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Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand

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.

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Figure 1: Activated T cells induce osteoclastogenesis through OPGL.
Figure 2: Activated T cells affect bone physiology in vivo.
Figure 3: OPG blocks bone loss in adjuvant-induced arthritis (AdA).
Figure 4: OPG prevents bone and cartilage destruction even in the presence of severe inflammation.

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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.

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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

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