Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand (original) (raw)
- Letter
- Published: 18 November 1999
- Ulrich Feige2 na1,
- Iidiko Sarosi3,
- Brad Bolon3,
- Anna Tafuri1,
- Sean Morony3,
- Casey Capparelli3,
- Ji Li4,
- Robin Elliott4,
- Susan McCabe4,
- Thomas Wong5,
- Giuseppe Campagnuolo2,
- Erika Moran6,
- Earl R. Bogoch6,
- Gwyneth Van3,
- Linh T. Nguyen7 na1,
- Pamela S. Ohashi7 na1,
- David L. Lacey3,
- Eleanor Fish5,
- William J. Boyle4 &
- …
- Josef M. Penninger1,7 na1
Nature volume 402, pages 304–309 (1999)Cite this article
- 4285 Accesses
- 1326 Citations
- 12 Altmetric
- Metrics details
Abstract
Bone remodelling and bone loss are controlled by a balance between the tumour necrosis factor family molecule osteoprotegerin ligand (OPGL) and its decoy receptor osteoprotegerin (OPG)1,2,3. In addition, OPGL regulates lymph node organogenesis, lymphocyte development and interactions between T cells and dendritic cells in the immune system3,4,5. The OPGL receptor, RANK, is expressed on chondrocytes, osteoclast precursors and mature osteoclasts4,6. OPGL expression in T cells is induced by antigen receptor engagement7, which suggests that activated T cells may influence bone metabolism through OPGL and RANK. Here we report that activated T cells can directly trigger osteoclastogenesis through OPGL. Systemic activation of T cells in vivo leads to an OPGL-mediated increase in osteoclastogenesis and bone loss. In a T-cell-dependent model of rat adjuvant arthritis characterized by severe joint inflammation, bone and cartilage destruction and crippling, blocking of OPGL through osteoprotegerin treatment at the onset of disease prevents bone and cartilage destruction but not inflammation. These results show that both systemic and local T-cell activation can lead to OPGL production and subsequent bone loss, and they provide a novel paradigm for T cells as regulators of bone physiology.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Similar content being viewed by others
References
- Simonet,W. S. et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89, 309–319 (1997).
Article CAS PubMed Google Scholar - Lacey,D. L. et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165–176 (1998).
Article CAS PubMed Google Scholar - Kong,Y. Y. et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999).
Article ADS CAS PubMed Google Scholar - Anderson,D. M. et al. A homologue of the TNF receptor and its ligand enhance T-cell growth and dendritic-cell fucntion. Nature 390, 175–179 (1997).
Article ADS CAS PubMed Google Scholar - Wong,B. r. et al. TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. J. Exp. Med. 186, 2075–2080 (1997).
Article CAS PubMed PubMed Central Google Scholar - Hsu,H. et al. Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc. Natl Acad. Sci. USA 96, 3540–3545 (1999).
Article ADS CAS PubMed PubMed Central Google Scholar - Wong,B. R. et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J. Biol. Chem. 272, 25190–25194 (1997).
Article CAS PubMed Google Scholar - Felix,R., Hofstetter,W. & Cecchini,M. G. Recent developments in the understanding of the pathophysiology of osteopetrosis. Eur. J. Endocrinol. 134, 143–156 (1996).
Article CAS PubMed Google Scholar - Roodman,G. D. Advances in bone biology: the osteoclast. Endocr. Rev. 17, 308–332 (1996).
CAS PubMed Google Scholar - Roodman,G. D. Paget's disease and osteoclast biology. Bone 19, 209–212 (1996).
Article CAS PubMed Google Scholar - Coleman,R. E., Smith,P. & Rubens,R. D. Clinical course and prognostic factors following bone recurrence from breast cancer. Br. J. Cancer 77, 336–340 (1998).
Article CAS PubMed PubMed Central Google Scholar - Stellon,A. J., Davies,A., Compston,J. & Williams,R. Bone loss in autoimmune chronic active hepatitis on maintenance corticosteroid therapy. Gastroenterology 89, 1078–1083 (1985).
Article CAS PubMed Google Scholar - Oliveri,M. B., Mautalen,C. A., Rodriguez Fuchs,C. A. & Romanelli,M. C. Vertebral compression fractures at the onset of acute lymphoblastic leukemia in a child. Henry Ford Hosp. Med. J. 39, 45–48 (1991).
CAS PubMed Google Scholar - Piepkorn,B. et al. Bone mineral density and bone metabolism in diabetes mellitus. Horm. Metab. Res. 29, 584–591 (1997).
Article CAS PubMed Google Scholar - Feldmann,M., Brennan,F. M. & Maini,R. N. Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol. 14, 397–440 (1996).
Article CAS PubMed Google Scholar - Kotake,S. et al. IL-17 in synovial fluids from patients with rheumatoid arthritis is a potent stimulator of osteoclastogenesis. J. Clin. Invest. 103, 1345–1352 (1999).
