GP130 cytokines and bone remodelling in health and disease

  • Sims, Natalie A. (St Vincent's Institute, Australia and Department of Medicine at St. Vincent's Hospital, The University of Melbourne) ;
  • Walsh, Nicole C. (St Vincent's Institute, Australia and Department of Medicine at St. Vincent's Hospital, The University of Melbourne)
  • Received : 2010.07.15
  • Published : 2010.08.31


Cytokines that bind to and signal through the gp130 co-receptor subunit include interleukin (IL)-6, IL-11, oncostatin M (OSM), leukemia inhibitory factor (LIF), cardiotrophin-1 (CT-1), and ciliary neutrophic factor (CNTF). Apart from contributing to inflammation, gp130 signalling cytokines also function in the maintenance of bone homeostasis. Expression of each of these cytokines and their ligand-specific receptors is observed in bone and joint cells, and bone-active hormones and inflammatory cytokines regulate their expression. gp130 signalling cytokines have been shown to regulate the differentiation and activity of osteoblasts, osteoclasts and chondrocytes. Furthermore, cytokine and receptor specific gene-knockout mouse models have identified distinct roles for each of these cytokines in regulating bone resorption, bone formation and bone growth. This review will discuss the current models of paracrine and endocrine actions of gp130-signalling cytokines in bone remodelling and growth, as well as their impact in pathologic bone remodelling evident in periodontal disease, rheumatoid arthritis, spondylarthropathies and osteoarthritis.


  1. Bravo, J. and Heath, J. K. (2000) Receptor recognition by gp130 cytokines. Embo J. 19, 2399-2411.
  2. Yamasaki, K., Taga, T., Hirata, Y., Yawata, H., Kawanishi, Y., Seed, B., Taniguchi, T., Hirano, T. and Kishimoto, T. (1988) Cloning and expression of the human interleukin-6 (BSF-2/IFN beta 2) receptor. Science 241, 825-828.
  3. Hilton, D. J., Hilton, A. A., Raicevic, A., Rakar, S., Harrison-Smith, M., Gough, N. M., Begley, C. G., Metcalf, D., Nicola, N. A. and Willson, T. A. (1994) Cloning of a murine IL-11 receptor alpha-chain; requirement for gp130 for high affinity binding and signal transduction. Embo J. 13, 4765-4775.
  4. Elson, G. C., Lelievre, E., Guillet, C., Chevalier, S., Plun-Favreau, H., Froger, J., Suard, I., de Coignac, A. B., Delneste, Y., Bonnefoy, J. Y., Gauchat, J. F. and Gascan, H. (2000) CLF associates with CLC to form a functional heteromeric ligand for the CNTF receptor complex. Nat. Neurosci. 3, 867-872.
  5. Plun-Favreau, H., Elson, G., Chabbert, M., Froger, J., deLapeyriere, O., Lelievre, E., Guillet, C., Hermann, J., Gauchat, J. F., Gascan, H. and Chevalier, S. (2001) The ciliary neurotrophic factor receptor alpha component induces the secretion of and is required for functional responses to cardiotrophin-like cytokine. Embo J. 20, 1692-1703.
  6. Hibi, M., Murakami, M., Saito, M., Hirano, T., Taga, T. and Kishimoto, T. (1990) Molecular cloning and expression of an IL-6 signal transducer, gp130. Cell 63, 1149-1157.
  7. Gearing, D. P., Thut, C. J., VandeBos, T., Gimpel, S. D., Delaney, P. B., King, J., Price, V., Cosman, D. and Beckmann, M. P. (1991) Leukemia inhibitory factor receptor is structurally related to the IL-6 signal transducer, gp130. Embo J. 10, 2839-2848.
  8. Mosley, B., De Imus, C., Friend, D., Boiani, N., Thoma, B., Park, L. S. and Cosman, D. (1996) Dual oncostatin M (OSM) receptors. Cloning and characterization of an alternative signaling subunit conferring OSM-specific receptor activation. J. Biol. Chem. 271, 32635-32643
  9. Lindberg, R. A., Juan, T. S., Welcher, A. A., Sun, Y., Cupples, R., Guthrie, B. and Fletcher, F. A. (1998) Cloning and characterization of a specific receptor for mouse oncostatin M. Mol. Cell Biol. 18, 3357-3367.
  10. Pflanz, S., Timans, J. C., Cheung, J., Rosales, R., Kanzler, H., Gilbert, J., Hibbert, L., Churakova, T., Travis, M., Vaisberg, E., Blumenschein, W. M., Mattson, J. D., Wagner, J. L., To, W., Zurawski, S., McClanahan, T. K., Gorman, D. M., Bazan, J. F., de Waal Malefyt, R., Rennick, D. and Kastelein, R. A. (2002) IL-27, a heterodimeric cytokine composed of EBI3 and p28 protein, induces proliferation of naive CD4(+) T cells. Immunity 16, 779-790.
