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Gene Review

TNFSF11  -  tumor necrosis factor (ligand) superfamily...

Homo sapiens

Synonyms: CD254, ODF, OPGL, OPTB2, Osteoclast differentiation factor, ...
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Disease relevance of TNFSF11


High impact information on TNFSF11

  • These data suggest that OPGL is an osteoclast differentiation and activation factor [1].
  • Receptor activator of NF-kappaB (RANK) and its ligand RANKL have been identified as essential factors involved in osteoclast development and bone remodeling, but their mechanism and interacting factors have not been fully characterized [8].
  • Thus RANK and RANKL seem to be important regulators of interactions between T cells and dendritic cells [9].
  • RANKL augments the ability of dendritic cells to stimulate naive T-cell proliferation in a mixed lymphocyte reaction, and increases the survival of RANK+ T cells generated with interleukin-4 and transforming growth factor (TGF)-beta [9].
  • RANKL, RANK, and OPG are three key molecules that regulate osteoclast recruitment and function [10].

Chemical compound and disease context of TNFSF11


Biological context of TNFSF11


Anatomical context of TNFSF11

  • OCPs arise from TNF-alpha-activated PBMCs that migrate to the inflamed synovium and subchondral bone, where they are exposed to unopposed RANKL and TNF-alpha [2].
  • RANKL expression was dramatically upregulated in the synovial lining layer, while OPG immunostaining was restricted to the endothelium [2].
  • In a coculture system, human myeloma cells up-regulated OPGL expression but strongly down-regulated OPG production in preosteoblastic (preOB) or stromal cells (BMSCs) of primary human BM at the mRNA and protein levels [19].
  • The present study investigated whether myeloma cells affect physiologic OPG/OPGL balance in the bone marrow (BM) environment [19].
  • Ten human myeloma cell lines and myeloma cells isolated from 26 consecutive patients with MM failed to express OPGL and only rarely produced a low amount of OPG [19].

Associations of TNFSF11 with chemical compounds

  • We here propose that beta1 integrin/FAK-mediated signaling on osteoblasts could be involved in ICAM-1- and RANKL-dependent osteoclast maturation [17].
  • Identification and Characterization of the Precursors Committed to Osteoclasts Induced by TNF-Related Activation-Induced Cytokine/Receptor Activator of NF-{kappa}B Ligand [20].
  • MATERIALS AND METHODS: We cultured human peripheral blood CD14(+) osteoclast precursors in the presence of RANKL, macrophage-colony stimulating factor (M-CSF), TNF-alpha, and dexamethasone to induce them to differentiate into osteoclasts [21].
  • Lipopolysaccharide supports survival and fusion of preosteoclasts independent of TNF-alpha, IL-1, and RANKL [22].
  • Estrogen, on the other hand, appears to inhibit production of RANKL and RANKL-stimulated osteoclastogenesis [23].
  • The relative protection against bone erosions in SpA cannot be explained by qualitative or quantitative differences in the synovial expression of RANKL, OPG, and RANK [24].

Physical interactions of TNFSF11

  • BACKGROUND: Osteoprotegerin (OPG) is involved in the regulation of bone turnover through binding to the receptor activator of nuclear factor kappaB ligand (RANKL), and has also been reported to be a potential survival factor for several different cell types [25].
  • Moreover, RANKL increased DNA binding of the essential osteoblast transcription factor cbfa-1 [26].
  • We thereby propose that the higher affinity adhesion via LFA-1/ICAM-1 is prerequisite for efficient function of membrane-bound ODF during osteoclast maturation [27].
  • Induction of RANKL expression and osteoclast maturation by the binding of fibroblast growth factor 2 to heparan sulfate proteoglycan on rheumatoid synovial fibroblasts [28].

Enzymatic interactions of TNFSF11

  • Using this antibody, we could demonstrate that MITF was rapidly and persistently phosphorylated upon stimulation of primary osteoclasts with RANKL and that phosphorylation of Ser(307) correlated with expression of the target gene tartrate-resistant acid phosphatase [29].

