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Gene Review

Tnfsf11  -  tumor necrosis factor (ligand) superfamily...

Rattus norvegicus

Synonyms: ODF, OPGL, Opgl, Osteoclast differentiation factor, Osteoprotegerin ligand, ...
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Disease relevance of Tnfsf11

  • This finding indicated that T cell-mediated bone resorption is RANKL-dependent [1].
  • In humans, prominent T lymphocytes have been identified in periodontal disease, and diseased tissues showed elevated RANKL mRNA expression, as well as decreased OPG mRNA expression [1].
  • The purpose of this study was to evaluate Actinobacillus actinomycetemcomitans-responsive B lymphocytes in their level of RANKL expression and their effects on periodontal bone resorption [2].
  • Increased RANKL levels were associated with local (hind paw) and systemic (vertebral) osteopenia in both models [3].
  • We sought to determine whether serum RANKL was elevated early in disease progression and whether RANKL suppression could prevent both local and systemic bone loss in these models [3].
  • We hypothesized that prenatal RANKL inhibition via OPG overexpression would suppress bone resorption without influencing lymph node formation or subsequent immune responses [4].

High impact information on Tnfsf11

  • The OPGL receptor, RANK, is expressed on chondrocytes, osteoclast precursors and mature osteoclasts [5].
  • Here we report that activated T cells can directly trigger osteoclastogenesis through OPGL [5].
  • In addition, OPGL regulates lymph node organogenesis, lymphocyte development and interactions between T cells and dendritic cells in the immune system [5].
  • Mechanistically, OPGL binds specifically to mature OCs and rapidly (within 30 min) induces actin ring formation; a marked cytoskeletal rearrangement that necessarily precedes bone resorption [6].
  • This study demonstrates the significant attenuation of osteoblast function concurrent with increased expression of receptor activator of nuclear factor kappaB ligand (RANKL), a dominant signal for osteoclast recruitment, which is regulated differentially, depending on the size of the Ti particle [7].

Chemical compound and disease context of Tnfsf11


Biological context of Tnfsf11

  • OPG, a decoy receptor for RANKL, also binds to RANKL, and competitive binding of RANKL with RANK or OPG is thought to regulate bone metabolism [11].
  • MATERIALS AND METHODS: RANKL-induced RAW(264.7) cell differentiation into osteoclast-like cells was used to assess the effect of TPA on osteoclastogenesis [12].
  • METHODS AND RESULTS: Our main and novel findings were as follows: (1) In a rat model of postinfarction HF, we found persistently increased gene expression of OPG, RANK, and RANKL in the ischemic part of the left ventricle (LV) and, for OPG, in the nonischemic part that involved both noncardiomyocyte and in particular cardiomyocyte tissue [13].
  • This effect is associated with the up-regulation of RANKL expression [2].
  • CONCLUSIONS: In the early stages of arthritis, synovial RANKL is closely involved in osteoclastogenesis, and various changes in synovial cytokines, including down-regulation of OPG, probably accelerate osteoclast formation [14].

Anatomical context of Tnfsf11

  • In the ovariectomized rat bones, the expression of RANKL, RANK, and OPG mRNA increased, and high expression of OPG mRNA was induced in resting chondrocytes and osteocytes [11].
  • In the control 8-week-old male and sham-operated female rat bones, the expression of RANKL mRNA was detected in hypertrophic chondrocytes of the growth plate and some periosteal and endosteal mesenchymal cells [11].
  • Receptor activator of nuclear factor kappaB ligand (RANKL), a critical osteoclast differentiation factor, is expressed on T lymphocytes in human periodontal disease as determined by immunohistochemical and confocal microscopic analyses [1].
  • In other experiments, adoptive transfer of antigen-specific, RANKL-expressing B cells, and infection with the antigen-bearing Actinobaccillus actinomycetemcomitans gave rise to periodontal bone resorption, indicating that B cells also have the capacity to mediate bone resorption, probably via RANKL expression [1].
  • Detection of osteoprotegerin (OPG) and its ligand (RANKL) mRNA and protein in femur and tibia of the rat [15].

Associations of Tnfsf11 with chemical compounds


Regulatory relationships of Tnfsf11


Other interactions of Tnfsf11

  • The co-expression of OPG and RANKL in the same bone cell types confirms their strictly coupled action in the regulation of bone metabolism [15].
  • Using a quantitative, tartrate-resistant acid phosphatase (TRAP) assay, it was shown that ODF and CSF-1 promoted osteoclastogenesis in the spleen cell cultures, but the addition of the follicle cells inhibited this and returned the TRAP activities to those seen in cultures of spleen cells only [21].
  • The integrity of mRNA was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) for the housekeeping gene GAPDH, and that of primers specific for OPG and RANKL was determined by RT-PCR for these genes in material isolated from the UM106 rat cell line known to express both proteins [22].
  • Osteoclastogenesis stimulated by the receptor activator of nuclear factor kappa B (NF-kappaB) ligand/osteoclast differentiation factor was further augmented by mAb Kat1 in the presence of calcitonin [23].
  • Expression levels of EP4, BMP-2, and RANKL mRNAs increased at 7 days in the high-dose group [24].

