Advertisement

Functional Genetic and Genomic Analysis of Modeled Arthritis

  • Eleni Douni
  • Maria Armaka
  • Dimitris L. Kontoyiannis
  • George Kollias
Part of the Advances in Experimental Medicine and Biology book series (volume 602)

Rheumatoid Arthritis (RA) is a chronic inflammatory disease, where pathological interactions between synovial fibroblasts, inflammatory infiltrates and osteoclasts mediate destruction of the inflamed joint. RA and other inflammatory bone diseases illustrate the close link between bone biology and immunology. There is growing evidence that certain molecules regulate both the skeletal and immune systems. Among these factors, tumor necrosis factor (TNF) has received great attention because of its position at the apex of the pro-inflammatory cytokine cascade, which is responsible for the development of inflammatory diseases such as RA and inflammatory bowel disease (IBD). TNF is expressed at high levels in inflamed synovium from RA patients (Saxne, Palladino, Heinegard, et al. 1988; Brennan, Chantry, Jackson, et al. 1989; Firestein, Alvaro-Gracia, and Maki 1990; Feldmann, Brennan, and Maini 1996) where it has pleiotropic functions such as the induction of joint inflammation, the proliferation of synovial fibroblasts (SFs) (Butler, Piccoli, Hart, et al. 1988), the destruction of cartilage by induction of collagenase (Dayer, Beutler, and Cerami 1985) and inhibition of proteoglycan synthesis by articular chondrocytes (Saklatvala 1986). In addition, TNF has a central role in bone pathophysiology by stimulating osteoclastogenesis and bone resorption, while stimultaneously inhibiting the function of bone-forming osteoblasts (Nanes 2003). Experimental studies in animal models of arthritis offer critical information regarding the specific function of TNF and its receptors, TNFRI and TNFRII (Douni, Akassoglou, Alexopoulou, et al. 1995). Particularly, transgenic mice overexpressing human TNF developed an erosive inflammatory arthritis closely resembling human RA (Keffer, Probert, Cazlaris, et al. 1991) and foreshadowed the remarkable effectiveness of anti-TNF therapy in RA (Elliott, Maini, Feldmann, et al. 1993). In this review, we describe the cellular and molecular pathways involved in the pathogenesis of TNF-mediated arthritis in animal models generated by our research group in the past.

Keywords

Rheumatoid Arthritis Tumor Necrosis Factor Synovial Fibroblast Model Arthritis Mature Osteoclast 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Abu-Amer, Y., J. Erdmann, L. Alexopoulou, G. Kollias, F.P. Ross, and S.L. Teitelbaum. 2000. Tumor necrosis factor receptors types 1 and 2 differentially regulate osteoclastogenesis. J Biol Chem 275: 27307–27310.PubMedGoogle Scholar
  2. Aidinis, V., P. Carninci, M. Armaka, W. Witke, V. Harokopos, N. Pavelka, D. Koczan, C. Argyropoulos, M.M. Thwin, S. Moller, W. Kazunori, P. Gopalakrishnakone, P. Ricciardi-Castagnoli, H.J. Thiesen, Y. Hayashizaki, and G. Kollias. 2005. Cytoskeletal rearrangements in synovial fibroblasts as a novel pathophysiological determinant of modeled rheumatoid arthritis. PLoS Genet 1: e48.CrossRefPubMedGoogle Scholar
  3. Alonzi, T., E. Fattori, D. Lazzaro, P. Costa, L. Probert, G. Kollias, F. De Benedetti, V. Poli, and G. Ciliberto. 1998. Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med 187: 461–468.CrossRefPubMedGoogle Scholar
