Home LiteratureArticle Details
PMID: 17088434 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction.

The Journal of experimental medicine ·Vol. 203 ·No. 12 ·2006-11-27 ·Pages 2673-82

Sato K, Suematsu A, Okamoto K, Yamaguchi A, Morishita Y, Kadono Y, Tanaka S, Kodama T, Akira S, Iwakura Y, Cua DJ, Takayanagi H

Abstract

In autoimmune arthritis, traditionally classified as a T helper (Th) type 1 disease, the activation of T cells results in bone destruction mediated by osteoclasts, but how T cells enhance osteoclastogenesis despite the anti-osteoclastogenic effect of interferon (IFN)-gamma remains to be elucidated. Here, we examine the effect of various Th cell subsets on osteoclastogenesis and identify Th17, a specialized inflammatory subset, as an osteoclastogenic Th cell subset that links T cell activation and bone resorption. The interleukin (IL)-23-IL-17 axis, rather than the IL-12-IFN-gamma axis, is critical not only for the onset phase, but also for the bone destruction phase of autoimmune arthritis. Thus, Th17 is a powerful therapeutic target for the bone destruction associated with T cell activation.

MeSH Terms
Animals Arthritis, Experimental/immunology,pathology Bone Resorption/immunology,pathology Bone and Bones/immunology,pathology Cell Differentiation/immunology Lymphocyte Activation/immunology Mice Mice, Inbred C57BL Mice, Knockout Osteoclasts/immunology,pathology T-Lymphocyte Subsets/immunology,pathology T-Lymphocytes, Helper-Inducer/immunology,pathology
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Sato Kojiro
Department of Cell Signaling, Graduate School, and COE Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Tokyo 113-8549, Japan.
Suematsu Ayako
Okamoto Kazuo
Yamaguchi Akira
Morishita Yasuyuki
Kadono Yuho
Tanaka Sakae
Kodama Tatsuhiko
Akira Shizuo
Iwakura Yoichiro
Cua Daniel J
Takayanagi Hiroshi
References (52)
52 references, click to expand
  1. Interleukin-1beta and tumor necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells.
    Bone. 1999 Sep;25(3):255-9 PMID: 10495128
  2. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families.
    Endocr Rev. 1999 Jun;20(3):345-57 PMID: 10368775
  3. RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis.
    EMBO J. 2005 Feb 23;24(4):790-9 PMID: 15678102
  4. Mechanistic insight into osteoclast differentiation in osteoimmunology.
    J Mol Med (Berl). 2005 Mar;83(3):170-9 PMID: 15776286
  5. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self.
    Nat Immunol. 2005 Apr;6(4):345-52 PMID: 15785760
  6. Inflammatory bone destruction and osteoimmunology.
    J Periodontal Res. 2005 Aug;40(4):287-93 PMID: 15966905
  7. Contribution of nuclear factor of activated T cells c1 to the transcriptional control of immunoreceptor osteoclast-associated receptor but not triggering receptor expressed by myeloid cells-2 during osteoclastogenesis.
    J Biol Chem. 2005 Sep 23;280(38):32905-13 PMID: 16046394
  8. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17.
    Nat Immunol. 2005 Nov;6(11):1133-41 PMID: 16200068
  9. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages.
    Nat Immunol. 2005 Nov;6(11):1123-32 PMID: 16200070
  10. Autoamplification of NFATc1 expression determines its essential role in bone homeostasis.
    J Exp Med. 2005 Nov 7;202(9):1261-9 PMID: 16275763
  11. alphavbeta3 and macrophage colony-stimulating factor: partners in osteoclast biology.
    Immunol Rev. 2005 Dec;208:88-105 PMID: 16313343
  12. Denosumab in postmenopausal women with low bone mineral density.
    N Engl J Med. 2006 Feb 23;354(8):821-31 PMID: 16495394
  13. Osteoimmunology: interplay between the immune system and bone metabolism.
    Annu Rev Immunol. 2006;24:33-63 PMID: 16551243
  14. Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells.
    Nat Rev Immunol. 2006 Apr;6(4):329-33 PMID: 16557264
  15. Transforming growth factor-beta induces development of the T(H)17 lineage.
    Nature. 2006 May 11;441(7090):231-4 PMID: 16648837
  16. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells.
    Nature. 2006 May 11;441(7090):235-8 PMID: 16648838
  17. Osteoclasts, rheumatoid arthritis, and osteoimmunology.
    Curr Opin Rheumatol. 2006 Jul;18(4):419-26 PMID: 16763464
  18. Th17: an effector CD4 T cell lineage with regulatory T cell ties.
    Immunity. 2006 Jun;24(6):677-88 PMID: 16782025
  19. Identification of an alternatively spliced variant of Ca2+-promoted Ras inactivator as a possible regulator of RANKL shedding.
    J Biol Chem. 2005 Dec 16;280(50):41700-6 PMID: 16234249
  20. Activated T lymphocytes support osteoclast formation in vitro.
    Biochem Biophys Res Commun. 1999 Nov;265(1):144-50 PMID: 10548505
  21. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand.
    Nature. 1999 Nov 18;402(6759):304-9 PMID: 10580503
  22. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor.
    Arthritis Rheum. 2000 Feb;43(2):250-8 PMID: 10693863