  11. Hashimoto, Y., Kurita, M., Aiso, S., Nishimoto, I. and Matsuoka, M. (2009) Humanin inhibits neuronal cell death by interacting with a cytokine receptor complex or complexes involving CNTF receptor alpha/WSX-1/gp130. Mol. Biol. Cell 20, 2864-2873.
  12. Sims, N. A. and Gooi, J. H. (2008) Bone remodeling: multiple cellular interactions required for coupling of bone formation and resorption. Semin. Cell Dev. Biol. 19, 444-451.
  13. Martin, T. J. and Sims, N. A. (2009) Bone remodeling: cellular and molecular events; in The Skeletal System, Pourquie, O. (ed.), pp. 297-316, Cold Spring Harbor Press, New York, USA.
  14. Walker, E. C., McGregor, N. E., Poulton, I. J., Pompolo, S., Allan, E. H., Quinn, J. M., Gillespie, M. T., Martin, T. J. and Sims, N. A. (2008) Cardiotrophin-1 is an osteoclast-derived stimulus of bone formation required for normal bone remodeling. J. Bone Miner Res. 23, 2025-2032.
  15. Pederson, L., Ruan, M., Westendorf, J. J., Khosla, S. and Oursler, M. J. (2008) Regulation of bone formation by osteoclasts involves Wnt/BMP signaling and the chemokine sphingosine-1-phosphate. Proc. Natl. Acad. Sci. U.S.A. 105, 20764-20769.
  16. van Bezooijen, R. L., ten Dijke, P., Papapoulos, S. E. and Lowik, C. W. (2005) SOST/sclerostin, an osteocyte- derived negative regulator of bone formation. Cytokine Growth Factor Rev. 16, 319-327.
  17. Kogianni, G., Mann, V. and Noble, B. S. (2008) Apoptotic bodies convey activity capable of initiating osteoclastogenesis and localised bone destruction. J. Bone Miner Res. 23, 915-927.
  18. Laaksovirta, H., Soinila, S., Hukkanen, V., Roytta, M. and Soilu-Hanninen, M. (2008) Serum level of CNTF is elevated in patients with amyotrophic lateral sclerosis and correlates with site of disease onset. Eur. J. Neurol. 15, 355-359.
  19. Waring, P., Wycherley, K., Cary, D., Nicola, N. and Metcalf, D. (1992) Leukemia inhibitory factor levels are elevated in septic shock and various inflammatory body fluids. J. Clin. Invest 90, 2031-2037.
  20. Talwar, S., Downie, P. F., Squire, I. B., Barnett, D. B., Davies, J. D. and Ng, L. L. (1999) An immunoluminometric assay for cardiotrophin-1: a newly identified cytokine is present in normal human plasma and is increased in heart failure. Biochem. Biophys. Res. Commun. 261, 567-571.
  21. Daynes, R. A., Araneo, B. A., Ershler, W. B., Maloney, C., Li, G. Z. and Ryu, S. Y. (1993) Altered regulation of IL-6 production with normal aging. Possible linkage to the age-associated decline in dehydroepiandrosterone and its sulfated derivative. J. Immunol. 150, 5219-5230.
  22. Romas, E., Udagawa, N., Zhou, H., Tamura, T., Saito, M., Taga, T., Hilton, D. J., Suda, T., Ng, K. W. and Martin, T. J. (1996) The role of gp130-mediated signals in osteoclast development: regulation of interleukin 11 production by osteoblasts and distribution of its receptor in bone marrow cultures. J. Exp. Med. 183, 2581-2591.
  23. Manolagas, S. C. (1998) The role of IL-6 type cytokines and their receptors in bone. Ann. N. Y. Acad. Sci. 840, 194-204.
  24. Greenfield, E. M., Shaw, S. M., Gornik, S. A. and Banks, M. A. (1995) Adenyl cyclase and interleukin 6 are downstream effectors of parathyroid hormone resulting in stimulation of bone resorption. J. Clin. Invest. 96, 1238-1244.
  25. Liang, J. D., Hock, J. M., Sandusky, G. E., Santerre, R. F. and Onyia, J. E. (1999) Immunohistochemical localization of selected early response genes expressed in trabecular bone of young rats given hPTH 1-34. Calcif. Tissue Int. 65, 369-373.
  26. Tamura, T., Udagawa, N., Takahashi, N., Miyaura, C., Tanaka, S., Yamada, Y., Koishihara, Y., Ohsugi, Y., Kumaki, K., Taga, T., Kishimoto, T. and Suda, T. (1993) Soluble interleukin-6 receptor triggers osteoclast formation by interleukin 6. Proc. Natl. Acad. Sci. U.S.A. 90, 11924-11928.
