

Canonical transcript exons

ENST00000398795 — 5 exons

Exon	Start	End
ENSE00000817246	42600752	42600797
ENSE00000817247	42600883	42600981
ENSE00000817248	42606497	42608013
ENSE00001885296	42574152	42574522
ENSE00003758084	42581126	42581293

Expression profiles

Bgee: expression breadth broad, 98 present calls, max score 94.03.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.2051 / max 19.8560, expressed in 89 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134884	0.2051	89

Top tissues by expression

249 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	94.03	gold quality
tibia	UBERON:0000979	92.69	gold quality
lymph node	UBERON:0000029	83.91	gold quality
buccal mucosa cell	CL:0002336	79.95	gold quality
palpebral conjunctiva	UBERON:0001812	76.24	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.84	silver quality
vermiform appendix	UBERON:0001154	73.21	gold quality
amniotic fluid	UBERON:0000173	70.58	gold quality
epithelium of nasopharynx	UBERON:0001951	70.54	gold quality
caecum	UBERON:0001153	68.45	gold quality
rectum	UBERON:0001052	67.82	gold quality
islet of Langerhans	UBERON:0000006	66.38	gold quality
periodontal ligament	UBERON:0008266	65.11	silver quality
gall bladder	UBERON:0002110	64.46	gold quality
mucosa of sigmoid colon	UBERON:0004993	61.84	gold quality
colonic mucosa	UBERON:0000317	60.47	gold quality
cartilage tissue	UBERON:0002418	60.34	silver quality
epithelial cell of pancreas	CL:0000083	59.67	gold quality
mucosa of transverse colon	UBERON:0004991	58.92	gold quality
cranial nerve II	UBERON:0000941	58.83	silver quality
tonsil	UBERON:0002372	56.42	gold quality
liver	UBERON:0002107	56.08	gold quality
right lobe of liver	UBERON:0001114	55.70	gold quality
endometrium epithelium	UBERON:0004811	54.48	gold quality
ileal mucosa	UBERON:0000331	54.26	gold quality
pons	UBERON:0000988	53.72	gold quality
small intestine Peyer’s patch	UBERON:0003454	51.35	gold quality
Brodmann (1909) area 10	UBERON:0013541	50.95	gold quality
colonic epithelium	UBERON:0000397	50.64	silver quality
small intestine	UBERON:0002108	50.47	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	9.47
E-ENAD-17	no	98.11
E-ANND-3	no	3.88

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ATF2, ATF4, CEBPB, CREB1, DACH1, E2F1, EGR1, EGR2, ESR1, FOXC1, HSF2, ID1, ID2, IRF4, IRF8, JUN, JUND, KLF10, MAFB, MEF2A, MEF2C, MITF, MN1, MYC, NCOR1, NFAT5, NFATC1, NFATC2, NFATC3, NFKB, NFYA, NFYB, NFYC, NOTCH1, NR3C1, NR4A1, PARP1, PAX6, PGR

miRNA regulators (miRDB)

116 targeting TNFSF11, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-557	99.96	70.01	1640
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872

Literature-anchored findings (GeneRIF, showing 40)