  4. Beardmore, V.A., H.J. Hinton, C. Eftychi, M. Apostolaki, M. Armaka, J. Darragh, J. McIlrath, J.M. Carr, L.J. Armit, C. Clacher, L. Malone, G. Kollias, and J.S. Arthur. 2005. Generation and characterization of p38beta (MAPK11) gene-targeted mice. Mol Cell Biol 25: 10454–10464.CrossRefPubMedGoogle Scholar
  5. Brennan, F.M., D. Chantry, A. Jackson, R. Maini, and M. Feldmann. 1989. Inhibitory effect of TNF alpha antibodies on synovial cell interleukin-1 production in rheumatoid arthritis. Lancet 2: 244–247.CrossRefPubMedGoogle Scholar
  6. Brentano, F., D. Kyburz, O. Schorr, R. Gay, and S. Gay. 2005. The role of Toll-like receptor signalling in the pathogenesis of arthritis. Cell Immunol 233: 90–96.CrossRefPubMedGoogle Scholar
  7. Buckley, C.D., D. Pilling, J.M. Lord, A.N. Akbar, D. Scheel-Toellner, and M. Salmon. 2001. Fibroblasts regulate the switch from acute resolving to chronic persistent inflammation. Trends Immunol 22: 199–204.CrossRefPubMedGoogle Scholar
  8. Butler, D.M., D.S. Piccoli, P.H. Hart, and J.A. Hamilton. 1988. Stimulation of human synovial fibroblast DNA synthesis by recombinant human cytokines. J Rheumatol 15: 1463–1470.PubMedGoogle Scholar
  9. Butler, D.M., T. Leizer, and J.A. Hamilton. 1989. Stimulation of human synovial fibroblast DNA synthesis by platelet-derived growth factor and fibroblast growth factor. Differences to the activation by IL-1. J Immunol 142: 3098–3103.PubMedGoogle Scholar
  10. Carballo, E., W.S. Lai, and P.J. Blackshear. 1998. Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science 281: 1001–1005.CrossRefPubMedGoogle Scholar
  11. Cenci, S., M.N. Weitzmann, C. Roggia, N. Namba, D. Novack, J. Woodring, and R. Pacifici. 2000. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha. J Clin Invest 106: 1229–1237.CrossRefPubMedGoogle Scholar
  12. Collin-Osdoby, P., L. Rothe, F. Anderson, M. Nelson, W. Maloney, and P. Osdoby. 2001. Receptor activator of NF-kappa B and osteoprotegerin expression by human microvascular endothelial cells, regulation by inflammatory cytokines, and role in human osteoclastogenesis. J Biol Chem 276: 20659–20672.CrossRefPubMedGoogle Scholar
  13. Dayer, J.M., B. Beutler, and A. Cerami. 1985. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J Exp Med. 162: 2163–2168.CrossRefPubMedGoogle Scholar
  14. Dougall, W.C., M. Glaccum, K. Charrier, K. Rohrbach, K. Brasel, T. De Smedt, E. Daro, J. Smith, M.E. Tometsko, C.R. Maliszewski, A. Armstrong, V. Shen, S. Bain, D. Cosman, D. Anderson, P.J. Morrissey, J.J. Peschon, and J. Schuh. 1999. RANK is essential for osteoclast and lymph node development. Genes Dev 13: 2412–2424.CrossRefPubMedGoogle Scholar
  15. Douni, E., and G. Kollias. 1998. A critical role of the p75 tumor necrosis factor receptor (p75TNF-R) in organ inflammation independent of TNF, lymphotoxin alpha, or the p55TNF-R. J Exp Med 188: 1343–1352.CrossRefPubMedGoogle Scholar
  16. Douni, E., K. Akassoglou, L. Alexopoulou, S. Georgopoulos, S. Haralambous, S. Hill, G. Kassiotis, D. Kontoyiannis, M. Pasparakis, D. Plows, L. Probert, and G. Kollias. 1995. Transgenic and knockout analyses of the role of TNF in immune regulation and disease pathogenesis. J Inflamm 47: 27–38.PubMedGoogle Scholar
