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Tumor necrosis factor (ligand) superfamily, member 11

PDB rendering based on 1s55.
Available structures
PDB Ortholog search: PDBe, RCSB
External IDs OMIM602642 MGI1100089 HomoloGene2744 GeneCards: TNFSF11 Gene
RNA expression pattern
PBB GE TNFSF11 210643 at tn.png
PBB GE TNFSF11 211153 s at tn.png
More reference expression data
Species Human Mouse
Entrez 8600 21943
Ensembl ENSG00000120659 ENSMUSG00000022015
UniProt O14788 O35235
RefSeq (mRNA) NM_003701 NM_011613
RefSeq (protein) NP_003692 NP_035743
Location (UCSC) Chr 13:
43.14 – 43.18 Mb
Chr 14:
78.28 – 78.31 Mb
PubMed search [1] [2]
Not to be confused with RANK, the osteoclast cell-surface receptor that binds to RANKL.

Receptor activator of nuclear factor kappa-B ligand (RANKL), also known as tumor necrosis factor ligand superfamily member 11 (TNFSF11), TNF-related activation-induced cytokine (TRANCE), osteoprotegerin ligand (OPGL), and osteoclast differentiation factor (ODF), is a protein that in humans is encoded by the TNFSF11 gene.[1][2]

Critical for adequate bone metabolism, this surface-bound molecule (also known as CD254) found on osteoblasts serves to activate osteoclasts, which are the cells involved in bone resorption. Osteoclastic activity is triggered via the osteoblasts' surface-bound RANKL activating the osteoclasts' surface-bound receptor activator of nuclear factor kappa-B (RANK).


RANKL is 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. RANKL also has a function in the immune system, where it is expressed by T helper cells and is thought to be involved in dendritic cell maturation. 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 6 (TRAF6), which indicated this protein may have a role in the regulation of cell apoptosis.[3]

Animal models[edit]

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.[3]

Clinical significance[edit]


Overproduction of RANKL is implicated in a variety of degenerative bone diseases, such as rheumatoid arthritis and psoriatic arthritis. The first FDA-approved RANKL inhibitor was denosumab (to treat osteoporosis in post menopausal women).

Breast cancer[edit]

Treatment with medroxyprogesterone acetate (MPA), a synthetic progestin that is used in birth control pills and hormone replacement therapy, is associated with an increased risk of developing breast cancer. MPA causes a substantial induction of RANKL in mammary-gland epithelial cells while deletion of RANKL decreases the incidence MPA-induced breast cancer. Hence inhibition of RANKL has potential for the prevention and treatment of breast cancer.[4][5]

See also[edit]


  1. ^ Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, Kalachikov S, Cayani E, Bartlett FS, Frankel WN, Lee SY, Choi Y (October 1997). "TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells". J. Biol. Chem. 272 (40): 25190–4. doi:10.1074/jbc.272.40.25190. PMID 9312132. 
  2. ^ Anderson DM, Maraskovsky E, Billingsley WL, Dougall WC, Tometsko ME, Roux ER, Teepe MC, DuBose RF, Cosman D, Galibert L (November 1997). "A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function". Nature 390 (6656): 175–9. doi:10.1038/36593. PMID 9367155. 
  3. ^ a b "Entrez Gene: TNFSF11 tumor necrosis factor (ligand) superfamily, member 11". 
  4. ^ Schramek D, Leibbrandt A, Sigl V, Kenner L, Pospisilik JA, Lee HJ, Hanada R, Joshi PA, Aliprantis A, Glimcher L, Pasparakis M, Khokha R, Ormandy CJ, Widschwendter M, Schett G, Penninger JM (November 2010). "Osteoclast differentiation factor RANKL controls development of progestin-driven mammary cancer". Nature 468 (7320): 98–102. doi:10.1038/nature09387. PMID 20881962. 
  5. ^ Gonzalez-Suarez E, Jacob AP, Jones J, Miller R, Roudier-Meyer MP, Erwert R, Pinkas J, Branstetter D, Dougall WC (November 2010). "RANK ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis". Nature 468 (7320): 103–7. doi:10.1038/nature09495. PMID 20881963. 

Further reading[edit]

External links[edit]

This article incorporates text from the United States National Library of Medicine, which is in the public domain.