tumor necrosis factor ligand superfamily member 11; osteoclast differentiation factor; ODF; osteoprotegerin ligand; OPGL; receptor activator of nuclear factor kappa-B ligand; RANKL; TNF-related activation-induced cytokine; TRANCE; CD254; contains: tumor necrosis factor ligand superfamily member 11, membrane form; contains: tumor necrosis factor ligand superfamily member 11, soluble form (TNFSF11, OPGL, RANKL, TRANCE)

Function

• cytokine that regulates:
  • bone remodelling & resorption
  • lymph node organogenesis
  • lymphocyte development
  • interactions between T-cells & dendritic cells
• binds to TNFRSF11B/OPG & to TNFRSF11A/RANK
• osteoclast differentiation & activation factor
  • OPGL stimulates osteoclast activity
  • both forms of OPGL stimulate osteoclast activity
• augments the ability of dendritic cells to stimulate naive T-cell proliferation
• may regulate interactions between T-cells & dendritic cells & may play a role in regulation of the T-cell-dependent immune response
• the soluble form of isoform 1 derives from the membrane form by proteolytic processing (putative)
• the cleavage may be catalyzed by ADAM17
• activation of T-cells via protein kinase C, phosphoinositide 3-kinase & calcineurin-mediated signalling pathways increases OPGL expression
• systemic activation of T-cells results in an OPLG-mediated increase is osteoclast activity & bone loss blocked by osteoprotegerin
• TGF-beta inhibits OPGL

* see figure

Structure

• homotrimer (putative)
• belongs to the tumor necrosis factor family

Compartment

• tumor necrosis factor ligand superfamily member 11, soluble form: secreted (putative)
• isoform 1: cell membrane
• isoform 2: cytoplasm (putative)
• isoform 3: cell membrane
• OPGL is found on the surface of activated T-cells & is secreted as well

Alternative splicing

named isoforms=3

Expression

• highest expression in the peripheral lymph nodes
• weak expression in spleen, peripheral blood Leukocytes, bone marrow, heart, placenta, skeletal muscle, stomach & thyroid
• up-regulated by T-cell receptor stimulation
• the OPGL receptor, RANK, is expressed on:
  • chondrocytes
  • osteoclast precursors & mature osteoclasts

Pathology

• defects in TNFSF11 are the cause of osteopetrosis autosomal recessive type 2, characterized by paucity of osteoclasts, suggesting a molecular defect in osteoclast development
• it has been suggested that OPLG may be involved in the pathogenesis of rheumatoid arthritis
• may also play a role in enhanced bone-resorption in humoral hypercalcemia of malignancy

Pharmacology

• inhibited by monoclonal antibody denosumab (Prolia, Xgeva)

Comparative biology

• in mice, progestins stimulate production of RANKL, which in turn induces proliferation of mammary epithelial cells

More general terms

• tumor necrosis factor (TNF) family protein
• CD antigen

Additional terms

• denosumab (Prolia, Xgeva)
• tumor necrosis factor receptor superfamily member 11A; receptor activator of NF-KB; osteoclast differentiation factor receptor; ODFR; CD265 (TNFRSF11A, RANK)
• tumor necrosis factor receptor superfamily member 11B; osteoprotegerin; osteoclastogenesis inhibitory factor (TNFRSF11B OCIF OPG)

Database

• Entrez gene: http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=8600
• Kegg: http://www.genome.jp/dbget-bin/www_bget?hsa:8600
• OMIM: https://mirror.omim.org/entry/259710
• OMIM: https://mirror.omim.org/entry/602642
• UniProt: http://www.uniprot.org/uniprot/O14788.html