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Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems

Nature Reviews Immunology volume 7, pages 292–304 (2007)Cite this article

Key Points

  • Osteoimmunology is an interdisciplinary field, that covers the shared mechanisms and interactions between bone cells and immune cells

  • Receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL) is an osteoclast-differentiation factor that links the activated immune system and bone loss. In addition, abnormal bone homeostasis has been observed in various mice deficient in immunomodulatory molecules.

  • Osteoclast differentiation is dependent on the transcription factor nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), which is induced and activated by RANKL and its co-stimulatory (immunoglobulin-like) receptors.

  • Interleukin-17 (IL-17)-producing T helper cells (TH17 cells) are the key T-cell subset that links T-cell activation and bone destruction in autoimmune arthritis.

  • Bone cells are involved in the maintenance and mobilization of haematopoietic stem cells.

  • Osteoimmunology is becoming increasingly important for understanding the pathogenesis of, and developing new therapeutic strategies for, diseases that affect both systems.

Abstract

Osteoimmunology is an interdisciplinary research field focused on the molecular understanding of the interplay between the immune and skeletal systems. Although osteoimmunology started with the study of the immune regulation of osteoclasts, its scope has been extended to encompass a wide range of molecular and cellular interactions, including those between osteoblasts and osteoclasts, lymphocytes and osteoclasts, and osteoblasts and haematopoietic cells. Therefore, the two systems should be understood to be integrated and operating in the context of the 'osteoimmune' system, a heuristic concept that provides not only a framework for obtaining new insights by basic research, but also a scientific basis for the discovery of novel treatments for diseases related to both systems.

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Figure 1: The osteoimmune system.
Figure 2: Spatiotemporal control of signal transduction during osteoclastogenesis.
Figure 3: Osteoimmunological interactions in osteoclasts and osteoblasts.
Figure 4: How T cells induce osteoclastogenesis in autoimmune arthritis.

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Acknowledgements

We thank Y. Choi, G. Karsenty, N. Takahashi, K. Matsuo, T. Nakashima, M. Asagiri, T. Koga and M. Shinohara for critical reading of the manuscript and fruitful discussion. The work was supported in part by Grants-in-Aid for Creative Scientific Research from Japan Society for the Promotion of Science, SORST program of Japan Science and Technology Agency, Grants-in-Aid for the 21st century COE program and Genome Network Project from Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT), Grants-in-Aid for Scientific Research from MEXT, and Health Sciences Research Grants from the Ministry of Health, Labour and Welfare of Japan.

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  1. Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, 113-8549, Tokyo

    Hiroshi Takayanagi

  2. COE Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University; and SORST, Japan Science and Technology Agency, Honcho 4-1-8, Kawaguchi, 332-0012, Saitama, Japan

    Hiroshi Takayanagi

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Supplementary information S1 (table)

List of bone phenotypes in mice deficient in osteoimmunoregulatory molecules (PDF 799 kb)

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Glossary

Osteoclastogenesis

A process whereby haematopoietic stem cells differentiate into multinucleated osteoclasts with bone-resorbing activity.

Osteoporosis

A metabolic or ageing-related (often occurring in post-menopausal women) disease in which low bone mineral density causes bone fragility.

Mechanotransduction

A process by which the mechanical stress (such as gravity, loading and tension) is converted to biological responses, which in this case control bone remodelling.

Osteopetrosis

A rare congenital disease with extremely high bone mass and low strength (typically, no bone-marrow formation and no tooth eruption), which results from impaired differentiation or function of osteoclasts.

Familial expansile osteolysis

(FEO). A rare autosomal-dominant disorder resembling Paget's disease of bone (PDB), characterized by the erosion of long bones by progressive osteoclastic resorption (the constitutive active mutation of RANK has been reported).

Paget's disease of the bone

(PDB). A metabolic bone disorder in which focal abnormalities of increased bone turnover (excessive osteoclastic bone resorption and irregular bone formation) lead to bone pain and deformity.

Osteopaenia

A decrease in bone mineral density.

Nasu–Hakola disease

A rare autosomal-recessive disease characterized by systemic bone cysts and psychotic symptoms similar to dementia or schizophrenia (mutations in DAP12 or TREM2 genes are reported).

Trabecular bone

A spongy and low-density type of osseous tissue with high surface area, which fills up the inner cavity of long bones and vertebrae.

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Takayanagi, H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 7, 292–304 (2007). https://doi.org/10.1038/nri2062

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