Regulatory relationships of TNFSF11

  • MCP-1 and chemokine RANTES (regulated on activation normal T cell expressed and secreted) permitted formation of TRAP-positive multinuclear cells in the absence of RANKL [18].
  • Importantly, sorted CD14(+)RANK(high) PBMNCs treated with recombinant RANKL and macrophage-colony stimulating factor (M-CSF) gave rise to approximately twice the number of osteoclasts than RANK(mid) or RANK(low) cells [30].
  • Suppression of AdipoR1 with siRNA abolished the adiponectin-regulated RANKL and OPG mRNA expression in osteoblasts [31].
  • Thus, RANKL significantly induced the phosphorylation of ERK1/2, p38 and IkappaB in RANK-positive osteosarcoma cells [32].
  • Importantly, Ocl development induced by RANKL or RANKL and tumor necrosis factor (TNF)-alpha was blocked with the novel p38 inhibitor 4-(3-(4-chlorophenyl)-5-(1-methylpiperidin-4-yl)-1H-pyrazol-4-yl)pyrimidine (SC-409) [33].

Other interactions of TNFSF11


Analytical, diagnostic and therapeutic context of TNFSF11

  • RESULTS: CD40 ligation of RASFs by CD40L-transfected L cells or activated T cells induced RANKL expression and enhanced osteoclastogenesis [34].
  • Northern blotting revealed that RANKL/ODF was highly expressed in all tissues from RA and GCT patients, but not from OA or OS patients [35].
  • The structure reveals that the RANKL extracellular domain is trimeric, which was also shown by analytical ultracentrifugation, and each subunit has a beta-strand jellyroll topology like the other members of the TNF family [36].
  • Materials and Methods: Real-time quantitative PCR and ELISA were used to detect RANKL and OPG mRNA and protein expression in cultured human osteoblasts [31].
  • A competitive RT-PCR assay for RANKL and OPG mRNA using artificial cDNA standards was developed and used for quantification [37].