  17. Douni, E., P.P. Sfikakis, S. Haralambous, P. Fernandes, and G. Kollias. 2004. Attenuation of inflammatory polyarthritis in TNF transgenic mice by diacerein: comparative analysis with dexamethasone, methotrexate and anti-TNF protocols. Arthritis Res Ther 6: R65–R72.CrossRefPubMedGoogle Scholar
  18. Elliott, M.J., R.N. Maini, M. Feldmann, A. Long-Fox, P. Charles, P. Katsikis, F.M. Brennan, J. Walker, H. Bijl, J. Ghrayeb, et al. 1993. Treatment of rheumatoid arthritis with chimeric monoclonal antibodies to tumor necrosis factor alpha. Arthritis Rheum 36: 1681–1690.CrossRefPubMedGoogle Scholar
  19. Feldmann, M., F.M. Brennan, and R.N. Maini. 1996. Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14: 397–440.CrossRefPubMedGoogle Scholar
  20. Firestein, G.S., and N.J. Zvaifler. 2002. How important are T cells in chronic rheumatoid synovitis? II. T cell-independent mechanisms from beginning to end. Arthritis Rheum 46: 298–308.CrossRefPubMedGoogle Scholar
  21. Firestein, G.S., J.M. Alvaro-Gracia, and R. Maki. 1990. Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J Immunol 144: 3347–3353.PubMedGoogle Scholar
  22. Franz, J.K., T. Pap, K.M. Hummel, M. Nawrath, W.K. Aicher, Y. Shigeyama, U. Muller-Ladner, R.E. Gay, and S. Gay. 2000. Expression of sentrin, a novel antiapoptotic molecule, at sites of synovial invasion in rheumatoid arthritis. Arthritis Rheum 43: 599–607.CrossRefPubMedGoogle Scholar
  23. Geiler, T., J. Kriegsmann, G.M. Keyszer, R.E. Gay, and S. Gay. 1994. A new model for rheumatoid arthritis generated by engraftment of rheumatoid synovial tissue and normal human cartilage into SCID mice. Arthritis Rheum 37: 1664–1671.CrossRefPubMedGoogle Scholar
  24. Goldring, S.R. 2003. Inflammatory mediators as essential elements in bone remodeling. Calcif Tissue Int 73: 97–100.CrossRefPubMedGoogle Scholar
  25. Gortz, B., S. Hayer, B. Tuerck, J. Zwerina, J.S. Smolen, and G. Schett. 2005. Tumour necrosis factor activates the mitogen-activated protein kinases p38alpha and ERK in the synovial membrane in vivo. Arthritis Res Ther 7: R1140–1147.CrossRefPubMedGoogle Scholar
  26. Hofbauer, L.C., D.L. Lacey, C.R. Dunstan, T.C. Spelsberg, B.L. Riggs, and S. Khosla. 1999. Interleukin-1beta and tumor necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 25: 255–259.CrossRefPubMedGoogle Scholar
  27. Kanematsu, M., T. Sato, H. Takai, K. Watanabe, K. Ikeda, and Y. Yamada. 2000. Prostaglandin E2 induces expression of receptor activator of nuclear factor-kappa B ligand/osteoprotegrin ligand on pre-B cells: implications for accelerated osteoclastogenesis in estrogen deficiency. J Bone Miner Res 15: 1321–1329.CrossRefPubMedGoogle Scholar
  28. Karsenty, G. 2003. The complexities of skeletal biology. Nature 423: 316–318.CrossRefPubMedGoogle Scholar
  29. Katsanou, V., O. Papadaki, S. Milatos, P.J. Blackshear, P. Anderson, G. Kollias, and D.L. Kontoyiannis. 2005. HuR as a negative posttranscriptional modulator in inflammation. Mol Cell 19: 777–789.CrossRefPubMedGoogle Scholar
  30. Keffer, J., L. Probert, H. Cazlaris, S. Georgopoulos, E. Kaslaris, D. Kioussis, and G. Kollias. 1991. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. Embo J 10: 4025–4031.PubMedGoogle Scholar