Analytical, diagnostic and therapeutic context of Tnfsf11


  1. Immune response: the key to bone resorption in periodontal disease. Taubman, M.A., Valverde, P., Han, X., Kawai, T. J. Periodontol. (2005) [Pubmed]
  2. Bacterial-responsive B lymphocytes induce periodontal bone resorption. Han, X., Kawai, T., Eastcott, J.W., Taubman, M.A. J. Immunol. (2006) [Pubmed]
  3. RANKL is a marker and mediator of local and systemic bone loss in two rat models of inflammatory arthritis. Stolina, M., Adamu, S., Ominsky, M., Dwyer, D., Asuncion, F., Geng, Z., Middleton, S., Brown, H., Pretorius, J., Schett, G., Bolon, B., Feige, U., Zack, D., Kostenuik, P.J. J. Bone Miner. Res. (2005) [Pubmed]
  4. Continuous RANKL inhibition in osteoprotegerin transgenic mice and rats suppresses bone resorption without impairing lymphorganogenesis or functional immune responses. Stolina, M., Dwyer, D., Ominsky, M.S., Corbin, T., Van, G., Bolon, B., Sarosi, I., McCabe, J., Zack, D.J., Kostenuik, P. J. Immunol. (2007) [Pubmed]
  5. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Kong, Y.Y., Feige, U., Sarosi, I., Bolon, B., Tafuri, A., Morony, S., Capparelli, C., Li, J., Elliott, R., McCabe, S., Wong, T., Campagnuolo, G., Moran, E., Bogoch, E.R., Van, G., Nguyen, L.T., Ohashi, P.S., Lacey, D.L., Fish, E., Boyle, W.J., Penninger, J.M. Nature (1999) [Pubmed]
  6. The ligand for osteoprotegerin (OPGL) directly activates mature osteoclasts. Burgess, T.L., Qian, Y., Kaufman, S., Ring, B.D., Van, G., Capparelli, C., Kelley, M., Hsu, H., Boyle, W.J., Dunstan, C.R., Hu, S., Lacey, D.L. J. Cell Biol. (1999) [Pubmed]
  7. Effects of titanium particle size on osteoblast functions in vitro and in vivo. Choi, M.G., Koh, H.S., Kluess, D., O'Connor, D., Mathur, A., Truskey, G.A., Rubin, J., Zhou, D.X., Sung, K.L. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  8. Estradiol Protects against Ethanol-Induced Bone Loss by Inhibiting Up-Regulation of Receptor Activator of Nuclear Factor-{kappa}B Ligand in Osteoblasts. Chen, J.R., Haley, R.L., Hidestrand, M., Shankar, K., Liu, X., Lumpkin, C.K., Simpson, P.M., Badger, T.M., Ronis, M.J. J. Pharmacol. Exp. Ther. (2006) [Pubmed]
  9. Dried plum prevents bone loss in a male osteoporosis model via IGF-I and the RANK pathway. Franklin, M., Bu, S.Y., Lerner, M.R., Lancaster, E.A., Bellmer, D., Marlow, D., Lightfoot, S.A., Arjmandi, B.H., Brackett, D.J., Lucas, E.A., Smith, B.J. Bone (2006) [Pubmed]
  10. Receptor activator of NF-kappaB ligand protein expression in UMR-106 cells is differentially regulated by parathyroid hormone and calcitriol. Dossing, D.A., Stern, P.H. J. Cell. Biochem. (2005) [Pubmed]
  11. Expression profiles of receptor activator of nuclear factor kappaB ligand, receptor activator of nuclear factor kappaB, and osteoprotegerin messenger RNA in aged and ovariectomized rat bones. Ikeda, T., Utsuyama, M., Hirokawa, K. J. Bone Miner. Res. (2001) [Pubmed]
  12. 12-O-tetradecanoylphorbol-13-acetate (TPA) inhibits osteoclastogenesis by suppressing RANKL-induced NF-kappaB activation. Wang, C., Steer, J.H., Joyce, D.A., Yip, K.H., Zheng, M.H., Xu, J. J. Bone Miner. Res. (2003) [Pubmed]
  13. Dysregulated osteoprotegerin/RANK ligand/RANK axis in clinical and experimental heart failure. Ueland, T., Yndestad, A., Øie, E., Florholmen, G., Halvorsen, B., Frøland, S.S., Simonsen, S., Christensen, G., Gullestad, L., Aukrust, P. Circulation (2005) [Pubmed]
