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A Comprehensive Review of Immunoreceptor Regulation of Osteoclasts

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Abstract

Osteoclasts require coordinated co-stimulation by several signaling pathways to initiate and regulate their cellular differentiation. Receptor activator for NF-κB ligand (RANKL or TNFSF11), a tumor necrosis factor (TNF) superfamily member, is the master cytokine required for osteoclastogenesis with essential co-stimulatory signals mediated by immunoreceptor tyrosine-based activation motif (ITAM)-signaling adaptors, DNAX-associated protein 12 kDa size (DAP12) and FcεRI gamma chain (FcRγ). The ITAM-signaling adaptors do not have an extracellular ligand-binding domain and, therefore, must pair with ligand-binding immunoreceptors to interact with their extracellular environment. DAP12 pairs with a number of different immunoreceptors including triggering receptor expressed on myeloid cells 2 (TREM2), myeloid DAP12-associated lectin (MDL-1), and sialic acid-binding immunoglobulin-type lectin 15 (Siglec-15); while FcRγ pairs with a different set of receptors including osteoclast-specific activating receptor (OSCAR), paired immunoglobulin receptor A (PIR-A), and Fc receptors. The ligands for many of these receptors in the bone microenvironment remain unknown. Here, we will review immunoreceptors known to pair with either DAP12 or FcRγ that have been shown to regulate osteoclastogenesis. Co-stimulation and the effects of ITAM-signaling have turned out to be complex, and now include paradoxical findings that ITAM-signaling adaptor-associated receptors can inhibit osteoclastogenesis and immunoreceptor tyrosine-based inhibitory motif (ITIM) receptors can promote osteoclastogenesis. Thus, co-stimulation of osteoclastogenesis continues to reveal additional complexities that are important in the regulatory mechanisms that seek to maintain bone homeostasis.

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Acknowledgments

We thank T. P. Quinn for helpful suggestions and editing the manuscript. M. B. H. is supported by NIH grant AR064211. M. C. N. is supported by a VA Merit Review, NIH grant AG046282, the UCSF-Stanford Arthritis Center of Excellence funded by the Great Western Region of the Arthritis Foundation, the Rheumatology Research Foundation, and the Russell/Engleman Rheumatology Research Center.

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  1. Division of Rheumatology, Immunology, and Allergy, Department of Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th St., BRC209, Oklahoma City, OK, 73104, USA

    Mary Beth Humphrey

  2. Division of Rheumatology, Department of Medicine, University of California, San Francisco, CA, USA

    Mary C. Nakamura

  3. Arthritis/Immunology Section, San Francisco Veterans Administration Medical Center, 4150 Clement St 111R, San Francisco, CA, 94121, USA

    Mary C. Nakamura

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Correspondence to Mary C. Nakamura.

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Mary Beth Humphrey and Mary C. Nakamura declare that they have no conflict of interest.

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Humphrey, M.B., Nakamura, M.C. A Comprehensive Review of Immunoreceptor Regulation of Osteoclasts. Clinic Rev Allerg Immunol 51, 48–58 (2016). https://doi.org/10.1007/s12016-015-8521-8

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