  27. Richards, C. D., Langdon, C., Deschamps, P., Pennica, D. and Shaughnessy, S. G. (2000) Stimulation of osteoclast differentiation in vitro by mouse oncostatin M, leukaemia inhibitory factor, cardiotrophin-1 and interleukin 6: synergy with dexamethasone. Cytokine 12, 613-621.
  28. McGregor, N. E., Poulton, I. J., Walker, E. C., Pompolo, S., Quinn, J. M., Martin, T. J. and Sims, N. A. (2010) Ciliary neurotrophic factor inhibits bone formation and plays a sex-specific role in bone growth and remodeling. Calcif Tissue Int. 86, 261-270.
  29. Horwood, N. J., Elliott, J., Martin, T. J. and Gillespie, M. T. (1998) Osteotropic agents regulate the expression of osteoclast differentiation factor and osteoprotegerin in osteoblastic stromal cells. Endocrinology 139, 4743-4746.
  30. Fu, Q., Manolagas, S. C. and O'Brien, C. A. (2006) Parathyroid hormone controls receptor activator of NFkappaB ligand gene expression via a distant transcriptional enhancer. Mol. Cell Biol. 26, 6453-6468.
  31. Atkins, G. J., Haynes, D. R., Geary, S. M., Loric, M., Crotti, T. N. and Findlay, D. M. (2000) Coordinated cytokine expression by stromal and hematopoietic cells during human osteoclast formation. Bone 26, 653-661.
  32. Shin, H. I., Divieti, P., Sims, N. A., Kobayashi, T., Miao, D., Karaplis, A. C., Baron, R., Bringhurst, R. and Kronenberg, H. M. (2004) Gp130-mediated signaling is necessary for normal osteoblastic function in vivo and in vitro. Endocrinology 145, 1376-1385.
  33. Girasole, G., Passeri, G., Jilka, R. L. and Manolagas, S. C. (1994) Interleukin-11: a new cytokine critical for osteoclast development. J. Clin. Invest. 93, 1516-1524.
  34. Gorny, G., Shaw, A. and Oursler, M. J. (2004) IL-6, LIF, and TNF-alpha regulation of GM-CSF inhibition of osteoclastogenesis in vitro. Exp. Cell Res. 294, 149-158.
  35. Sims, N. A., Jenkins, B. J., Quinn, J. M., Nakamura, A., Glatt, M., Gillespie, M. T., Ernst, M. and Martin, T. J. (2004) Glycoprotein 130 regulates bone turnover and bone size by distinct downstream signaling pathways. J. Clin. Invest 113, 379-389.
  36. Sims, N. A., Jenkins, B. J., Nakamura, A., Quinn, J. M., Li, R., Gillespie, M. T., Ernst, M., Robb, L. and Martin, T. J. (2005) Interleukin-11 receptor signaling is required for normal bone remodeling. J. Bone Miner Res. 20, 1093-1102.
  37. Kamiya, S., Nakamura, C., Fukawa, T., Ono, K., Ohwaki, T., Yoshimoto, T. and Wada, S. (2007) Effects of IL-23 and IL-27 on osteoblasts and osteoclasts: inhibitory effects on osteoclast differentiation. J. Bone Miner Metab. 25, 277-285.
  38. Kawasaki, K., Gao, Y. H., Yokose, S., Kaji, Y., Nakamura, T., Suda, T., Yoshida, K., Taga, T., Kishimoto, T., Kataoka, H., Yuasa, T., Norimatsu, H. and Yamaguchi, A. (1997) Osteoclasts are present in gp130-deficient mice. Endocrinology 138, 4959-4965.
  39. Poli, V., Balena, R., Fattori, E., Markatos, A., Yamamoto, M., Tanaka, H., Ciliberto, G., Rodan, G. A. and Costantini, F. (1994) Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion. Embo J. 13, 1189-1196.
  40. Grey, A., Mitnick, M. A., Masiukiewicz, U., Sun, B. H., Rudikoff, S., Jilka, R. L., Manolagas, S. C. and Insogna, K. (1999) A role for interleukin-6 in parathyroid hormone-induced bone resorption in vivo. Endocrinology 140, 4683-4690.
  41. Bozec, A., Bakiri, L., Hoebertz, A., Eferl, R., Schilling, A. F., Komnenovic, V., Scheuch, H., Priemel, M., Stewart, C. L., Amling, M. and Wagner, E. F. (2008) Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia. Nature 454, 221-225.
  42. Ware, C. B., Horowitz, M. C., Renshaw, B. R., Hunt, J. S., Liggitt, D., Koblar, S. A., Gliniak, B. C., McKenna, H. J., Papayannopoulou, T., Thoma, B., Cheng, L., Donovan, P. J., Peschon, J. J., Bartlett, P. F., Willis, C. R., Wright, B. D., Carpenter, M. K., Davison, B. L. and Gearing, D. P. (1995) Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. Development 121, 1283-1299.