  23. Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis.
    Arthritis Rheum. 2000 Feb;43(2):259-69 PMID: 10693864
  24. The inhibitory effect of interleukin-10 on mouse osteoclast formation involves novel tyrosine-phosphorylated proteins.
    J Bone Miner Res. 2000 May;15(5):911-8 PMID: 10804021
  25. T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma.
    Nature. 2000 Nov 30;408(6812):600-5 PMID: 11117749
  26. IL-12 alone and in synergy with IL-18 inhibits osteoclast formation in vitro.
    J Immunol. 2001 Apr 15;166(8):4915-21 PMID: 11290769
  27. TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis.
    Am J Pathol. 2001 Nov;159(5):1689-99 PMID: 11696430
  28. RANK-L and RANK: T cells, bone loss, and mammalian evolution.
    Annu Rev Immunol. 2002;20:795-823 PMID: 11861618
  29. Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses.
    Immunity. 2002 Sep;17(3):375-87 PMID: 12354389
  30. Osteoclasts are essential for TNF-alpha-mediated joint destruction.
    J Clin Invest. 2002 Nov;110(10):1419-27 PMID: 12438440
  31. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts.
    Dev Cell. 2002 Dec;3(6):889-901 PMID: 12479813
  32. Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain.
    Nature. 2003 Feb 13;421(6924):744-8 PMID: 12610626
  33. Exposure to receptor-activator of NFkappaB ligand renders pre-osteoclasts resistant to IFN-gamma by inducing terminal differentiation.
    Arthritis Res Ther. 2003;5(1):R49-59 PMID: 12716453
  34. Osteoclast differentiation and activation.
    Nature. 2003 May 15;423(6937):337-42 PMID: 12748652
  35. Genetic regulation of osteoclast development and function.
    Nat Rev Genet. 2003 Aug;4(8):638-49 PMID: 12897775
  36. Anti-TNF-alpha therapies: the next generation.
    Nat Rev Drug Discov. 2003 Sep;2(9):736-46 PMID: 12951580
  37. Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice.
    J Immunol. 2003 Dec 1;171(11):6173-7 PMID: 14634133
  38. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation.
    J Exp Med. 2003 Dec 15;198(12):1951-7 PMID: 14662908
  39. Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis.
    Nature. 2004 Apr 15;428(6984):758-63 PMID: 15085135
  40. Immunohistochemical studies of interleukin-2 and gamma-interferon in rheumatoid arthritis.
    Arthritis Rheum. 1985 Feb;28(2):174-81 PMID: 3918543
  41. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins.
    J Immunol. 1986 Apr 1;136(7):2348-57 PMID: 2419430
  42. Immune response in mice that lack the interferon-gamma receptor.
    Science. 1993 Mar 19;259(5102):1742-5 PMID: 8456301
  43. Essential role of Stat6 in IL-4 signalling.
    Nature. 1996 Apr 18;380(6575):627-30 PMID: 8602263
  44. The role of T-lymphocytes and cytokines in rheumatoid arthritis.
    Scand J Rheumatol. 1996;25(1):1-4 PMID: 8774548
  45. Effects of T cell adoptive transfer into nude mice on alveolar bone resorption induced by endotoxin.
    J Periodontal Res. 1996 Aug;31(6):414-22 PMID: 8884635
  46. Shift toward T lymphocytes with a T helper 1 cytokine-secretion profile in the joints of patients with rheumatoid arthritis.
    Arthritis Rheum. 1996 Dec;39(12):1961-9 PMID: 8961900
  47. Interleukin-18 (interferon-gamma-inducing factor) is produced by osteoblasts and acts via granulocyte/macrophage colony-stimulating factor and not via interferon-gamma to inhibit osteoclast formation.
    J Exp Med. 1997 Mar 17;185(6):1005-12 PMID: 9091574
  48. T-cells in the pathogenesis of rheumatoid arthritis villains or accomplices?
    Biochim Biophys Acta. 1997 Apr 12;1360(2):109-41 PMID: 9128178
  49. High susceptibility to collagen-induced arthritis in mice lacking IFN-gamma receptors.
    J Immunol. 1997 Jun 1;158(11):5501-6 PMID: 9164973
  50. Accelerated collagen-induced arthritis in IFN-gamma receptor-deficient mice.
    J Immunol. 1997 Jun 1;158(11):5507-13 PMID: 9164974
  51. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis.
    J Clin Invest. 1999 May;103(9):1345-52 PMID: 10225978
  52. Strength of TRAF6 signalling determines osteoclastogenesis.
    EMBO Rep. 2005 Feb;6(2):171-6 PMID: 15678156
Article Info
Journal
The Journal of experimental medicine
Abbr.
J Exp Med
ISSN
0022-1007
DOI
10.1084/jem.20061775
Published
2006-11-27
Epub
2006-00-06
Pages
2673-82
Language
English
Region
United States
NLM ID
2985109R
PMCID
PMC2118166
Subset
IM
External Links
PubMed source DOI: 10.1084/jem.20061775 PMC Full Text View journal details
Analysis Services
Analysis Services

Contact

No. 2 Wenbo Road, Zhangqiu District, Jinan, Shandong

Qilu Normal University · Genelibs Bioinformatics Lab

750 Shunhua Rd, Jinan

2F, Bldg F, University Science Park

Tel: 0531-88819269

WeChat Official Account

Follow our WeChat subscription account for real-time updates and the latest in medical and biological research.


Business Email

E-mail: product@genelibs.com

Copyright © 2026.Genelibs Jinan Honghui Biotechnology Co., Ltd. 鲁ICP备20007159号-2