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  2. Mechanisms of TNF-alpha- and RANKL-mediated osteoclastogenesis and bone resorption in psoriatic arthritis. Ritchlin, C.T., Haas-Smith, S.A., Li, P., Hicks, D.G., Schwarz, E.M. J. Clin. Invest. (2003) [Pubmed]
  3. Human myeloma cells stimulate the receptor activator of nuclear factor-kappa B ligand (RANKL) in T lymphocytes: a potential role in multiple myeloma bone disease. Giuliani, N., Colla, S., Sala, R., Moroni, M., Lazzaretti, M., La Monica, S., Bonomini, S., Hojden, M., Sammarelli, G., Barillè, S., Bataille, R., Rizzoli, V. Blood (2002) [Pubmed]
  4. Cooperation of TNF family members CD40 ligand, receptor activator of NF-kappa B ligand, and TNF-alpha in the activation of dendritic cells and the expansion of viral specific CD8+ T cell memory responses in HIV-1-infected and HIV-1-uninfected individuals. Yu, Q., Gu, J.X., Kovacs, C., Freedman, J., Thomas, E.K., Ostrowski, M.A. J. Immunol. (2003) [Pubmed]
  5. Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL. Sobacchi, C., Frattini, A., Guerrini, M.M., Abinun, M., Pangrazio, A., Susani, L., Bredius, R., Mancini, G., Cant, A., Bishop, N., Grabowski, P., Del Fattore, A., Messina, C., Errigo, G., Coxon, F.P., Scott, D.I., Teti, A., Rogers, M.J., Vezzoni, P., Villa, A., Helfrich, M.H. Nat. Genet. (2007) [Pubmed]
  6. Role of RANKL in bone diseases. Anandarajah, A.P. Trends Endocrinol. Metab. (2009) [Pubmed]
  7. Molecular Pathways: Osteoclast-Dependent and Osteoclast-Independent Roles of the RANKL/RANK/OPG Pathway in Tumorigenesis and Metastasis. Dougall, W.C. Clin. Cancer Res. (2012) [Pubmed]
  8. The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis. Wada, T., Nakashima, T., Oliveira-dos-Santos, A.J., Gasser, J., Hara, H., Schett, G., Penninger, J.M. Nat. Med. (2005) [Pubmed]
  9. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell function. Anderson, D.M., Maraskovsky, E., Billingsley, W.L., Dougall, W.C., Tometsko, M.E., Roux, E.R., Teepe, M.C., DuBose, R.F., Cosman, D., Galibert, L. Nature (1997) [Pubmed]
  10. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Suda, T., Takahashi, N., Udagawa, N., Jimi, E., Gillespie, M.T., Martin, T.J. Endocr. Rev. (1999) [Pubmed]
  11. Osteoprotegerin and RANKL in alcoholic liver cirrhosis. Fábrega, E., Orive, A., García-Suarez, C., García-Unzueta, M., Antonio Amado, J., Pons-Romero, F. Liver Int. (2005) [Pubmed]
  12. HIV envelope gp120-mediated regulation of osteoclastogenesis via receptor activator of nuclear factor kappa B ligand (RANKL) secretion and its modulation by certain HIV protease inhibitors through interferon-gamma/RANKL cross-talk. Fakruddin, J.M., Laurence, J. J. Biol. Chem. (2003) [Pubmed]
  13. The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Theoleyre, S., Wittrant, Y., Tat, S.K., Fortun, Y., Redini, F., Heymann, D. Cytokine Growth Factor Rev. (2004) [Pubmed]
  14. The HIV protease inhibitor ritonavir blocks osteoclastogenesis and function by impairing RANKL-induced signaling. Wang, M.W., Wei, S., Faccio, R., Takeshita, S., Tebas, P., Powderly, W.G., Teitelbaum, S.L., Ross, F.P. J. Clin. Invest. (2004) [Pubmed]
  15. Intraarticular corticosteroids decrease synovial RANKL expression in inflammatory arthritis. Makrygiannakis, D., af Klint, E., Catrina, S.B., Botusan, I.R., Klareskog, E., Klareskog, L., Ulfgren, A.K., Catrina, A.I. Arthritis Rheum. (2006) [Pubmed]
  16. Functional role for heat shock factors in the transcriptional regulation of human RANK ligand gene expression in stromal/osteoblast cells. Roccisana, J.L., Kawanabe, N., Kajiya, H., Koide, M., Roodman, G.D., Reddy, S.V. J. Biol. Chem. (2004) [Pubmed]
  17. Beta1 integrin/focal adhesion kinase-mediated signaling induces intercellular adhesion molecule 1 and receptor activator of nuclear factor kappaB ligand on osteoblasts and osteoclast maturation. Nakayamada, S., Okada, Y., Saito, K., Tamura, M., Tanaka, Y. J. Biol. Chem. (2003) [Pubmed]
  18. MCP-1 is induced by receptor activator of nuclear factor-{kappa}B ligand, promotes human osteoclast fusion, and rescues granulocyte macrophage colony-stimulating factor suppression of osteoclast formation. Kim, M.S., Day, C.J., Morrison, N.A. J. Biol. Chem. (2005) [Pubmed]
  19. Myeloma cells induce imbalance in the osteoprotegerin/osteoprotegerin ligand system in the human bone marrow environment. Giuliani, N., Bataille, R., Mancini, C., Lazzaretti, M., Barillé, S. Blood (2001) [Pubmed]
  20. Identification and Characterization of the Precursors Committed to Osteoclasts Induced by TNF-Related Activation-Induced Cytokine/Receptor Activator of NF-{kappa}B Ligand. Mochizuki, A., Takami, M., Kawawa, T., Suzumoto, R., Sasaki, T., Shiba, A., Tsukasaki, H., Zhao, B., Yasuhara, R., Suzawa, T., Miyamoto, Y., Choi, Y., Kamijo, R. J. Immunol. (2006) [Pubmed]