  43. Walker, E. C., McGregor, N. E., Poulton, I. J., Solano, M., Pompolo, S., Fernandes, T. J., Constable, M. J., Nicholson, G. C., Zhang, J. G., Nicola, N. A., Gillespie, M. T., Martin, T. J. and Sims, N. A. (2010) Oncostatin M promotes bone formation independently of resorption when signaling through leukemia inhibitory factor receptor in mice. J. Clin. Invest 120, 582-592.
  44. Bellido, T., Borba, V. Z., Roberson, P. and Manolagas, S. C. (1997) Activation of the Janus kinase/STAT (signal transducer and activator of transcription) signal transduction pathway by interleukin-6-type cytokines promotes osteoblast differentiation. Endocrinology 138, 3666-3676.
  45. Kitamura, H., Kawata, H., Takahashi, F., Higuchi, Y., Furuichi, T. and Ohkawa, H. (1995) Bone marrow neutrophilia and suppressed bone turnover in human interleukin-6 transgenic mice. A cellular relationship among hematopoietic cells, osteoblasts, and osteoclasts mediated by stromal cells in bone marrow. Am. J. Pathol. 147, 1682-1692.
  46. De Benedetti, F., Rucci, N., Del Fattore, A., Peruzzi, B., Paro, R., Longo, M., Vivarelli, M., Muratori, F., Berni, S., Ballanti, P., Ferrari, S. and Teti, A. (2006) Impaired skeletal development in interleukin-6-transgenic mice: a model for the impact of chronic inflammation on the growing skeletal system. Arthritis. Rheum. 54, 3551-3563.
  47. Li, X., Ominsky, M. S., Warmington, K. S., Morony, S., Gong, J., Cao, J., Gao, Y., Shalhoub, V., Tipton, B., Haldankar, R., Chen, Q., Winters, A., Boone, T., Geng, Z., Niu, Q. T., Ke, H. Z., Kostenuik, P. J., Simonet, W. S., Lacey, D. L. and Paszty, C. (2009) Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J. Bone Miner Res. 24, 578-588.
  48. Keller, H. and Kneissel, M. (2005) SOST is a target gene for PTH in bone. Bone 37, 148-158.
  49. Robling, A. G., Bellido, T. and Turner, C. H. (2006) Mechanical stimulation in vivo reduces osteocyte expression of sclerostin. J. Musculoskelet Neuronal Interact 6, 354.
  50. Jenkins, B. J., Grail, D., Inglese, M., Quilici, C., Bozinovski, S., Wong, P. and Ernst, M. (2004) Imbalanced gp130-dependent signaling in macrophages alters macrophage colony-stimulating factor responsiveness via regulation of c-fms expression. Mol. Cell Biol. 24, 1453-1463.
  51. Dagoneau, N., Scheffer, D., Huber, C., Al-Gazali, L. I., Di Rocco, M., Godard, A., Martinovic, J., Raas-Rothschild, A., Sigaudy, S., Unger, S., Nicole, S., Fontaine, B., Taupin, J. L., Moreau, J. F., Superti-Furga, A., Le Merrer, M., Bonaventure, J., Munnich, A., Legeai-Mallet, L. and Cormier-Daire, V. (2004) Null leukemia inhibitory factor receptor (LIFR) mutations in Stuve-Wiedemann/Schwartz-Jampel type 2 syndrome. Am. J. Hum. Genet. 74, 298-305.
  52. Sims, N. A. (2009) gp130 signaling in bone cell biology: multiple roles revealed by analysis of genetically altered mice. Mol. Cell Endocrinol. 310, 30-39.
  53. Qi, L., Zhang, C., van Dam, R. M. and Hu, F. B. (2007) Interleukin-6 genetic variability and adiposity: associations in two prospective cohorts and systematic review in 26,944 individuals. J. Clin. Endocrinol. Metab. 92, 3618-3625.
  54. Takacs, I., Koller, D. L., Peacock, M., Christian, J. C., Evans, W. E., Hui, S. L., Conneally, P. M., Johnston, C. C., Jr., Foroud, T. and Econs, M. J. (2000) Sib pair linkage and association studies between bone mineral density and the interleukin-6 gene locus. Bone 27, 169-173.
  55. Tsukamoto, K., Yoshida, H., Watanabe, S., Suzuki, T., Miyao, M., Hosoi, T., Orimo, H. and Emi, M. (1999) Association of radial bone mineral density with CA repeat polymorphism at the interleukin 6 locus in postmenopausal Japanese women. J. Hum. Genet. 44, 148-151.
  56. Ogura, N., Shibata, Y., Kamino, Y., Matsuda, U., Hayakawa, M., Oikawa, T., Takiguchi, H., Izumi, H. and Abiko, Y. (1994) Stimulation of interleukin-6 production of periodontal ligament cells by Porphyromonas endodontalis lipopolysaccharide. Biochem. Med. Metab. Biol. 53, 130-136.