  31. Kim, N., P.R. Odgren, D.K. Kim, S.C. Marks, Jr., and Y. Choi. 2000. Diverse roles of the tumor necrosis factor family member TRANCE in skeletal physiology revealed by TRANCE deficiency and partial rescue by a lymphocyte-expressed TRANCE transgene. Proc Natl Acad Sci USA 97: 10905–10910.CrossRefPubMedGoogle Scholar
  32. Kim, N., Y. Kadono, M. Takami, J. Lee, S.H. Lee, F. Okada, J.H. Kim, T. Kobayashi, P.R. Odgren, H. Nakano, W.C. Yeh, S.K. Lee, J.A. Lorenzo, and Y. Choi. 2005. Osteoclast differentiation independent of the TRANCE-RANK-TRAF6 axis. J Exp Med 202: 589–595.CrossRefPubMedGoogle Scholar
  33. Koller, M., S. Hayer, K. Redlich, R. Ricci, J.P. David, G. Steiner, J.S. Smolen, E.F. Wagner, and G. Schett. 2005. JNK1 is not essential for TNF-mediated joint disease. Arthritis Res Ther 7: R166–R173.CrossRefPubMedGoogle Scholar
  34. Kontoyiannis, D., and G. Kollias. 2000. Fibroblast biology: Synovial fibroblasts in rheumatoid arthritis – leading role or chorus line? Arthritis Res 2: 342–343.CrossRefPubMedGoogle Scholar
  35. Kontoyiannis, D., M. Pasparakis, T.T. Pizarro, F. Cominelli, and G. Kollias. 1999. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 10: 387–398.CrossRefPubMedGoogle Scholar
  36. Kontoyiannis, D., G. Boulougouris, M. Manoloukos, M. Armaka, M. Apostolaki, T. Pizarro, A. Kotlyarov, I. Forster, R. Flavell, M. Gaestel, P. Tsichlis, F. Cominelli, and G. Kollias. 2002. Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn’s-like inflammatory bowel disease. J Exp Med 196: 1563–1574.CrossRefPubMedGoogle Scholar
  37. Lam, J., S. Takeshita, J.E. Barker, O. Kanagawa, F.P. Ross, and S.L. Teitelbaum. 2000. TNF-alpha induces osteoclastogenesis by direct stimulation of macrophages exposed to permissive levels of RANK ligand. J Clin Invest 106: 1481–1488.CrossRefPubMedGoogle Scholar
  38. Lewis, M., L.A. Tartaglia, A. Lee, G.L. Bennett, G.C. Rice, G.H. Wong, E.Y. Chen, and D.V. Goeddel. 1991. Cloning and expression of cDNAs for two distinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. Proc Natl Acad Sci USA 88: 2830–2834.CrossRefPubMedGoogle Scholar
  39. Li, P., E.M. Schwarz, R.J. O’Keefe, L. Ma, B.F. Boyce, and L. Xing. 2004a. RANK signaling is not required for TNF alpha-mediated increase in CD11(hi) osteoclast precursors but is essential for mature osteoclast formation in TNF alpha-mediated inflammatory arthritis. J Bone Miner Res 19: 207–213.CrossRefPubMedGoogle Scholar
  40. Li, P., E.M. Schwarz, R.J. O’Keefe, L. Ma, R.J. Looney, C.T. Ritchlin, B.F. Boyce, and L. Xing. 2004b. Systemic tumor necrosis factor alpha mediates an increase in peripheral CD11bhigh osteoclast precursors in tumor necrosis factor alpha-transgenic mice. Arthritis Rheum 50: 265–276.CrossRefPubMedGoogle Scholar
  41. Muller-Ladner, U., J. Kriegsmann, B.N. Franklin, S. Matsumoto, T. Geiler, R.E. Gay, and S. Gay. 1996. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am J Pathol 149: 1607–1615.PubMedGoogle Scholar
  42. Nakano, K., Y. Okada, K. Saito, and Y. Tanaka. 2004. Induction of RANKL expression and osteoclast maturation by the binding of fibroblast growth factor 2 to heparan sulfate proteoglycan on rheumatoid synovial fibroblasts. Arthritis Rheum 50: 2450–2458.CrossRefPubMedGoogle Scholar
  43. Nanes, M.S. 2003. Tumor necrosis factor-alpha: molecular and cellular mechanisms in skeletal pathology. Gene 321: 1–15.CrossRefPubMedGoogle Scholar
