TREM2, a DAP12-associated receptor, regulates osteoclast differentiation and function
Open accessAbstract
UNLABELLED: Deficiency of the signaling adapter protein DAP12 or its associated receptor TREM2 is associated with abnormal OC development in humans. Here we examine the role of TREM2 in mouse OC development and function, including migration and resorption in vitro. These results provide new evidence that TREM2 regulates OC function independent of its effects on multinucleated OC differentiation. INTRODUCTION: TREM2 (triggering receptor expressed in myeloid cells-2) associates with the signaling adapter DAP12 in osteoclasts (OCs). Genetic mutation or deletion of either the TYROBP (DAP12) or TREM2 gene is associated with the human disorder of brain and bone, Nasu-Hakola disease. We and others recently showed the critical requirement for immunoreceptor tyrosine-based activation motif (ITAM) signals through DAP12 and the Fc Receptor gamma chain (FcRgamma) during OC development. Here, we further define the role of TREM2 in OC differentiation and describe a role for TREM2 in OC migration and bone resorption. MATERIALS AND METHODS: We generated monoclonal anti-mouse TREM2 antibodies (mAb), analyzed pre-osteoclasts and mature OCs for TREM2 surface expression, and determined the effect of antibody ligation on in vitro OC differentiation, resorption, and migration. TREM2 RNA interference (RNAi) was used to disrupt expression of TREM2 in pre-osteoclasts. RESULTS: Using flow cytometry, our studies reveal that TREM2 is weakly expressed on C57BL/6 bone marrow macrophages (BMMs) and is upregulated during culture with RANKL and macrophage-colony stimulating factor (M-CSF). The expression of TREM2 is unaltered in DAP12-deficient OCs. Using C57BL/6 BMMs or RAW264.7 precursors, anti-TREM2 mAb treatment with RANKL and M-CSF enhances the formation of multinuclear TRACP+ OCs compared with control mAb treatment. In contrast, these agents have no effect on DAP12-deficient precursors. Monoclonal Ab blockade of TREM2 on OCs generated from C57BL/6 BMMs results in decreased resorption of artificial calcium-phosphate substrate and dentine. Reduction of TREM2 expression in RAW264.7 cells by RNAi results in loss of OC formation in response to RANKL and M-CSF. Anti-TREM2 cross-linking enhances migration of C57BL/6 OCs and RAW246.7 OCs in response to M-CSF. CONCLUSIONS: Our studies indicate that the TREM2 receptor regulates OC multinucleation as well as resorption and migration of mature OCs. Thus, TREM2-DAP12 signals regulate both OC formation and function.
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TREM2 is widely expressed in various cell types derived from the myeloid lineage, such as bone osteoclasts, and lung and peritoneal macrophages.
“It has been reported to be widely expressed in various cell types derived from the myeloid lineage, such as bone osteoclasts (12,13), and lung and peritoneal macrophages (14).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [12]
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- Authors
- Humphrey, M. B., Daws, M. R., Spusta, S. C., Niemi, E. C., Torchia, J. A., Lanier, L. L., Seaman, W. E., & Nakamura, M. C.
- Affiliations
- San Francisco VA Medical Center (US)
- University of Oslo (NO)
- University of California, San Francisco (US)
- Corresponding author
- Humphrey, Mary Beth
- Venue
- Journal of Bone and Mineral Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2006-02-01
- Volume
- 21
- Issue
- 2
- Pages
- 237-245
- ISSN
- 0884-0431 (ISSN-L)
- 1523-4681
- OpenAlex
- W2168525870
- Cited by
- 162
- References
- 21
- Citations by year
- 2026: 4 · 2025: 8 · 2024: 12 · 2023: 7 · 2022: 9 · 2021: 8 · 2020: 7 · 2019: 5 · 2018: 6 · 2017: 8 · 2016: 7 · 2015: 8 · 2014: 10 · 2013: 6 · 2012: 13
- FWCI
- 4.89
- Type
- journal article
- Language
- en
- Open access
- green
- www.escholarship.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Journal of Bone and Mineral Research (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (I01 BX000615)
- National Institutes of Health
- National Cancer Institute (R01CA087922, R01-CA87922, R01 CA89294, R01CA089294)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR050038)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- TREM2, DAP12, osteoclastogenesis, osteoclast migration, bone resorption, ITAM signaling, RANKL, macrophage colony-stimulating factor, bone marrow-derived macrophages, Nasu-Hakola disease, tartrate-resistant acid phosphatase, FcRγ, ITAM, RAW 264.7 macrophages
- MeSH terms
- Animals, Antibodies, Monoclonal, Bone Resorption, Carrier Proteins, Cell Differentiation, Cells, Cultured, Chemotaxis, Membrane Glycoproteins, Mice, Inbred C57BL, Osteoclasts, Receptors, Immunologic, Macrophage Colony-Stimulating Factor, RNA Interference, Adaptor Proteins, Signal Transducing, Mice, RANK Ligand, Receptor Activator of Nuclear Factor-kappa B
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