  57. Barkhordar, R. A., Hayashi, C. and Hussain, M. Z. (1999) Detection of interleukin-6 in human dental pulp and periapical lesions. Endod. Dent. Traumatol. 15, 26-27.
  58. Johnson, R. B., Wood, N. and Serio, F. G. (2004) Interleukin-11 and IL-17 and the pathogenesis of periodontal disease. J. Periodontol. 75, 37-43.
  59. Kawashima, N. and Stashenko, P. (1999) Expression of bone-resorptive and regulatory cytokines in murine periapical inflammation. Arch. Oral. Biol. 44, 55-66.
  60. Tsai, C. H., Huang, F. M. and Chang, Y. C. (2008) Immunohistochemical localization of oncostatin M in epithelialized apical periodontitis lesions. Int. Endod. J. 41, 772-776.
  61. Lin, S. J., Chen, Y. L., Kuo, M. Y., Li, C. L. and Lu, H. K. (2005) Measurement of gp130 cytokines oncostatin M and IL-6 in gingival crevicular fluid of patients with chronic periodontitis. Cytokine 30, 160-167.
  62. Pradeep, A. R., S, T. M., Garima, G. and Raju, A. (2010) Serum levels of oncostatin M (a gp 130 cytokine): an inflammatory biomarker in periodontal disease. Biomarkers 15, 277-282.
  63. Gravallese, E. M., Harada, Y., Wang, J. T., Gorn, A. H., Thornhill, T. S. and Goldring, S. R. (1998) Identification of cell types responsible for bone resorption in rheumatoid arthritis and juvenile rheumatoid arthritis. Am. J. Pathol. 152, 943-951.
  64. Romas, E., Bakharevski, O., Hards, D. K., Kartsogiannis, V., Quinn, J. M., Ryan, P. F., Martin, T. J. and Gillespie, M. T. (2000) Expression of osteoclast differentiation factor at sites of bone erosion in collagen-induced arthritis. Arthritis Rheum 43, 821-826.<821::AID-ANR12>3.0.CO;2-T
  65. Scott, D. L. (2000) Prognostic factors in early rheumatoid arthritis. Rheumatology (Oxford) 39 (Suppl 1), 24-29.
  66. Pettit, A. R., Walsh, N. C., Manning, C., Goldring, S. R. and Gravallese, E. M. (2006) RANKL protein is expressed at the pannus-bone interface at sites of articular bone erosion in rheumatoid arthritis. Rheumatology (Oxford) 45, 1068-1076.
  67. Horwood, N. J., Kartsogiannis, V., Quinn, J. M., Romas, E., Martin, T. J. and Gillespie, M. T. (1999) Activated T lymphocytes support osteoclast formation in vitro. Biochem. Biophys. Res. Commun. 265, 144-150.
  68. Crotti, T. N., Smith, M. D., Weedon, H., Ahern, M. J., Findlay, D. M., Kraan, M., Tak, P. P. and Haynes, D. R. (2002) Receptor activator NF-kappaB ligand (RANKL) expression in synovial tissue from patients with rheumatoid arthritis, spondyloarthropathy, osteoarthritis, and from normal patients: semiquantitative and quantitative analysis. Ann. Rheum. Dis. 61, 1047-1054.
  69. Walsh, N. C., Reinwald, S., Manning, C. A., Condon, K. W., Iwata, K., Burr, D. B. and Gravallese, E. M. (2009) Osteoblast function is compromised at sites of focal bone erosion in inflammatory arthritis. J. Bone Miner Res. 24, 1572-1585.
  70. Okamoto, H., Yamamura, M., Morita, Y., Harada, S., Makino, H. and Ota, Z. (1997) The synovial expression and serum levels of interleukin-6, interleukin-11, leukemia inhibitory factor, and oncostatin M in rheumatoid arthritis. Arthritis. Rheum. 40, 1096-1105.
  71. Kotake, S., Sato, K., Kim, K. J., Takahashi, N., Udagawa, N., Nakamura, I., Yamaguchi, A., Kishimoto, T., Suda, T. and Kashiwazaki, S. (1996) Interleukin-6 and soluble interleukin-6 receptors in the synovial fluids from rheumatoid arthritis patients are responsible for osteoclast-like cell formation. J. Bone Miner Res. 11, 88-95.
  72. Nowell, M. A., Richards, P. J., Horiuchi, S., Yamamoto, N., Rose-John, S., Topley, N., Williams, A. S. and Jones, S. A. (2003) Soluble IL-6 receptor governs IL-6 activity in experimental arthritis: blockade of arthritis severity by soluble glycoprotein 130. J. Immunol. 171, 3202-3209.
  73. Al-Awadhi, A., Olusi, S., Al-Zaid, N. and Prabha, K. (1999) Serum concentrations of interleukin 6, osteocalcin, intact parathyroid hormone, and markers of bone resorption in patients with rheumatoid arthritis. J. Rheumatol. 26, 1250-1256.
