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Mechanistic insight into osteoclast differentiation in osteoimmunology

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Abstract

Recently a close relationship between the immune and skeletal systems or the interdisciplinary field called osteoimmunology has attracted much attention due to the observations that bone destruction is caused by an abnormal activation of the immune system in rheumatoid arthritis, and that mice lacking immunomodulatory molecules often exhibit an unexpected bone phenotype. Osteoclasts are cells of monocyte/macrophage origin that degrade the bone matrix. They are among the key players in the control of bone metabolism in health and disease. Receptor activator of NF-κB ligand (RANKL), a tumor necrosis factor (TNF) family cytokine, induces the differentiation of osteoclasts in the presence of macrophage-colony stimulating factor. RANKL activates TRAF6, c-Fos, and calcium signaling pathways, all of which are indispensable for the induction and activation of nuclear factor of activated T cells (NFAT) c1, the master transcription factor for osteoclastogenesis. The autoamplification of NFATc1 gene results in the efficient induction of osteoclast-specific genes. An AP-1 transcription factor complex containing c-Fos plays a crucial role in these processes, although results in conditional knockout mice show that Jun family members have a redundant role. The immunoreceptor tyrosine-based activation motif (ITAM) is an important signaling component for a number of receptors in the immune system including T-cell, B-cell, NK-cell, and Fc receptors, but its contribution to the skeletal system remains unclarified. In search for the calcium-mobilizing mechanism during osteoclastogenesis we determined that multiple immunoglobulinlike receptors associated with ITAM-harboring adaptors, Fc receptor common γ chain (FcRγ), and DNAX-activating protein (DAP) 12, are essential for osteoclastogenesis. In osteoclast precursor cells FcRγ-associated receptors include osteoclast-associated receptor and paired immunoglobulinlike receptor A, while triggering receptor expressed in myeloid cells 2 and signal-regulatory protein β1 preferentially associate with DAP12. In cooperation with RANKL these receptors activate phospholipase Cγ and calcium signaling essential for the induction of NFATc1 through ITAM phosphorylation. Thus we have established the importance of the ITAM-mediated costimulatory signals in RANKL-induced osteoclast differentiation, which is analogous to the role of costimulatory signals in the immune system. Here we summarize recent advances in the study of signaling mechanism of osteoclast differentiation in the context of osteoimmunology.

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Abbreviations

AP :

Activator protein

BMM :

Bone marrow-derived monocyte/macrophage precursor cell

DAP :

DNAX-activating protein

FcRγ :

Fc receptor common γ chain

IFN :

Interferon

ITAM :

Immunoreceptor tyrosine-based activation motif

JNK :

Jun N-terminal kinase

MAPK :

Mitogen-activated protein kinase

M-CSF :

Macrophage-colony stimulating factor

MITF :

Microphthalmia transcription factor

NF :

Nuclear factor

NFAT :

Nuclear factor of activated T cell

OPG :

Osteoprotegerin

OSCAR :

Osteoclast-associated receptor

RANK :

Receptor activator of nuclear factor κB

RANKL :

Receptor activator of nuclear factor κB ligand

TNF :

Tumor necrosis factor

TRAF :

TNF receptor-associated factor

TREM :

Triggering receptor expressed in myeloid cells

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Acknowledgements

I appreciate T. Taniguchi, T. Takai, M. Inui, T. Koga and S. Kim for their great contribution to the publications, on which this work is based. I also thank K. Matsuo, T. Nakajima, A. Suematsu, K. Sato, M. Asagiri and Y. Kim for critical reading of the manuscript and discussion. This work was supported in part by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan and JSPS, the PRESTO program of JST, grants for the 21st century COE program, Health Sciences Research Grants from the Ministry of Health, Labor and Welfare of Japan, and grants from the Mitsubishi Foundation, The Kato Trust for Nambyo Research and Takeda Science foundation.

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  1. Department of Cellular Physiological Chemistry, COE Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Graduate School, Tokyo Medical and Dental University, Yushima 1-5-45, Bunkyo-ku, 113-8549, Tokyo, Japan

    Hiroshi Takayanagi

  2. PRESTO, Japan Science and Technology Agency, Huncho 4-1-8, Kawaguchi, 332-0012, Saitama, Japan

    Hiroshi Takayanagi

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Takayanagi, H. Mechanistic insight into osteoclast differentiation in osteoimmunology. J Mol Med 83, 170–179 (2005). https://doi.org/10.1007/s00109-004-0612-6

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