  21. Estrogen and testosterone use different cellular pathways to inhibit osteoclastogenesis and bone resorption. Michael, H., Härkönen, P.L., Väänänen, H.K., Hentunen, T.A. J. Bone Miner. Res. (2005) [Pubmed]
  22. Lipopolysaccharide supports survival and fusion of preosteoclasts independent of TNF-alpha, IL-1, and RANKL. Suda, K., Woo, J.T., Takami, M., Sexton, P.M., Nagai, K. J. Cell. Physiol. (2002) [Pubmed]
  23. Osteoprotegerin and its ligand: a new paradigm for regulation of osteoclastogenesis and bone resorption. Aubin, J.E., Bonnelye, E. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. (2000) [Pubmed]
  24. The abundant synovial expression of the RANK/RANKL/Osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation. Vandooren, B., Cantaert, T., Noordenbos, T., Tak, P.P., Baeten, D. Arthritis Rheum. (2008) [Pubmed]
  25. Expression of osteoprotegerin (OPG), TNF related apoptosis inducing ligand (TRAIL), and receptor activator of nuclear factor kappaB ligand (RANKL) in human breast tumours. Van Poznak, C., Cross, S.S., Saggese, M., Hudis, C., Panageas, K.S., Norton, L., Coleman, R.E., Holen, I. J. Clin. Pathol. (2006) [Pubmed]
  26. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulate aortic valve calcification. Kaden, J.J., Bickelhaupt, S., Grobholz, R., Haase, K.K., Sarikoç, A., Kiliç, R., Brueckmann, M., Lang, S., Zahn, I., Vahl, C., Hagl, S., Dempfle, C.E., Borggrefe, M. J. Mol. Cell. Cardiol. (2004) [Pubmed]
  27. Intercellular adhesion molecule 1 discriminates functionally different populations of human osteoblasts: characteristic involvement of cell cycle regulators. Tanaka, Y., Maruo, A., Fujii, K., Nomi, M., Nakamura, T., Eto, S., Minami, Y. J. Bone Miner. Res. (2000) [Pubmed]
  28. Induction of RANKL expression and osteoclast maturation by the binding of fibroblast growth factor 2 to heparan sulfate proteoglycan on rheumatoid synovial fibroblasts. Nakano, K., Okada, Y., Saito, K., Tanaka, Y. Arthritis Rheum. (2004) [Pubmed]
  29. Microphthalmia transcription factor is a target of the p38 MAPK pathway in response to receptor activator of NF-kappa B ligand signaling. Mansky, K.C., Sankar, U., Han, J., Ostrowski, M.C. J. Biol. Chem. (2002) [Pubmed]
  30. RANK Expression as a cell surface marker of human osteoclast precursors in peripheral blood, bone marrow, and giant cell tumors of bone. Atkins, G.J., Kostakis, P., Vincent, C., Farrugia, A.N., Houchins, J.P., Findlay, D.M., Evdokiou, A., Zannettino, A.C. J. Bone Miner. Res. (2006) [Pubmed]
  31. Adiponectin Stimulates RANKL and Inhibits OPG Expression in Human Osteoblasts Through the MAPK Signaling Pathway. Luo, X.H., Guo, L.J., Xie, H., Yuan, L.Q., Wu, X.P., Zhou, H.D., Liao, E.Y. J. Bone Miner. Res. (2006) [Pubmed]
  32. Human osteosarcoma cells express functional receptor activator of nuclear factor-kappa B. Mori, K., Le Goff, B., Berreur, M., Riet, A., Moreau, A., Blanchard, F., Chevalier, C., Guisle-Marsollier, I., Léger, J., Guicheux, J., Masson, M., Gouin, F., Rédini, F., Heymann, D. J. Pathol. (2007) [Pubmed]
  33. Inhibition of p38 mitogen-activated protein kinase prevents inflammatory bone destruction. Mbalaviele, G., Anderson, G., Jones, A., De Ciechi, P., Settle, S., Mnich, S., Thiede, M., Abu-Amer, Y., Portanova, J., Monahan, J. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  34. CD40 ligation of rheumatoid synovial fibroblasts regulates RANKL-mediated osteoclastogenesis: evidence of NF-kappaB-dependent, CD40-mediated bone destruction in rheumatoid arthritis. Lee, H.Y., Jeon, H.S., Song, E.K., Han, M.K., Park, S.I., Lee, S.I., Yun, H.J., Kim, J.R., Kim, J.S., Lee, Y.C., Kim, S.I., Kim, H.R., Choi, J.Y., Kang, I., Kim, H.Y., Yoo, W.H. Arthritis Rheum. (2006) [Pubmed]
  35. Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Takayanagi, H., Iizuka, H., Juji, T., Nakagawa, T., Yamamoto, A., Miyazaki, T., Koshihara, Y., Oda, H., Nakamura, K., Tanaka, S. Arthritis Rheum. (2000) [Pubmed]
  36. Crystal structure of the extracellular domain of mouse RANK ligand at 2.2-A resolution. Ito, S., Wakabayashi, K., Ubukata, O., Hayashi, S., Okada, F., Hata, T. J. Biol. Chem. (2002) [Pubmed]
  37. Skeletal changes in osteoprotegerin and receptor activator of nuclear factor-kappab ligand mRNA levels in primary hyperparathyroidism: effect of parathyroidectomy and association with bone metabolism. Stilgren, L.S., Rettmer, E., Eriksen, E.F., Hegedüs, L., Beck-Nielsen, H., Abrahamsen, B. Bone (2004) [Pubmed]
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