  74. Walsh, N. C., Crotti, T. N., Goldring, S. R. and Gravallese, E. M. (2005) Rheumatic diseases: the effects of inflammation on bone. Immunol. Rev. 208, 228-251.
  75. Fonseca, J. E., Santos, M. J., Canhao, H. and Choy, E. (2009) Interleukin-6 as a key player in systemic inflammation and joint destruction. Autoimmun. Rev. 8, 538-542.
  76. Takagi, N., Mihara, M., Moriya, Y., Nishimoto, N., Yoshizaki, K., Kishimoto, T., Takeda, Y. and Ohsugi, Y. (1998) Blockage of interleukin-6 receptor ameliorates joint disease in murine collagen-induced arthritis. Arthritis. Rheum. 41, 2117-2121.<2117::AID-ART6>3.0.CO;2-P
  77. Kato, A., Matsuo, S., Takai, H., Uchiyama, Y., Mihara, M. and Suzuki, M. (2008) Early effects of tocilizumab on bone and bone marrow lesions in a collagen-induced arthritis monkey model. Exp. Mol. Pathol. 84, 262-270.
  78. Jones, G., Sebba, A., Gu, J., Lowenstein, M. B., Calvo, A., Gomez-Reino, J. J., Siri, D. A., Tomsic, M., Alecock, E., Woodworth, T. and Genovese, M. C. (2010) Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: The AMBITION study. Ann. Rheum. Dis. 69, 88-96.
  79. Plater-Zyberk, C., Buckton, J., Thompson, S., Spaull, J., Zanders, E., Papworth, J. and Life, P. F. (2001) Amelioration of arthritis in two murine models using antibodies to oncostatin M. Arthritis. Rheum. 44, 2697-2702.<2697::AID-ART450>3.0.CO;2-#
  80. Field, M., Chu, C., Feldmann, M. and Maini, R. N. (1991) Interleukin-6 localisation in the synovial membrane in rheumatoid arthritis. Rheumatol. Int. 11, 45-50.
  81. Chu, C. Q., Field, M., Allard, S., Abney, E., Feldmann, M. and Maini, R. N. (1992) Detection of cytokines at the cartilage/pannus junction in patients with rheumatoid arthritis: implications for the role of cytokines in cartilage destruction and repair. Br. J. Rheumatol. 31, 653-661.
  82. Wong, P. K., Quinn, J. M., Sims, N. A., van Nieuwenhuijze, A., Campbell, I. K. and Wicks, I. P. (2006) Interleukin-6 modulates production of T lymphocytederived cytokines in antigen-induced arthritis and drives inflammation-induced osteoclastogenesis. Arthritis. Rheum. 54, 158-168.
  83. Mihara, M., Ohsugi, Y. and Kishimoto, T. (2009) Evidence for the role of Th17 cell inhibition in the prevention of autoimmune diseases by anti-interluekin-6 receptor antibody. Biofactors 35, 47-51.
  84. Fujimoto, M., Serada, S., Mihara, M., Uchiyama, Y., Yoshida, H., Koike, N., Ohsugi, Y., Nishikawa, T., Ripley, B., Kimura, A., Kishimoto, T. and Naka, T. (2008) Interleukin-6 blockade suppresses autoimmune arthritis in mice by the inhibition of inflammatory Th17 responses. Arthritis. Rheum. 58, 3710-3719.
  85. Benjamin, M., Moriggl, B., Brenner, E., Emery, P., McGonagle, D. and Redman, S. (2004) The "enthesis organ" concept: why enthesopathies may not present as focal insertional disorders. Arthritis. Rheum. 50, 3306-3313.
  86. McGonagle, D. (2005) Imaging the joint and enthesis: insights into pathogenesis of psoriatic arthritis. Ann. Rheum. Dis. 64 (Suppl 2), ii58-60.
  87. McGonagle, D., Lories, R. J., Tan, A. L. and Benjamin, M. (2007) The concept of a "synovio-entheseal complex" and its implications for understanding joint inflammation and damage in psoriatic arthritis and beyond. Arthritis. Rheum. 56, 2482-2491.
  88. Benjamin, M. and McGonagle, D. (2007) Histopathologic changes at "synovio-entheseal complexes" suggesting a novel mechanism for synovitis in osteoarthritis and spondylarthritis. Arthritis. Rheum. 56, 3601-3609.
  89. Lories, R. J., Derese, I. and Luyten, F. P. (2005) Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis. J. Clin. Invest. 115, 1571-1579.
  90. Diarra, D., Stolina, M., Polzer, K., Zwerina, J., Ominsky, M. S., Dwyer, D., Korb, A., Smolen, J., Hoffmann, M., Scheinecker, C., van der Heide, D., Landewe, R., Lacey, D., Richards, W. G. and Schett, G. (2007) Dickkopf-1 is a master regulator of joint remodeling. Nat. Med. 13, 156-163.