  14. Gene expression relevant to osteoclastogenesis in the synovium and bone marrow of mature rats with collagen-induced arthritis. Kishimoto, Y., Fukumoto, S., Nishihara, S., Mizumura, H., Hirai, K., Teshima, R. Rheumatology (Oxford, England) (2004) [Pubmed]
  15. Detection of osteoprotegerin (OPG) and its ligand (RANKL) mRNA and protein in femur and tibia of the rat. Silvestrini, G., Ballanti, P., Patacchioli, F., Leopizzi, M., Gualtieri, N., Monnazzi, P., Tremante, E., Sardella, D., Bonucci, E. J. Mol. Histol. (2005) [Pubmed]
  16. Nitric oxide donor increases osteoprotegerin production and osteoclastogenesis inhibitory activity in bone marrow stromal cells from ovariectomized rats. Wang, F.S., Wang, C.J., Chen, Y.J., Huang, Y.T., Huang, H.C., Chang, P.R., Sun, Y.C., Yang, K.D. Endocrinology (2004) [Pubmed]
  17. Upregulation of receptor activator of nuclear factor-kappaB ligand expression in the thymic subcapsular, paraseptal, perivascular, and medullary epithelial cells during thymus regeneration. Lee, H.W., Kim, B.S., Kim, H.J., Lee, C.W., Yoo, H.J., Kim, J.B., Yoon, S. Histochem. Cell Biol. (2005) [Pubmed]
  18. Molecular and functional expression of voltage-operated calcium channels during osteogenic differentiation of human mesenchymal stem cells. Zahanich, I., Graf, E.M., Heubach, J.F., Hempel, U., Boxberger, S., Ravens, U. J. Bone Miner. Res. (2005) [Pubmed]
  19. Chronology and regulation of gene expression of RANKL in the rat dental follicle. Liu, D., Yao, S., Pan, F., Wise, G.E. Eur. J. Oral Sci. (2005) [Pubmed]
  20. Inhibition of histone deacetylase suppresses osteoclastogenesis and bone destruction by inducing IFN-beta production. Nakamura, T., Kukita, T., Shobuike, T., Nagata, K., Wu, Z., Ogawa, K., Hotokebuchi, T., Kohashi, O., Kukita, A. J. Immunol. (2005) [Pubmed]
  21. Inhibition of osteoclastogenesis by the secretion of osteoprotegerin in vitro by rat dental follicle cells and its implications for tooth eruption. Wise, G.E., Yao, S., Zhang, Q., Ren, Y. Arch. Oral Biol. (2002) [Pubmed]
  22. Expression of mRNA for osteoprotegerin and receptor activator of nuclear factor kappa beta ligand (RANKL) during root resorption induced by the application of heavy orthodontic forces on rat molars. Low, E., Zoellner, H., Kharbanda, O.P., Darendeliler, M.A. American journal of orthodontics and dentofacial orthopedics : official publication of the American Association of Orthodontists, its constituent societies, and the American Board of Orthodontics. (2005) [Pubmed]
  23. Osteoclast differentiation antigen, distinct from receptor activator of nuclear factor kappa B, is involved in osteoclastogenesis under calcitonin-regulated conditions. Kukita, T., Kukita, A., Watanabe, T., Iijima, T. J. Endocrinol. (2001) [Pubmed]
  24. Prostaglandin E2 receptor (EP4) selective agonist (ONO-4819.CD) accelerates bone repair of femoral cortex after drill-hole injury associated with local upregulation of bone turnover in mature rats. Tanaka, M., Sakai, A., Uchida, S., Tanaka, S., Nagashima, M., Katayama, T., Yamaguchi, K., Nakamura, T. Bone (2004) [Pubmed]
  25. Osteoprotegerin reduces osteoclast numbers and prevents bone erosion in collagen-induced arthritis. Romas, E., Sims, N.A., Hards, D.K., Lindsay, M., Quinn, J.W., Ryan, P.F., Dunstan, C.R., Martin, T.J., Gillespie, M.T. Am. J. Pathol. (2002) [Pubmed]
  26. Selective blockade of voltage-gated potassium channels reduces inflammatory bone resorption in experimental periodontal disease. Valverde, P., Kawai, T., Taubman, M.A. J. Bone Miner. Res. (2004) [Pubmed]
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