• RANKL induces formation of avian osteoclasts from macrophages but not from macrophage polykaryons. (PMID:11606048)
• TRANCE stimulated DNA synthesis, chemotactic motility, and capillary-like tube formation in primary cultured human umbilical vein endothelial cells (HUVECs) (PMID:11741951)
• Macrophage colony-stimulating factor and receptor activator NF-kappaB ligand fail to rescue osteoclast-poor human malignant infantile osteopetrosis in vitro. (PMID:11792569)
• immunohistochemical localization of RANK and its ligand (this protein) in human deciduous teeth (PMID:12043011)
• stimulation by parathyroid hormone (PMID:12364326)
• Long-lived immature dendritic cells mediated by TRANCE-RANK interaction (PMID:12393586)
• Human myeloma cell lines increased the expression & secretion of RANKL in activated T-celes & MM cells stimulated RANKL production in autologous T-cells. This confirms the critical role of RANKL in MM bone disease. (PMID:12393684)
• compared the gene expression of RANKL and osteoprogerin in periodontitis and healthy subjects; data suggest up regulation of RANKL in inflammatory cells and epithelium may be associated with activation of osteoclastic bone destruction in periodontitis (PMID:12469211)
• REVIEW: role of these molecules in immunology and skeletal remodelling and assess their involvement in diseases of bones and joints, including rheumatoid arthritis, Paget’s disease, post-menopausal osteoporosis and malignant bone diseases (PMID:12564836)
• RANKL can induce maturation of monocyte-derived dendritic cells and elicit sustained antiviral cytotoxic T lymphocyte responses, either alone or cooperatively with TNF-alpha or CD40L. (PMID:12574344)
• examination as indices of bone turnover in different bone diseases (PMID:12619938)
• RANKL-induced osteoclast formation and matrix metalloproteinase dependent matrix degradation are associated with osteolysis because of bone metastasis of breast cancer. (PMID:12698202)
• Receptor activator of nuclear factor kappaB ligand plays a nonredundant role in doxorubicin-induced apoptosis. (PMID:12702561)
• the first case of Follicular Lymphoma with bone involvement displaying an aberrant expression of RANKL in malignant cells (PMID:12756027)
• Vitamin D upregulated the expression of RANKL mRNA preferentially in cultured osteoblasts. (PMID:12817763)
• endothelial nitric-oxide synthase and receptor activator of nuclear kappa B ligand expression are regulated via ERK1/2 MAPK after mechanical stress (PMID:12824189)
• osteoprotegerin and RANK ligand have roles in breast cancer bone metastasis (PMID:12923331)
• ICAM1 and RANKL are induced by Beta1 integrin/focal adhesion kinase on osteoblasts and in osteoclast maturation (PMID:12954625)
• RANKL has a role in regulation of osteoclastogenesis mediated by HIV gp120 (PMID:12975380)
• RANKL gene expression in the bone microenvironment is regulated by HSF2 (PMID:14699143)
• RANKL-OPG pathway may regulate valvular calcification in calcific aortic stenosis (PMID:14734048)
• induces osteoclastogenesis by binding with the receptor, receptor activator of nuclear factor-kappaB in the presence of macrophage colony-stimulating factor (PMID:14751235)
• specimens of ameloblastomas, dentigerous cysts, odontogenic keratocysts, and radicular cysts were subjected to immunohistochemical analysis for RANKL and tartrate-resistant acid phosphatase (TRAP). (PMID:15044512)
• RANKL mRNA could be detected in bone marrow plasma cells from myeloma patients with osteolytic myeloma bone disease (PMID:15205949)
• in-situ involvement of RANKL in both osteoclastogenesis and osteoclastic bone resorptive events occurring in prosthetic joint loosening (PMID:15221493)
• Since RANK-L and OPG mRNA levels are elevated in peripheral blood monocytes in rheumatoid arthritis(RA) and CD4+ T cells are major contributors to RANK-L mRNA expression, monocytes in RA may be involved in pathways regulating bone metabolism. (PMID:15290725)
• Enhanced apoptosis adjacent to vascular calcification and concurrent expression of regulators of apoptosis and osteoclastic differentiation, TNF-related apoptosis-inducing ligand and OPG. May be involved in pathogenesis of vascular calcification. (PMID:15292354)
• RANKL-induced cathepsin K gene expression is cooperatively regulated by the combination of the transcription factors and p38 MAP kinase in a gradual manner. (PMID:15304486)
• Thus, the RANKL/OPG ratio was markedly increased, suggesting a potential mechanism of ATRA-induced bone resorption. (PMID:15313187)
• (RANK-L)/osteoprotegerin (OPG) signalling pathway is central to the processes regulating bone turnover in a wide variety of medical conditions, including diabetic neuropathy (review) (PMID:15322748)
• RANKL treatment induced a significant increase of IL-6 & IL-11 secretion by both bone marrow stromal & endothelial cells. (PMID:15377473)
• Parathyroid hormone [PTH (1-34)] induced RANKL messenger ribonucleic acid (mRNA) expression in cultured normal human osteoblast-like cells (hOB). (PMID:15554353)
• Review. The RANKL/RANK/OPG system may mediate links between the vascular, skeletal, & immune systems and play a central role in regulating the vascular calcification coincident with declines in skeletal mineralization with age, osteoporosis, or disease. (PMID:15564564)
• may play a role in apical periodontitis-induced bone resorption (PMID:15613999)
• Activating mutations in TNFRSF11A encoding RANK and deactivating mutations in TNFRSF11B encoding OPG cause systemic bone disease (PMID:15615493)
• disruption of the RANKL-RANK axis with OPG inhibited tumor-induced osteoclastogenesis and decreased bone cancer pain (PMID:15615497)
• RANKL has a role in breast carcinoma metastasis (PMID:15671541)
• human myeloma cells do not express significant levels of RANKL mRNA or produce RANKL able to stimulate osteoclast formation (PMID:15710592)
• When RANKL signaling through NFATc1 was blocked with cyclosporin A, both MCP-1 and RANTES expression was down-regulated (PMID:15722361)
• reactive oxygen species stimulate RANKL expression via ERKs and the PKA-CREB pathway (PMID:15731115)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnfsf11	ENSDARG00000068141
mus_musculus	Tnfsf11	ENSMUSG00000022015
rattus_norvegicus	Tnfsf11	ENSRNOG00000071047

Paralogs (8): CD40LG (ENSG00000102245), FASLG (ENSG00000117560), TNFSF10 (ENSG00000121858), TNFSF14 (ENSG00000125735), TNFSF15 (ENSG00000181634), LTA (ENSG00000226979), LTB (ENSG00000227507), TNF (ENSG00000232810)

Protein

Protein identifiers

Tumor necrosis factor ligand superfamily member 11 — O14788 (reviewed: O14788)

Alternative names: Osteoclast differentiation factor, Osteoprotegerin ligand, Receptor activator of nuclear factor kappa-B ligand, TNF-related activation-induced cytokine

All UniProt accessions (3): O14788, Q54A98, Q5T9Y4

UniProt curated annotations — full annotation on UniProt →

Function. Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK. Osteoclast differentiation and activation factor. Augments the ability of dendritic cells to stimulate naive T-cell proliferation. May be an important regulator of interactions between T-cells and dendritic cells and may play a role in the regulation of the T-cell-dependent immune response. May also play an important role in enhanced bone-resorption in humoral hypercalcemia of malignancy. Induces osteoclastogenesis by activating multiple signaling pathways in osteoclast precursor cells, chief among which is induction of long lasting oscillations in the intracellular concentration of Ca (2+) resulting in the activation of NFATC1, which translocates to the nucleus and induces osteoclast-specific gene transcription to allow differentiation of osteoclasts. During osteoclast differentiation, in a TMEM64 and ATP2A2-dependent manner induces activation of CREB1 and mitochondrial ROS generation necessary for proper osteoclast generation.

Subunit / interactions. Homotrimer. Interacts with TNFRSF11B. Interacts with TNFRSF11A. Interacts with FBN1 (via N-terminal domain) in a Ca(+2)-dependent manner. Interacts with TNFAIP6 (via both Link and CUB domains).

Subcellular location. Cell membrane Cell membrane Cytoplasm Secreted.

Tissue specificity. Highest in the peripheral lymph nodes, weak in spleen, peripheral blood Leukocytes, bone marrow, heart, placenta, skeletal muscle, stomach and thyroid.

Post-translational modifications. The soluble form of isoform 1 derives from the membrane form by proteolytic processing. The cleavage may be catalyzed by ADAM17.

Disease relevance. Osteopetrosis, autosomal recessive 2 (OPTB2) [MIM:259710] A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. Deafness and blindness are generally thought to represent effects of pressure on nerves. OPTB2 is characterized by paucity of osteoclasts, suggesting a molecular defect in osteoclast development. The disease is caused by variants affecting the gene represented in this entry.

Induction. Up-regulated by T-cell receptor stimulation.

Similarity. Belongs to the tumor necrosis factor family.