  91. Appel, H., Ruiz-Heiland, G., Listing, J., Zwerina, J., Herrmann, M., Mueller, R., Haibel, H., Baraliakos, X., Hempfing, A., Rudwaleit, M., Sieper, J. and Schett, G. (2009) Altered skeletal expression of sclerostin and its link to radiographic progression in ankylosing spondylitis. Arthritis. Rheum. 60, 3257-3262.
  92. Partsch, G., Steiner, G., Leeb, B. F., Dunky, A., Broll, H. and Smolen, J. S. (1997) Highly increased levels of tumor necrosis factor-alpha and other proinflammatory cytokines in psoriatic arthritis synovial fluid. J. Rheumatol. 24, 518-523.
  93. Gratacos, J., Collado, A., Filella, X., Sanmarti, R., Canete, J., Llena, J., Molina, R., Ballesta, A. and Munoz-Gomez, J. (1994) Serum cytokines (IL-6, TNF-alpha, IL-1 beta and IFN-gamma) in ankylosing spondylitis: a close correlation between serum IL-6 and disease activity and severity. Br. J. Rheumatol. 33, 927-931.
  94. Hayer, S., Niederreiter, B., Nagelreiter, I., Smolen, J. and Redlich, K. (2010) Interleukin 6 is not a crucial regulator in an animal model of tumour necrosis factor-mediated bilateral sacroiliitis. Ann. Rheum. Dis. 69, 1403-1406.
  95. Dieppe, P. A. and Lohmander, L. S. (2005) Pathogenesis and management of pain in osteoarthritis. Lancet 365, 965-973.
  96. Sakao, K., Takahashi, K. A., Arai, Y., Saito, M., Honjo, K., Hiraoka, N., Asada, H., Shin-Ya, M., Imanishi, J., Mazda, O. and Kubo, T. (2009) Osteoblasts derived from osteophytes produce interleukin-6, interleukin-8, and matrix metalloproteinase-13 in osteoarthritis. J. Bone Miner Metab. 27, 412-423.
  97. Durigova, M., Roughley, P. J. and Mort, J. S. (2008) Mechanism of proteoglycan aggregate degradation in cartilage stimulated with oncostatin M. Osteoarthritis Cartilage 16, 98-104.
  98. Langdon, C., Kerr, C., Hassen, M., Hara, T., Arsenault, A. L. and Richards, C. D. (2000) Murine oncostatin M stimulates mouse synovial fibroblasts in vitro and induces inflammation and destruction in mouse joints in vivo. Am. J. Pathol. 157, 1187-1196.
  99. de Hooge, A. S., van de Loo, F. A., Bennink, M. B., de Jong, D. S., Arntz, O. J., Lubberts, E., Richards, C. D. and vandDen Berg, W. B. (2002) Adenoviral transfer of murine oncostatin M elicits periosteal bone apposition in knee joints of mice, despite synovial inflammation and up-regulated expression of interleukin-6 and receptor activator of nuclear factor-kappa B ligand. Am. J. Pathol. 160, 1733-1743.
  100. Karsdal, M. A., Madsen, S. H., Christiansen, C., Henriksen, K., Fosang, A. J. and Sondergaard, B. C. (2008) Cartilage degradation is fully reversible in the presence of aggrecanase but not matrix metalloproteinase activity. Arthritis. Res. Ther. 10, R63.
  101. de Hooge, A. S., van de Loo, F. A., Bennink, M. B., Arntz, O. J., de Hooge, P. and van den Berg, W. B. (2005) Male IL-6 gene knock out mice developed more advanced osteoarthritis upon aging. Osteoarthritis. Cartilage. 13, 66-73.
  102. Upadhyay, A., Sharma, G., Kivivuori, S., Raye, W. S., Zabihi, E., Carroll, G. J. and Jazayeri, J. A. (2009) Role of a LIF antagonist in LIF and OSM induced MMP-1, MMP-3, and TIMP-1 expression by primary articular chondrocytes. Cytokine 46, 332-338.
  103. Fan, Z., Bau, B., Yang, H. and Aigner, T. (2004) IL-1beta induction of IL-6 and LIF in normal articular human chondrocytes involves the ERK, p38 and NFkappaB signaling pathways. Cytokine 28, 17-24.
  104. Rowan, A. D., Koshy, P. J., Shingleton, W. D., Degnan, B. A., Heath, J. K., Vernallis, A. B., Spaull, J. R., Life, P. F., Hudson, K. and Cawston, T. E. (2001) Synergistic effects of glycoprotein 130 binding cytokines in combination with interleukin-1 on cartilage collagen breakdown. Arthritis. Rheum. 44, 1620-1632.<1620::AID-ART285>3.0.CO;2-B
  105. Gao, Y., Morita, I., Maruo, N., Kubota, T., Murota, S. and Aso, T. (1998) Expression of IL-6 receptor and GP130 in mouse bone marrow cells during osteoclast differentiation. Bone 22, 487-493.