  44. Pap, T., J.K. Franz, K.M. Hummel, E. Jeisy, R. Gay, and S. Gay. 2000. Activation of synovial fibroblasts in rheumatoid arthritis: lack of expression of the tumour suppressor PTEN at sites of invasive growth and destruction. Arthritis Res 2: 59–64.CrossRefPubMedGoogle Scholar
  45. Pap, T., U. Móller-Ladner, R.E. Gay, and S. Gay. 2000. Fibroblast biology: role of synovial fibroblasts in the pathogenesis of rheumatoid arthritis. Arthritis Res 2: 361–367.CrossRefPubMedGoogle Scholar
  46. Pap, T., M. Nawrath, J. Heinrich, M. Bosse, A. Baier, K.M. Hummel, P. Petrow, S. Kuchen, B.A. Michel, R.E. Gay, U. Muller-Ladner, K. Moelling, and S. Gay. 2004. Cooperation of Ras- and c-Myc-dependent pathways in regulating the growth and invasiveness of synovial fibroblasts in rheumatoid arthritis. Arthritis Rheum 50: 2794–2802.CrossRefPubMedGoogle Scholar
  47. Pasparakis, M., L. Alexopoulou, V. Episkopou, and G. Kollias. 1996. Immune and inflammatory responses in TNF alpha-deficient mice: a critical requirement for TNF alpha in the formation of primary B cell follicles, follicular dendritic cell networks and germinal centers, and in the maturation of the humoral immune response. J Exp Med 184: 1397–1411.CrossRefPubMedGoogle Scholar
  48. Phillips, K., N. Kedersha, L. Shen, P.J. Blackshear, and P. Anderson. 2004. Arthritis suppressor genes TIA-1 and TTP dampen the expression of tumor necrosis factor alpha, cyclooxygenase 2, and inflammatory arthritis. Proc Natl Acad Sci USA 101: 2011–2016.CrossRefPubMedGoogle Scholar
  49. Piecyk, M., S. Wax, A.R. Beck, N. Kedersha, M. Gupta, B. Maritim, S. Chen, C. Gueydan, V. Kruys, M. Streuli, and P. Anderson. 2000. TIA-1 is a translational silencer that selectively regulates the expression of TNF-alpha. Embo J19: 4154–4163.CrossRefPubMedGoogle Scholar
  50. Probert, L., D. Plows, G. Kontogeorgos, and G. Kollias. 1995. The type I interleukin-1 receptor acts in series with tumor necrosis factor (TNF) to induce arthritis in TNF-transgenic mice. Eur J Immunol 25: 1794–1797.CrossRefPubMedGoogle Scholar
  51. Redlich, K., S. Hayer, R. Ricci, J.P. David, M. Tohidast-Akrad, G. Kollias, G. Steiner, J.S. Smolen, E.F. Wagner, and G. Schett. 2002. Osteoclasts are essential for TNF-alpha-mediated joint destruction. J Clin Invest 110: 1419–1427.PubMedGoogle Scholar
  52. Saklatvala, J. 1986. Tumour necrosis factor alpha stimulates resorption and inhibits synthesis of proteoglycan in cartilage. Nature 322: 547–549.CrossRefPubMedGoogle Scholar
  53. Saxne, T., M.A. Palladino, Jr., D. Heinegard, N. Talal, and F.A. Wollheim. 1988. Detection of tumor necrosis factor alpha but not tumor necrosis factor beta in rheumatoid arthritis synovial fluid and serum. Arthritis Rheum 31: 1041–1045.CrossRefPubMedGoogle Scholar
  54. Schett, G., K. Redlich, S. Hayer, J. Zwerina, B. Bolon, C. Dunstan, B. Gortz, A. Schulz, H. Bergmeister, G. Kollias, G. Steiner, and J.S. Smolen. 2003. Osteoprotegerin protects against generalized bone loss in tumor necrosis factor-transgenic mice. Arthritis Rheum 48: 2042–2051.CrossRefPubMedGoogle Scholar
  55. Schett, G., S. Hayer, J. Zwerina, K. Redlich, and J.S. Smolen. 2005. Mechanisms of Disease: the link between RANKL and arthritic bone disease. Nat Clin Pract Rheumatol 1: 47–54.CrossRefPubMedGoogle Scholar