Article CAS PubMed PubMed Central Google Scholar - Josien,R., Wong,B. R., Li,H. L., Steinman,R. M. & Choi,Y. TRANCE, a TNF family member, is differentially expressed on T cell subsets and induces cytokine production in dendritic cells. J. Immunol. 162, 2562–2568 (1999).
Article CAS PubMed Google Scholar - Waterhouse,P. et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270, 985–988 (1995).
Article ADS CAS PubMed Google Scholar - Mombaerts,P. et al. RAG-1-deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992).
Article CAS PubMed Google Scholar - Bendele,A. et al. Efficacy of sustained blood levels of interleukin-1 receptor antagonist in animal models of arthritis: comparison of efficacy in animal models with human clinical data. Arthritis Rheum. 42, 498–506 (1999).
Article CAS PubMed Google Scholar - Panayi,G. S., Lanchbury,J. S. & Kingsley,G. H. The importance of the T cell in initiating and maintaining the chronic synovitis of rheumatoid arthritis. Arthritis Rheum. 35, 729–735 (1992).
Article CAS PubMed Google Scholar - Muller-Ladner,U., Gay,R. E. & Gay,S. Molecular biology of cartilage and bone destruction. Curr. Opin. Rheumatol. 10, 212–219 (1998).
Article CAS PubMed Google Scholar - Conway,J. G. et al. Inhibition of cartilage and bone destruction in adjuvant arthritis in the rat by a matrix metalloproteinase inhibitor. J. Exp. Med. 182, 449–457 (1995).
Article CAS PubMed Google Scholar - Faust,J. et al. Osteoclast markers accumulate on cells developing from human peripheral blood mononuclear precursors. J. Cell. Biochem. 72, 67–80 (1999).
Article CAS PubMed Google Scholar
Acknowledgements
We thank E. C. Keystone for providing patient samples and C. Dunstan for critical comments. Technical assistance was provided by Y. Cheng, E. Julian, C. Burgh, A. Shahinian and D. Duryea. We are grateful to M. E. Saunders for scientific editing and A. Hessel, A. Oliveira dos Santos, K. Bachmaier, T. Sasaki and all other members of the laboratory for comments.
Author information
Author notes
- Young-Yun Kong, Ulrich Feige, Linh T. Nguyen, Pamela S. Ohashi and Josef M. Penninger: These authors contributed equally to this work
Authors and Affiliations
- Amgen Institute, 620 University Avenue, Toronto, M5G 2C1, Ontario, Canada
Young-Yun Kong, Anna Tafuri & Josef M. Penninger - Department of Pharmacology,
Ulrich Feige & Giuseppe Campagnuolo - Pathology, and,
Iidiko Sarosi, Brad Bolon, Sean Morony, Casey Capparelli, Gwyneth Van & David L. Lacey - Cell Biology, Amgen Inc., One Amgen Center Drive, Thousand Oaks, 91320-1789, California, USA
Ji Li, Robin Elliott, Susan McCabe & William J. Boyle - Department of Medical Genetics & Microbiology,
Thomas Wong & Eleanor Fish - St Michael's Hospital,
Erika Moran & Earl R. Bogoch - Ontario Cancer Institute and the Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada
Linh T. Nguyen, Pamela S. Ohashi & Josef M. Penninger
Authors
- Young-Yun Kong
You can also search for this author inPubMed Google Scholar - Ulrich Feige
You can also search for this author inPubMed Google Scholar - Iidiko Sarosi
You can also search for this author inPubMed Google Scholar - Brad Bolon
You can also search for this author inPubMed Google Scholar - Anna Tafuri
You can also search for this author inPubMed Google Scholar - Sean Morony
You can also search for this author inPubMed Google Scholar - Casey Capparelli
You can also search for this author inPubMed Google Scholar - Ji Li
You can also search for this author inPubMed Google Scholar - Robin Elliott
You can also search for this author inPubMed Google Scholar - Susan McCabe
You can also search for this author inPubMed Google Scholar - Thomas Wong
You can also search for this author inPubMed Google Scholar - Giuseppe Campagnuolo
You can also search for this author inPubMed Google Scholar - Erika Moran
You can also search for this author inPubMed Google Scholar - Earl R. Bogoch
You can also search for this author inPubMed Google Scholar - Gwyneth Van
You can also search for this author inPubMed Google Scholar - Linh T. Nguyen
You can also search for this author inPubMed Google Scholar - Pamela S. Ohashi
You can also search for this author inPubMed Google Scholar - David L. Lacey
You can also search for this author inPubMed Google Scholar - Eleanor Fish
You can also search for this author inPubMed Google Scholar - William J. Boyle
You can also search for this author inPubMed Google Scholar - Josef M. Penninger
You can also search for this author inPubMed Google Scholar
Supplementary information
Rights and permissions
About this article
Cite this article
Kong, YY., Feige, U., Sarosi, I. et al. Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand.Nature 402, 304–309 (1999). https://doi.org/10.1038/46303
- Received: 06 August 1999
- Accepted: 23 September 1999
- Issue Date: 18 November 1999
- DOI: https://doi.org/10.1038/46303