Isoforms (3)

UniProt ID	Names	Canonical?
O14788-1	1	yes
O14788-2	2, SODF
O14788-3	3

RefSeq proteins (2): NP_003692, NP_143026 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006052	TNF_dom	Domain
IPR008983	Tumour_necrosis_fac-like_dom	Homologous_superfamily
IPR017355	TNF_ligand_10/11	Family

Pfam: PF00229

UniProt features (34 total): strand 13, chain 2, glycosylation site 2, splice variant 2, mutagenesis site 2, helix 2, topological domain 2, compositionally biased region 2, sequence variant 1, sequence conflict 1, transmembrane region 1, turn 1, domain 1, region of interest 1, site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3URF	X-RAY DIFFRACTION	2.7
5BNQ	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14788-F1	79.45	0.50

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 139–140 (cleavage)

Glycosylation sites (2): 171, 198

Mutagenesis-validated functional residues (2):

Position	Phenotype
223	reduces affinity for tnfrsf11b.
257	reduces affinity for tnfrsf11b.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-5668541	TNFR2 non-canonical NF-kB pathway
R-HSA-5669034	TNFs bind their physiological receptors
R-HSA-5676594	TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway
R-HSA-9856649	Transcriptional and post-translational regulation of MITF-M expression and activity

MSigDB gene sets: 569 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, GOBP_REGULATION_OF_ICOSANOID_SECRETION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_REGULATION_OF_PROSTAGLANDIN_SECRETION, GOBP_REGULATION_OF_ORGANIC_ACID_TRANSPORT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_MYELOID_CELL_DEVELOPMENT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE

GO Biological Process (44): negative regulation of transcription by RNA polymerase II (GO:0000122), ossification (GO:0001503), osteoclast proliferation (GO:0002158), monocyte chemotaxis (GO:0002548), immune response (GO:0006955), cell surface receptor signaling pathway (GO:0007166), JNK cascade (GO:0007254), positive regulation of gene expression (GO:0010628), cytokine-mediated signaling pathway (GO:0019221), calcium-mediated signaling (GO:0019722), osteoclast differentiation (GO:0030316), tumor necrosis factor-mediated signaling pathway (GO:0033209), mammary gland epithelial cell proliferation (GO:0033598), positive regulation of homotypic cell-cell adhesion (GO:0034112), osteoclast development (GO:0036035), paracrine signaling (GO:0038001), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of MAPK cascade (GO:0043410), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), tooth eruption (GO:0044691), bone resorption (GO:0045453), positive regulation of osteoclast differentiation (GO:0045672), positive regulation of bone resorption (GO:0045780), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of JNK cascade (GO:0046330), positive regulation of T cell activation (GO:0050870), positive regulation of corticotropin-releasing hormone secretion (GO:0051466), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), calcium ion homeostasis (GO:0055074), mammary gland alveolus development (GO:0060749), positive regulation of ERK1 and ERK2 cascade (GO:0070374), positive regulation of fever generation by positive regulation of prostaglandin secretion (GO:0071812), positive regulation of non-canonical NF-kappaB signal transduction (GO:1901224), positive regulation of intracellular signal transduction (GO:1902533), cellular response to leukemia inhibitory factor (GO:1990830), positive regulation of osteoclast development (GO:2001206), positive regulation of extrinsic apoptotic signaling pathway (GO:2001238), cell communication (GO:0007154), signal transduction (GO:0007165), animal organ morphogenesis (GO:0009887)

GO Molecular Function (7): cytokine activity (GO:0005125), tumor necrosis factor receptor binding (GO:0005164), identical protein binding (GO:0042802), signaling receptor binding (GO:0005102), protein binding (GO:0005515), tumor necrosis factor receptor superfamily binding (GO:0032813), receptor ligand activity (GO:0048018)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
TNFR2 non-canonical NF-kB pathway	2
Cytokine Signaling in Immune system	1
MITF-M-regulated melanocyte development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
signal transduction	2
MAPK cascade	2
intracellular signaling cassette	2
positive regulation of intracellular signal transduction	2
protein binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
multicellular organismal process	1
leukocyte proliferation	1
leukocyte chemotaxis	1
mononuclear cell migration	1
myeloid leukocyte migration	1
immune system process	1
response to stimulus	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
cell surface receptor signaling pathway	1
cellular response to cytokine stimulus	1
myeloid leukocyte differentiation	1
cytokine-mediated signaling pathway	1
cellular response to tumor necrosis factor	1
epithelial cell proliferation	1
mammary gland epithelium development	1
positive regulation of cell-cell adhesion	1
homotypic cell-cell adhesion	1
regulation of homotypic cell-cell adhesion	1
osteoclast differentiation	1
myeloid cell development	1
bone cell development	1
cell-cell signaling	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
regulation of MAPK cascade	1
odontogenesis	1
anatomical structure development	1
receptor ligand activity	1
tumor necrosis factor receptor superfamily binding	1

Protein interactions and networks

STRING

3332 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNFSF11	TNFRSF11A	Q9Y6Q6	999
TNFSF11	TNFRSF11B	O00300	997
TNFSF11	CSF1R	P07333	987
TNFSF11	TRAF6	Q9Y4K3	986
TNFSF11	ACP5	P13686	962
TNFSF11	NFATC1	O95644	942
TNFSF11	SOST	Q9BQB4	928
TNFSF11	SFRP1	Q8N474	925
TNFSF11	BGLAP	P02818	915
TNFSF11	CSF1	P09603	909
TNFSF11	LGR4	Q9BXB1	893
TNFSF11	CTSK	P43235	891
TNFSF11	RUNX2	Q13950	875
TNFSF11	PTH	P01270	875
TNFSF11	BMP2	P12643	864

IntAct

36 interactions, top by confidence:

A	B	Type	Score
TNFRSF11B	TNFSF11	psi-mi:“MI:0407”(direct interaction)	0.620
TNFSF11	TNFRSF11B	psi-mi:“MI:0407”(direct interaction)	0.620
TNFSF11	TNFRSF11A	psi-mi:“MI:0407”(direct interaction)	0.620
TNFAIP6	TNFSF11	psi-mi:“MI:0407”(direct interaction)	0.560
UPK2	TNFSF11	psi-mi:“MI:0915”(physical association)	0.560
TNFSF11	OLFM4	psi-mi:“MI:0915”(physical association)	0.560
BBS10	TNFSF11	psi-mi:“MI:0915”(physical association)	0.370
TNFSF11	PRXL2B	psi-mi:“MI:0915”(physical association)	0.370
DDAH2	TNFSF11	psi-mi:“MI:0915”(physical association)	0.370
TNFSF11	EEF1A1	psi-mi:“MI:0915”(physical association)	0.370
EZH2	TNFSF11	psi-mi:“MI:0915”(physical association)	0.370
TNFSF11	CEP126	psi-mi:“MI:0915”(physical association)	0.370
LMO4	TNFSF11	psi-mi:“MI:0915”(physical association)	0.370
TNFSF11	MBTPS1	psi-mi:“MI:0915”(physical association)	0.370
TNFSF11	MED24	psi-mi:“MI:0915”(physical association)	0.370
TNFSF11	PHAX	psi-mi:“MI:0915”(physical association)	0.370
PLK1	TNFSF11	psi-mi:“MI:0915”(physical association)	0.370
TNFSF11	SBF1	psi-mi:“MI:0915”(physical association)	0.370
TNFSF11	SNRNP35	psi-mi:“MI:0915”(physical association)	0.370
TMOD3	TNFSF11	psi-mi:“MI:0915”(physical association)	0.370
TNFSF11	TRMT2A	psi-mi:“MI:0915”(physical association)	0.370
ZC3HC1	TNFSF11	psi-mi:“MI:0915”(physical association)	0.370
TNFSF11	GOSR1	psi-mi:“MI:0914”(association)	0.350
ZC3H3	TNFSF11	psi-mi:“MI:0914”(association)	0.350

BioGRID (42): GALNT7 (Affinity Capture-MS), GOSR1 (Affinity Capture-MS), ATP5G1 (Affinity Capture-MS), ND1 (Affinity Capture-MS), DNAJB9 (Affinity Capture-MS), B4GALT7 (Affinity Capture-MS), TNFSF11 (Affinity Capture-MS), GOSR1 (Affinity Capture-MS), ATP5G1 (Affinity Capture-MS), DNAJB9 (Affinity Capture-MS), ND1 (Affinity Capture-MS), TNFSF11 (Affinity Capture-MS), TNFSF11 (Two-hybrid), TNFSF11 (Two-hybrid), SRC (Affinity Capture-Western)

ESM2 similar proteins: B8XY56, C0HKG5, C0HKG6, O00584, O14788, O43278, O61887, O80322, O80323, O80324, O80325, O97827, P04007, P08037, P12804, P61644, P83618, P93460, Q01796, Q0P4P2, Q14314, Q29RY7, Q38716, Q38717, Q40379, Q40381, Q40875, Q40965, Q40966, Q5XK91, Q640P2, Q6AX44, Q6UX71, Q75BW5, Q765H6, Q7M329, Q7M456, Q7SID5, Q8IUK5, Q8VCM7

Diamond homologs: O14788, O35235, P50592, Q5UBV8, Q6UY13, Q8K3Y7, Q9ESE2, O95150, P41047, P50591, Q9I8D8, Q9QYH9, O43557, P09225, P10154, P16599, P26445, P36940, P48023, P63306, P63307, P63308, Q06332, Q06600, Q5WR07, Q75N23, Q861W5, Q8JFG3, Q9BDN1, Q9BEA8, Q9JM09, Q9XT48, O35734, P01375, P04924, P19101, P29553, P33620, P51435, P59694

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
RUNX2	“up-regulates quantity by expression”	TNFSF11	“transcriptional regulation”
TNFSF11	up-regulates	TNFRSF11B	binding
TNFSF11	“up-regulates activity”	TNFRSF11A	binding
TNFSF11	up-regulates	Osteoclast_differentiation
denosumab	“down-regulates activity”	TNFSF11	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

138 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	66
Likely benign	49
Benign	10

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1684676	NM_003701.4(TNFSF11):c.929del (p.Ala310fs)	Pathogenic
6973	NM_003701.4(TNFSF11):c.532+4_532+8del	Pathogenic
6974	NM_003701.4(TNFSF11):c.596T>A (p.Met199Lys)	Pathogenic
6975	NM_003701.4(TNFSF11):c.828_829del (p.Val277fs)	Pathogenic
1526053	NM_003701.4(TNFSF11):c.667C>T (p.Arg223Ter)	Likely pathogenic

SpliceAI

738 predictions. Top by Δscore:

Variant	Effect	Δscore
13:42581121:CTCA:C	acceptor_loss	1.0000
13:42581123:CA:C	acceptor_loss	1.0000
13:42581124:A:AG	acceptor_gain	1.0000
13:42581124:A:AT	acceptor_loss	1.0000
13:42581124:AGAT:A	acceptor_gain	1.0000
13:42581124:AGATG:A	acceptor_gain	1.0000
13:42581125:G:GA	acceptor_gain	1.0000
13:42581125:GAT:G	acceptor_gain	1.0000
13:42581125:GATG:G	acceptor_gain	1.0000
13:42581125:GATGG:G	acceptor_gain	1.0000
13:42581292:AGGT:A	donor_loss	1.0000
13:42581293:GGT:G	donor_loss	1.0000
13:42581294:GTAA:G	donor_loss	1.0000
13:42581295:T:A	donor_loss	1.0000
13:42595176:GGC:G	donor_gain	1.0000
13:42600745:A:AG	acceptor_gain	1.0000
13:42600747:TTCA:T	acceptor_loss	1.0000
13:42600748:TCA:T	acceptor_loss	1.0000
13:42600749:CAG:C	acceptor_loss	1.0000
13:42600750:A:AG	acceptor_gain	1.0000
13:42600750:AG:A	acceptor_gain	1.0000
13:42600750:AGGA:A	acceptor_loss	1.0000
13:42600751:G:A	acceptor_loss	1.0000
13:42600751:G:GG	acceptor_gain	1.0000
13:42600751:GG:G	acceptor_gain	1.0000
13:42600751:GGA:G	acceptor_gain	1.0000
13:42600751:GGAA:G	acceptor_gain	1.0000
13:42600751:GGAAT:G	acceptor_gain	1.0000
13:42600793:GAAAG:G	donor_gain	1.0000
13:42600798:G:GA	donor_loss	1.0000

