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Osteoimmunology and the effects of the immune system on bone

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Abstract

In the pathogenesis of bone destruction associated with rheumatoid arthritis, the synovium is a site of active interplay between immune and bone cells. The interaction between T cells and osteoclasts is a critical issue in the field of osteoimmunology. Accumulating evidence lends support to the theory that interleukin-17-producing T-helper cells induce the expression of receptor activator of nuclear factor κB ligand in synovial cells, which, together with inflammatory cytokines, stimulates the differentiation and activation of bone-resorbing osteoclasts. In addition to cellular interactions via cytokines, the immune and skeletal systems share various other molecules, including transcription factors, signaling molecules and membrane receptors. Studies of intracellular signaling mechanisms in osteoclasts have revealed that numerous immunomodulatory molecules are involved in the regulation of bone metabolism. The regulation of immune cells by bone cells is a new feature of the investigative area of osteoimmunology that implies the novel concept of the bone marrow being a crucial part of the immune system. The emerging field of osteoimmunology is important for increasing our understanding of how antirheumatic drugs (including anti-cytokine biologics) work, as well as contributing to the development of new therapeutic strategies for rheumatic diseases.

Key Points

  • Osteoclasts perform an essential function in bone destruction associated with autoimmune arthritis

  • Aberrant expression of receptor activator of nuclear factor κB ligand (RANKL) causes enhanced osteoclastogenesis in arthritis

  • Interleukin-17-producing T-helper-17 cells comprise the crucial osteoclastogenic helper T-cell subset

  • Inflammatory cytokines directly contribute to enhanced osteoclastogenesis

  • Signaling pathways involving RANKL and immunoreceptor tyrosine-based activation motifs comprise novel therapeutic targets

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Figure 1: Mechanism of bone destruction in RA.
Figure 2: Signal transduction in osteoclast differentiation.
Figure 3: Antirheumatic drugs in the suppression of bone destruction.

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Acknowledgements

I thank T. Nakashima for critical reading and assistance in manuscript preparation. I am grateful to K. Okamoto and T. Koga for assistance in the preparation of figures. This work was supported in part by Grant-in-Aid for Creative Scientific Research from the Japan Society for the Promotion of Science, Grants-in-Aid for GCOE, Genome Network Project from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and ERATO, Takayanagi Osteonetwork Project from Japan Science and Technology Agency. It was also supported by grants from the Japan Medical Association, the Ichiro Kanehara Foundation, Takeda Science Foundation, Kowa Life Science Foundation, Naito Foundation, Inoue Foundation and Mochida Memorial Foundation.

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Takayanagi, H. Osteoimmunology and the effects of the immune system on bone. Nat Rev Rheumatol 5, 667–676 (2009). https://doi.org/10.1038/nrrheum.2009.217

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