  56. Smith, R.S., T.J. Smith, T.M. Blieden, and R.P. Phipps. 1997. Fibroblasts as sentinel cells. Synthesis of chemokines and regulation of inflammation. Am J Pathol 151: 317–322.PubMedGoogle Scholar
  57. Srivastava, S., G. Toraldo, M.N. Weitzmann, S. Cenci, F.P. Ross, and R. Pacifici. 2001. Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-kappa B ligand (RANKL)-induced JNK activation. J Biol Chem 276: 8836–8840.CrossRefPubMedGoogle Scholar
  58. Szekanecz, Z., G. Szucs, S. Szanto, and A.E. Koch. 2006. Chemokines in rheumatic diseases. Curr Drug Targets 7: 91–102.CrossRefPubMedGoogle Scholar
  59. Takayanagi, H., H. Iizuka, T. Juji, T. Nakagawa, A. Yamamoto, T. Miyazaki, Y. Koshihara, H. Oda, K. Nakamura, and S. Tanaka. 2000. Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum 43: 259–269.CrossRefPubMedGoogle Scholar
  60. Taniguchi, K., H. Kohsaka, N. Inoue, Y. Terada, H. Ito, K. Hirokawa, and N. Miyasaka. 1999. Induction of the p16INK4a senescence gene as a new therapeutic strategy for the treatment of rheumatoid arthritis. Nat Med 5: 760–767.CrossRefPubMedGoogle Scholar
  61. Taylor, G.A., E. Carballo, D.M. Lee, W.S. Lai, M.J. Thompson, D.D. Patel, D.I. Schenkman, G.S. Gilkeson, H.E. Broxmeyer, B.F. Haynes, and P.J. Blackshear. 1996. A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity 4: 445–454.CrossRefPubMedGoogle Scholar
  62. Thwin, M.M., E. Douni, V. Aidinis, G. Kollias, K. Kodama, K. Sato, R.L. Satish, R. Mahendran, and P. Gopalakrishnakone. 2004. Effect of phospholipase A2 inhibitory peptide on inflammatory arthritis in a TNF transgenic mouse model: a time-course ultrastructural study. Arthritis Res Ther 6: R282–294.CrossRefPubMedGoogle Scholar
  63. Tolar, J., S.L. Teitelbaum, and P.J. Orchard. 2004. Osteopetrosis. N Engl J Med 351: 2839–2849.CrossRefPubMedGoogle Scholar
  64. Wei, S., H. Kitaura, P. Zhou, F.P. Ross, and S.L. Teitelbaum. 2005. IL-1 mediates TNF-induced osteoclastogenesis. J Clin Invest 115: 282–290.PubMedGoogle Scholar
  65. Wiktor-Jedrzejczak, W., Bartocci, A., A.W. Ferrante, Jr., A. Ahmed-Ansari, K.W. Sell, J.W. Pollard, and E.R. Stanley. 1990. Total absence of colony-stimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci USA. 87: 4828–4832.CrossRefPubMedGoogle Scholar
  66. Woolf, A.D. 1991. Osteoporosis in rheumatoid arthritis–the clinical viewpoint. Br J Rheumatol 30: 82–84.CrossRefPubMedGoogle Scholar
  67. Yao, Z., P. Li, Q. Zhang, E.M. Schwarz, P. Keng, A. Arbini, B.F. Boyce, and L. Xing. 2006. Tumor necrosis factor-alpha increases circulating osteoclast precursor numbers by promoting their proliferation and differentiation in the bone marrow through up-regulation of c-Fms expression. J Biol Chem. 281: 11846–11855.CrossRefPubMedGoogle Scholar
  68. Zwerina, J., S. Hayer, K. Redlich, K. Bobacz, G. Kollias, J.S. Smolen, and G. Schett. 2006. Activation of p38 MAPK is a key step in tumor necrosis factor-mediated inflammatory bone destruction. Arthritis Rheum 54: 463–472.Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Eleni Douni
    • 1
  • Maria Armaka
    • 1
  • Dimitris L. Kontoyiannis
    • 1
  • George Kollias
    • 1
  1. 1.Institute of ImmunologyBiomedical Sciences Research Center “Alexander Fleming”Greece

Personalised recommendations