Inflammatory bone destruction and osteoimmunology.
OBJECTIVE
The metabolism of hard tissue is influenced by the immune system. Research into the bone destruction associated with inflammatory diseases such as periodontal disease and rheumatoid arthritis has highlighted the importance of the interplay of the immune and skeletal systems. This interdisciplinary research field, called 'osteoimmunology', has become increasingly important for each system by itself as well as the biology linking them. The history and recent progress of this field are reviewed.


METHODS
'Osteoimmunology' was coined to describe the pioneering work on the T-cell regulation of osteoclastogenesis by the receptor activator of nuclear factor-kappaB ligand (RANKL) and interferon (IFN)-gamma. Accumulating evidence suggests that the immune and skeletal systems share not only cytokines but also various signaling molecules, transcription factors and membrane receptors. The contribution of T cells to the pathogenesis of inflammatory bone destruction is discussed, and our recent findings are summarized to illustrate how the osteoimmunological network functions.


RESULTS
RANKL is an osteoclastogenic cytokine that links bone and the immune system. Immunomodulatory cytokines such as IFNs also participate in the regulation of RANKL signaling and inflammatory bone loss. The transcription factor nuclear factor of activated T cells c1 (NFATc1) has been identified as a master switch regulator of osteoclastogenesis. In addition, immunoglobulin-like receptors are critically involved in bone homeostasis.


CONCLUSIONS
Bone turns out to be a dynamic tissue that is constantly renewed, where the immune system participates to a hitherto unexpected extent. This emerging field will be of great importance to a better understanding and treatment of diseases of the skeletal and immune systems, as well as to the fundamental biology underpinning both.
Takayanagi
Hiroshi
H
Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Center of Excellence (COE) Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Bunkyo-ku, Tokyo, Japan. taka.csi@tnd.ac.jp
D000818:Animals; D020013:Calcium Signaling; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D016899:Interferon-beta / Q000378:metabolism; D007555:Isoxazoles / Q000494:pharmacology; D000077339:Leflunomide; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins / Q000378:metabolism; D010003:Osteoarthritis / Q000276:immunology* / Q000378:metabolism*; D010010:Osteoclasts / Q000187:drug effects / Q000276:immunology*; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D013601:T-Lymphocytes / Q000502:physiology; D014157:Transcription Factors / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D007555:Isoxazoles; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; C475087:NFAM1 protein, human; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D009687:Nuclear Proteins; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; D014157:Transcription Factors; D016899:Interferon-beta; D000077339:Leflunomide