AlphaMissense

2078 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:42600952:T:C	L168P	0.999
13:42606523:T:A	W187R	0.999
13:42606523:T:C	W187R	0.999
13:42606525:G:C	W187C	0.999
13:42606525:G:T	W187C	0.999
13:42606581:T:C	L206P	0.999
13:42606632:G:C	R223P	0.999
13:42606890:G:A	G309E	0.999
13:42574487:T:C	C62R	0.998
13:42600946:C:A	A166D	0.998
13:42606628:T:C	F222L	0.998
13:42606629:T:C	F222S	0.998
13:42606630:T:A	F222L	0.998
13:42606630:T:G	F222L	0.998
13:42606677:T:C	L238P	0.998
13:42606812:T:C	L283S	0.998
13:42606889:G:A	G309R	0.998
13:42606889:G:C	G309R	0.998
13:42606889:G:T	G309W	0.998
13:42574475:G:C	G58R	0.997
13:42574476:G:A	G58D	0.997
13:42574490:A:C	S63R	0.997
13:42574492:C:A	S63R	0.997
13:42574492:C:G	S63R	0.997
13:42600948:C:G	H167D	0.997
13:42600952:T:A	L168H	0.997
13:42606604:T:G	Y214D	0.997
13:42606616:G:C	A218P	0.997
13:42606735:A:C	K257N	0.997
13:42606735:A:T	K257N	0.997

dbSNP variants (sampled 300 via entrez): RS1000018735 (13:42599905 C>A,T), RS1000079488 (13:42606160 T>C), RS1000087697 (13:42563818 T>A), RS1000266146 (13:42581707 T>C), RS1000442219 (13:42584478 C>T), RS1000575543 (13:42582134 T>G), RS1000575826 (13:42581700 C>G,T), RS1000578480 (13:42579607 A>G), RS1000630813 (13:42579305 G>A), RS1000656051 (13:42569031 G>A), RS1000721334 (13:42568354 T>A,C), RS1000730311 (13:42575158 G>A), RS1000763250 (13:42575543 C>G,T), RS1000972233 (13:42598384 T>C), RS1001019926 (13:42598682 G>A)

Disease associations

OMIM: gene MIM:602642 | disease phenotypes: MIM:259710

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive osteopetrosis 2	Strong	Autosomal recessive
autosomal recessive osteopetrosis	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autosomal recessive osteopetrosis 2	Definitive	AR

Mondo (3): autosomal recessive osteopetrosis 2 (MONDO:0009816), bone disorder (MONDO:0005381), autosomal recessive osteopetrosis (MONDO:0019026)

Orphanet (2): Autosomal recessive malignant osteopetrosis (Orphanet:667), Rare bone disease related to a common gene or pathway defect (Orphanet:364803)

HPO phenotypes

66 total (30 of 66 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000238	Hydrocephalus
HP:0000256	Macrocephaly
HP:0000303	Mandibular prognathia
HP:0000365	Hearing impairment
HP:0000388	Otitis media
HP:0000505	Visual impairment
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000649	Abnormality of visual evoked potentials
HP:0000670	Carious teeth
HP:0000684	Delayed eruption of teeth
HP:0000772	Abnormal rib morphology
HP:0000774	Narrow chest
HP:0000944	Abnormal metaphysis morphology
HP:0000978	Bruising susceptibility
HP:0000980	Pallor
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001293	Cranial nerve compression
HP:0001337	Tremor
HP:0001363	Craniosynostosis
HP:0001433	Hepatosplenomegaly
HP:0001510	Growth delay
HP:0001641	Abnormal pulmonary valve morphology
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001876	Pancytopenia
HP:0001903	Anemia

GWAS associations

29 associations (top):

Study	Trait	p-value
GCST000180_6	Bone mineral density (spine)	2.000000e-21
GCST000181_1	Bone mineral density (hip)	2.000000e-08
GCST000295_6	Bone mineral density (spine)	2.000000e-17
GCST000877_1	Bone mineral density	2.000000e-14
GCST000879_35	Crohn’s disease	5.000000e-10
GCST001050_8	Bone mineral density	4.000000e-06
GCST001593_1	Cortical thickness	4.000000e-09
GCST001870_2	Bone mineral density	4.000000e-14
GCST001870_6	Bone mineral density	5.000000e-06
GCST002276_9	Bone mineral density	2.000000e-15
GCST002424_5	C-reactive protein levels	4.000000e-06
GCST002494_13	Bone mineral density (paediatric, total body less head)	3.000000e-07
GCST002494_6	Bone mineral density (paediatric, total body less head)	8.000000e-09
GCST002496_3	Bone mineral density (paediatric, upper limb)	2.000000e-06
GCST002496_4	Bone mineral density (paediatric, upper limb)	3.000000e-09
GCST002496_8	Bone mineral density (paediatric, upper limb)	2.000000e-08
GCST004785_50	Vitiligo	5.000000e-09
GCST006016_24	Serum alkaline phosphatase levels	4.000000e-21
GCST006409_16	Allergic rhinitis	1.000000e-10
GCST006979_1100	Heel bone mineral density	3.000000e-09
GCST006979_1101	Heel bone mineral density	6.000000e-15
GCST006979_1102	Heel bone mineral density	3.000000e-12
GCST007014_6	Lumbar spine bone mineral density (trabecular)	1.000000e-11
GCST007015_15	Lumbar spine bone mineral density (integral)	4.000000e-09
GCST007800_87	Asthma (childhood onset)	2.000000e-07
GCST010984_34	Allergic disease (asthma, hay fever and/or eczema) (multivariate analysis)	4.000000e-12
GCST010985_42	Allergic disease (asthma, hay fever and/or eczema) (age of onset)	4.000000e-12
GCST90010715_15	Arthritis (juvenile idiopathic)	2.000000e-09
GCST90011900_106	Serum alkaline phosphatase levels	2.000000e-61