  106. Allan, E. H., Hilton, D. J., Brown, M. A., Evely, R. S., Yumita, S., Metcalf, D., Gough, N. M., Ng, K. W., Nicola, N. A. and Martin, T. J. (1990) Osteoblasts display receptors for and responses to leukemia-inhibitory factor. J. Cell Physiol. 145, 110-119.
  107. Udagawa, N., Takahashi, N., Katagiri, T., Tamura, T., Wada, S., Findlay, D. M., Martin, T. J., Hirota, H., Taga, T., Kishimoto, T. and Suda, T. (1995) Interleukin (IL)-6 induction of osteoclast differentiation depends on IL-6 receptors expressed on osteoblastic cells but not on osteoclast progenitors. J. Exp. Med. 182, 1461-1468.
  108. Bellido, T., Stahl, N., Farruggella, T. J., Borba, V., Yancopoulos, G. D. and Manolagas, S. C. (1996) Detection of receptors for interleukin-6, interleukin-11, leukemia inhibitory factor, oncostatin M, and ciliary neurotrophic factor in bone marrow stromal/osteoblastic cells. J. Clin. Invest. 97, 431-437.
  109. Dame, J. B. and Juul, S. E. (2000) The distribution of receptors for the pro-inflammatory cytokines interleukin (IL)-6 and IL-8 in the developing human fetus. Early Hum. Dev. 58, 25-39.
  110. Legendre, F., Dudhia, J., Pujol, J. P. and Bogdanowicz, P. (2003) JAK/STAT but not ERK1/ERK2 pathway mediates interleukin (IL)-6/soluble IL-6R down-regulation of Type II collagen, aggrecan core, and link protein transcription in articular chondrocytes. Association with a down-regulation of SOX9 expression. J. Biol. Chem. 278, 2903-2912.
  111. Nowell, M. A., Richards, P. J., Fielding, C. A., Ognjanovic, S., Topley, N., Williams, A. S., Bryant-Greenwood, G. and Jones, S. A. (2006) Regulation of pre-B cell colony-enhancing factor by STAT-3-dependent interleukin-6 trans-signaling: implications in the pathogenesis of rheumatoid arthritis. Arthritis. Rheum. 54, 2084-2095.
  112. Hashizume, M., Hayakawa, N. and Mihara, M. (2008) IL-6 trans-signalling directly induces RANKL on fibroblast-like synovial cells and is involved in RANKL induction by TNF-alpha and IL-17. Rheumatology (Oxford) 47, 1635-1640.
  113. Wong, C., Chen, D., Tam, L., Li, E., Yin, Y. and Lam, C. (2010) Effects of inflammatory cytokine IL-27 on the activation of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Res. Ther. 12, doi:10.1186/ar3067.
  114. Ishimi, Y., Miyaura, C., Jin, C. H., Akatsu, T., Abe, E., Nakamura, Y., Yamaguchi, A., Yoshiki, S., Matsuda, T., Hirano, T., Kishimoto, T. and Suda, T. (1990) IL-6 is produced by osteoblasts and induces bone resorption. J. Immunol. 145, 3297-3303.
  115. Ishimi, Y., Abe, E., Jin, C. H., Miyaura, C., Hong, M. H., Oshida, M., Kurosawa, H., Yamaguchi, Y., Tomida, M., Hozumi, M. and Suda, T. (1992) Leukemia inhibitory factor/differentiation-stimulating factor (LIF/D-factor): regulation of its production and possible roles in bone metabolism. J. Cell Physiol. 152, 71-78.
  116. Liu, F., Aubin, J. E. and Malaval, L. (2002) Expression of leukemia inhibitory factor (LIF)/interleukin-6 family cytokines and receptors during in vitro osteogenesis: differential regulation by dexamethasone and LIF. Bone 31, 212-219.
  117. Guerne, P. A., Carson, D. A. and Lotz, M. (1990) IL-6 production by human articular chondrocytes. Modulation of its synthesis by cytokines, growth factors, and hormones in vitro. J. Immunol. 144, 499-505.
  118. Maier, R., Ganu, V. and Lotz, M. (1993) Interleukin-11, an inducible cytokine in human articular chondrocytes and synoviocytes, stimulates the production of the tissue inhibitor of metalloproteinases. J. Biol. Chem. 268, 21527-21532.
  119. Grimaud, E., Blanchard, F., Charrier, C., Gouin, F., Redini, F. and Heymann, D. (2002) Leukaemia inhibitory factor (lif) is expressed in hypertrophic chondrocytes and vascular sprouts during osteogenesis. Cytokine 20, 224-230.
  120. Sheng, Z., Pennica, D., Wood, W. I. and Chien, K. R. (1996) Cardiotrophin-1 displays early expression in the murine heart tube and promotes cardiac myocyte survival. Development 122, 419-428.

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