DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features
Open accessAbstract
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL), Nasu-Hakola disease, is a globally distributed recessively inherited disease. PLOSL is characterized by cystic bone lesions, osteoporotic features, and loss of white matter in the brain leading to spontaneous bone fractures and profound presenile dementia. We have earlier characterized the molecular genetic background of PLOSL by identifying mutations in two genes, DAP12 and TREM2. DAP12 is a transmembrane adaptor protein that associates with the cell surface receptor TREM2. The DAP12-TREM2 complex is involved in the maturation of dendritic cells. To test a hypothesis that osteoclasts would be the cell type responsible for the bone pathogenesis in PLOSL, we analyzed the differentiation of peripheral blood mononuclear cells isolated from DAP12- and TREM2-deficient PLOSL patients into osteoclasts. Here we show that loss of function mutations in DAP12 and TREM2 result in an inefficient and delayed differentiation of osteoclasts with a remarkably reduced bone resorption capability in vitro. These results indicate an important role for DAP12-TREM2 signaling complex in the differentiation and function of osteoclasts.
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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 [13]
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- Authors
- Paloneva, J., Mandelin, J., Kiialainen, A., Böhling, T., Prudlo, J., Hakola, P., Haltia, M., Konttinen, Y. T., & Peltonen, L.
- Affiliations
- 1Department of Molecular Medicine, National Public Health Institute, 00290 Helsinki, Finland
- 2Institute of Biomedicine, Department of Anatomy
- 4Department of Pathology, Helsinki University Central Hospital, 00014 University of Helsinki, Helsinki, Finland
- Universitätsklinikum des Saarlandes (DE)
- University of Eastern Finland (FI)
- University of Helsinki (FI)
- 7Department of Medicine/Invärtes medicin, 00029 Helsinki University Central Hospital and ORTON Orthopaedic Hospital of the Invalid Foundation, Helsinki, Finland
- Corresponding author
- Peltonen, Leena
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2003-08-18
- Volume
- 198
- Issue
- 4
- Pages
- 669-675
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2194176
- OpenAlex
- W2125075496
- Cited by
- 318
- References
- 25
- Citations by year
- 2026: 16 · 2025: 19 · 2024: 24 · 2023: 18 · 2022: 14 · 2021: 10 · 2020: 12 · 2019: 12 · 2018: 14 · 2017: 10 · 2016: 16 · 2015: 11 · 2014: 13 · 2013: 13 · 2012: 12
- FWCI
- 4.94
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- cc-by-nc-sa
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
- Health Sciences › Medicine › Rheumatology › Osteomyelitis and Bone Disorders Research
- Keywords
- DAP12, TREM2, Nasu-Hakola disease, osteoclastogenesis, osteoporosis, bone resorption, loss-of-function mutations, dendritic cell maturation, peripheral blood mononuclear cells, cystic bone lesions, leukoencephalopathy
- MeSH terms
- Triggering Receptor Expressed on Myeloid Cells-1, Bone and Bones, Bone Resorption, Cathepsins, Cell Differentiation, Glycoproteins, Humans, Membrane Glycoproteins, Membrane Proteins, Monocytes, Mutation, Osteoclasts, Osteoporosis, Receptors, Immunologic, Syndrome, Signal Transduction, Receptors, Tumor Necrosis Factor, Receptors, Cytoplasmic and Nuclear, Cell Size, Adaptor Proteins, Signal Transducing, Osteoprotegerin, Cathepsin K
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