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004840	cortical thickness
EFO:0004458	C-reactive protein measurement
EFO:0004533	alkaline phosphatase measurement
EFO:0009270	heel bone mineral density
EFO:0007620	volumetric bone mineral density
EFO:0004847	age at onset

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001847	Bone Diseases	C05.116
C536059	Osteopetrosis, mild autosomal recessive form (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2364162 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs7984870	Efficacy	3	anastrozole;letrozole	Breast Neoplasms

PharmGKB variants

5 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2277438	TNFSF11		0.00	0
rs7984870	TNFSF11	3	6.25	1	anastrozole;letrozole
rs9533166	TNFSF11		0.00	0
rs9566990	TNFSF11		0.00	0
rs9594782	TNFSF11		0.00	0

ChEMBL bioactivities

36 potent at pChembl≥5 of 51 total, top 36 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.21	Kd	614	nM	CHEMBL4457006
6.04	Kd	920	nM	CHEMBL6163127
6.00	IC50	1000	nM	CHEMBL255489
5.85	IC50	1400	nM	CHEMBL4760595
5.73	IC50	1880	nM	CHEMBL3742191
5.72	IC50	1900	nM	CHEMBL4797434
5.70	IC50	2000	nM	CHEMBL4750116
5.66	Kd	2180	nM	CHEMBL3742191
5.60	IC50	2500	nM	CHEMBL4756975
5.57	Kd	2700	nM	CHEMBL4560856
5.57	IC50	2700	nM	CHEMBL4745590
5.56	Kd	2750	nM	CHEMBL4165601
5.55	Kd	2820	nM	CHEMBL3742150
5.54	IC50	2860	nM	CHEMBL3741720
5.51	Kd	3100	nM	CHEMBL4554653
5.46	Kd	3500	nM	CHEMBL4454307
5.45	Kd	3550	nM	CHEMBL3741922
5.40	Kd	3984	nM	CHEMBL6188552
5.34	Kd	4540	nM	CHEMBL4161101
5.34	Kd	4600	nM	CHEMBL3741778
5.34	Kd	4600	nM	CHEMBL3741720
5.34	Kd	4600	nM	CHEMBL3741275
5.31	Kd	4900	nM	CHEMBL4787527
5.30	Kd	5030	nM	CHEMBL5187481
5.29	IC50	5070	nM	CHEMBL3741275
5.29	IC50	5100	nM	CHEMBL4752672
5.28	Kd	5240	nM	CHEMBL4756975
5.27	Kd	5340	nM	CHEMBL3741437
5.20	Kd	6300	nM	CHEMBL4514088
5.19	IC50	6400	nM	CHEMBL4745373
5.18	Kd	6620	nM	CHEMBL4783826
5.14	Kd	7300	nM	CHEMBL4470163
5.07	Kd	8490	nM	CHEMBL3741883
5.06	Kd	8710	nM	CHEMBL4794699
5.03	Kd	9310	nM	CHEMBL3741278
5.01	Kd	9800	nM	CHEMBL1978769

PubChem BioAssay actives

34 with measured affinity, of 138 total; 30 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
N-(2,6-dimethylphenyl)-3-(1H-indol-3-yl)-2-(3-phenylpropylamino)propanamide	1598819: Binding affinity to human RANKL by surface plasmon resonance analysis	kd	0.6140	uM
6,7-dimethyl-3-[[methyl-[2-[methyl-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]amino]ethyl]amino]methyl]chromen-4-one	1676890: Inhibition of human RANKL-induced osteoclastogenesis in RANKL cultured mouse bone marrow cells assessed as reduction in RANKL/M-CSF-induced TRAP activity preincubated with RANKL for 1 hr followed by cell addition and subsequent media replenishment every 48 hrs for 4 days	ic50	1.0000	uM
[4-(benzenesulfonyl)piperazin-1-yl]-[1-(3-nitrophenyl)sulfonylindol-3-yl]methanone	1676890: Inhibition of human RANKL-induced osteoclastogenesis in RANKL cultured mouse bone marrow cells assessed as reduction in RANKL/M-CSF-induced TRAP activity preincubated with RANKL for 1 hr followed by cell addition and subsequent media replenishment every 48 hrs for 4 days	ic50	1.4000	uM
N-methyl-N-[2-[methyl-(4-oxochromene-3-carbonyl)amino]ethyl]-1-(3-nitrophenyl)indole-3-carboxamide	1676890: Inhibition of human RANKL-induced osteoclastogenesis in RANKL cultured mouse bone marrow cells assessed as reduction in RANKL/M-CSF-induced TRAP activity preincubated with RANKL for 1 hr followed by cell addition and subsequent media replenishment every 48 hrs for 4 days	ic50	1.8800	uM
N-methyl-N-[2-[methyl-(3-nitrophenyl)sulfonylamino]ethyl]-1-(3-nitrophenyl)sulfonylindole-3-carboxamide	1676890: Inhibition of human RANKL-induced osteoclastogenesis in RANKL cultured mouse bone marrow cells assessed as reduction in RANKL/M-CSF-induced TRAP activity preincubated with RANKL for 1 hr followed by cell addition and subsequent media replenishment every 48 hrs for 4 days	ic50	1.9000	uM
N-[2-[(4-cyanophenyl)sulfonyl-methylamino]ethyl]-N-methyl-1-(3-nitrophenyl)sulfonylindole-3-carboxamide	1676890: Inhibition of human RANKL-induced osteoclastogenesis in RANKL cultured mouse bone marrow cells assessed as reduction in RANKL/M-CSF-induced TRAP activity preincubated with RANKL for 1 hr followed by cell addition and subsequent media replenishment every 48 hrs for 4 days	ic50	2.0000	uM
3-[[2-[[1-(benzenesulfonyl)indol-3-yl]methyl-methylamino]ethyl-methylamino]methyl]chromen-4-one	1676890: Inhibition of human RANKL-induced osteoclastogenesis in RANKL cultured mouse bone marrow cells assessed as reduction in RANKL/M-CSF-induced TRAP activity preincubated with RANKL for 1 hr followed by cell addition and subsequent media replenishment every 48 hrs for 4 days	ic50	2.5000	uM
N-(2,6-dimethylphenyl)-3-(1H-indol-3-yl)-2-(3-phenylpropanoylamino)propanamide	1598819: Binding affinity to human RANKL by surface plasmon resonance analysis	kd	2.7000	uM
N-[2-[benzenesulfonyl(methyl)amino]ethyl]-N-methyl-1-(3-nitrophenyl)sulfonylindole-3-carboxamide	1676890: Inhibition of human RANKL-induced osteoclastogenesis in RANKL cultured mouse bone marrow cells assessed as reduction in RANKL/M-CSF-induced TRAP activity preincubated with RANKL for 1 hr followed by cell addition and subsequent media replenishment every 48 hrs for 4 days	ic50	2.7000	uM
(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(4R,7S,10S,13S,16S,19R)-19-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-7-benzyl-13-[(2S)-butan-2-yl]-10,16-bis(2-carboxyethyl)-6,9,12,15,18-pentaoxo-1,2-dithia-5,8,11,14,17-pentazacycloicosane-4-carbonyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-methylpentanoyl]amino]-3-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoic acid	1352220: Binding affinity to recombinant human sRANKL expressed in Escherichia coli by SPR assay	kd	2.7500	uM
N-methyl-N-[2-[methyl-(4-oxochromene-3-carbonyl)amino]ethyl]-5-nitro-1-[3-(trifluoromethyl)phenyl]indole-3-carboxamide	1676891: Binding affinity to GST-fused human RANKL extracellular domain (Lys159 to Asp317 residues) expressed in Escherichia coli BL21(DE3) pLysS by fluorescence spectrophotometric assay	kd	2.8200	uM
1-(benzenesulfonyl)-N-methyl-N-[2-[methyl-(4-oxochromene-3-carbonyl)amino]ethyl]indole-3-carboxamide	1676890: Inhibition of human RANKL-induced osteoclastogenesis in RANKL cultured mouse bone marrow cells assessed as reduction in RANKL/M-CSF-induced TRAP activity preincubated with RANKL for 1 hr followed by cell addition and subsequent media replenishment every 48 hrs for 4 days	ic50	2.8600	uM
2-[3-(4-chlorophenyl)propanoylamino]-N-(2,6-dimethylphenyl)-3-(1H-indol-3-yl)propanamide	1598819: Binding affinity to human RANKL by surface plasmon resonance analysis	kd	3.1000	uM
N-(2,6-dimethylphenyl)-3-(6-fluoro-1H-indol-3-yl)-2-(3-phenylpropanoylamino)propanamide	1598819: Binding affinity to human RANKL by surface plasmon resonance analysis	kd	3.5000	uM
1-(benzenesulfonyl)-N-[2-(naphthalene-2-carbonylamino)ethyl]indole-3-carboxamide	1676891: Binding affinity to GST-fused human RANKL extracellular domain (Lys159 to Asp317 residues) expressed in Escherichia coli BL21(DE3) pLysS by fluorescence spectrophotometric assay	kd	3.5500	uM
3-[(4R,7S,10S,13S,16S,19S,22S,25S,31S,34S,37R)-37-[[(2S)-2-acetamido-4-[[(2R,3R,4R,5S,6R)-3-acetamido-4,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]amino]-4-oxobutanoyl]amino]-34-(4-aminobutyl)-4-[[(2S)-1-amino-4-methyl-1-oxopentan-2-yl]carbamoyl]-7-benzyl-13-[(2S)-butan-2-yl]-25-(3-carbamimidamidopropyl)-10,16-bis(2-carboxyethyl)-22-[(4-hydroxyphenyl)methyl]-19-(2-methylpropyl)-6,9,12,15,18,21,24,27,30,33,36-undecaoxo-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35-undecazacyclooctatriacont-31-yl]propanoic acid	1352220: Binding affinity to recombinant human sRANKL expressed in Escherichia coli by SPR assay	kd	4.5400	uM
N-methyl-N-[2-[methyl-(4-oxochromene-3-carbonyl)amino]ethyl]-1-(3-nitrophenyl)sulfonylindole-3-carboxamide	1676891: Binding affinity to GST-fused human RANKL extracellular domain (Lys159 to Asp317 residues) expressed in Escherichia coli BL21(DE3) pLysS by fluorescence spectrophotometric assay	kd	4.6000	uM
6,7-dimethyl-3-[4-[1-[3-(trifluoromethyl)phenyl]indole-3-carbonyl]piperazine-1-carbonyl]chromen-4-one	1676891: Binding affinity to GST-fused human RANKL extracellular domain (Lys159 to Asp317 residues) expressed in Escherichia coli BL21(DE3) pLysS by fluorescence spectrophotometric assay	kd	4.6000	uM
3-[[2-[[1-(benzenesulfonyl)indol-3-yl]methyl-methylamino]ethyl-methylamino]methyl]-7-methylchromen-4-one	1676891: Binding affinity to GST-fused human RANKL extracellular domain (Lys159 to Asp317 residues) expressed in Escherichia coli BL21(DE3) pLysS by fluorescence spectrophotometric assay	kd	4.9000	uM
N-(2,6-dimethylphenyl)-1-(2-phenylethyl)-9H-pyrido[3,4-b]indole-3-carboxamide	1870960: Binding affinity to human RANKL assessed as dissociation constant by surface plasmon resonance method	kd	5.0300	uM
4-[4-[1-(3-nitrophenyl)sulfonylindole-3-carbonyl]piperazin-1-yl]sulfonylbenzonitrile	1676890: Inhibition of human RANKL-induced osteoclastogenesis in RANKL cultured mouse bone marrow cells assessed as reduction in RANKL/M-CSF-induced TRAP activity preincubated with RANKL for 1 hr followed by cell addition and subsequent media replenishment every 48 hrs for 4 days	ic50	5.1000	uM
[4-(imidazole-1-carbonyl)piperazin-1-yl]-[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methanone	1676891: Binding affinity to GST-fused human RANKL extracellular domain (Lys159 to Asp317 residues) expressed in Escherichia coli BL21(DE3) pLysS by fluorescence spectrophotometric assay	kd	5.3400	uM
N-[(4-chlorobenzoyl)amino]-N’-[4-[5-thiophen-2-yl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]sulfonylpyrrolidine-1-carboximidamide	1598832: Binding affinity to human RANKL measured after 1 hr by fluorescence assay	kd	6.3000	uM
[1-(3-nitrophenyl)sulfonylindol-3-yl]-[4-(3-nitrophenyl)sulfonylpiperazin-1-yl]methanone	1676890: Inhibition of human RANKL-induced osteoclastogenesis in RANKL cultured mouse bone marrow cells assessed as reduction in RANKL/M-CSF-induced TRAP activity preincubated with RANKL for 1 hr followed by cell addition and subsequent media replenishment every 48 hrs for 4 days	ic50	6.4000	uM
3-[[2-[[1-(benzenesulfonyl)indol-3-yl]methyl-methylamino]ethyl-methylamino]methyl]-6-methylchromen-4-one	1676891: Binding affinity to GST-fused human RANKL extracellular domain (Lys159 to Asp317 residues) expressed in Escherichia coli BL21(DE3) pLysS by fluorescence spectrophotometric assay	kd	6.6200	uM
[4-acetyloxy-2-(2,5-diacetyloxy-4-methoxyphenyl)-5-methoxyphenyl] acetate	1598832: Binding affinity to human RANKL measured after 1 hr by fluorescence assay	kd	7.3000	uM
3-[4-[[1-[3-(trifluoromethyl)phenyl]indol-3-yl]methyl]piperazine-1-carbonyl]chromen-4-one	1676891: Binding affinity to GST-fused human RANKL extracellular domain (Lys159 to Asp317 residues) expressed in Escherichia coli BL21(DE3) pLysS by fluorescence spectrophotometric assay	kd	8.4900	uM
3-[[2-[[1-(benzenesulfonyl)indol-3-yl]methyl-methylamino]ethyl-methylamino]methyl]-6,7-dimethylchromen-4-one	1676891: Binding affinity to GST-fused human RANKL extracellular domain (Lys159 to Asp317 residues) expressed in Escherichia coli BL21(DE3) pLysS by fluorescence spectrophotometric assay	kd	8.7100	uM
3-[4-[5-amino-1-(3-aminophenyl)indole-3-carbonyl]piperazine-1-carbonyl]chromen-4-one	1676891: Binding affinity to GST-fused human RANKL extracellular domain (Lys159 to Asp317 residues) expressed in Escherichia coli BL21(DE3) pLysS by fluorescence spectrophotometric assay	kd	9.3100	uM
benzyl N-[1-(2,6-dimethylanilino)-3-(1H-indol-3-yl)-1-oxopropan-2-yl]carbamate	1598819: Binding affinity to human RANKL by surface plasmon resonance analysis	kd	9.8000	uM

CTD chemical–gene interactions

97 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, affects cotreatment, increases expression	7
Lipopolysaccharides	decreases expression, affects reaction, increases expression, increases response to substance, affects cotreatment (+5 more)	4
Acetaminophen	affects cotreatment, decreases expression	3
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, increases expression	2
entinostat	increases expression, affects cotreatment	2
Zoledronic Acid	decreases expression, increases reaction, decreases reaction, affects expression	2
Arsenic Trioxide	decreases expression, affects cotreatment	2
Fulvestrant	decreases reaction, affects cotreatment, affects methylation, decreases expression	2
Panobinostat	affects cotreatment, increases expression	2
Arsenic	affects expression, affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	2
Chenodeoxycholic Acid	affects cotreatment, increases expression, decreases expression	2
Deoxycholic Acid	affects cotreatment, increases expression, decreases expression	2
Fluorides	affects cotreatment, decreases expression, affects expression	2
Glycochenodeoxycholic Acid	affects cotreatment, increases expression, decreases expression	2
Glycocholic Acid	decreases expression, affects cotreatment, increases expression	2
Glycodeoxycholic Acid	decreases expression, affects cotreatment, increases expression	2
Phenobarbital	affects expression, increases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Raloxifene Hydrochloride	decreases expression	2
Polyethylene	affects secretion, increases secretion	2
GSK-J4	decreases expression	1
GW 506033X	increases expression, increases reaction, increases response to substance, decreases reaction	1
N2 Dental Cement	increases expression	1
2-anisidine	increases expression	1
daidzein	decreases expression, decreases reaction	1
methylmercuric chloride	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	affects cotreatment, affects methylation, decreases methylation	1
myricitrin	decreases reaction, increases expression	1

ChEMBL screening assays

30 unique, capped per target: 30 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4147117	Binding	Binding affinity to recombinant human sRANKL expressed in Escherichia coli by SPR assay	Structure-based development of an osteoprotegerin-like glycopeptide that blocks RANKL/RANK interactions and reduces ovariectomy-induced bone loss in mice. — Eur J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B8R8	Abcam HCT 116 TNFSF11 KO	Cancer cell line	Male
CVCL_B9CA	Abcam MCF-7 TNFSF11 KO	Cancer cell line	Female
CVCL_B9TM	Abcam A-549 TNFSF11 KO	Cancer cell line	Male

Clinical trials (associated diseases)

4 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04525352	PHASE1	TERMINATED	A Trial to Evaluate Safety and Efficacy of RP-L401-0120 in Subjects With Infantile Malignant Osteopetrosis
NCT01166854	Not specified	RECRUITING	Characterization of Familial Myopathy and Paget Disease of Bone
NCT03527511	Not specified	COMPLETED	Effect of Active Vitamin D and Etelcalcetide on Human Osteoclasts in Patients With Chronic Kidney Disease
NCT06444503	Not specified	RECRUITING	Clinico-biological Collection of Bone, Calcium and Growth Plate Pathologies