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¹ Department of Molecular Medicine, National Public Health Institute, 00290 Helsinki, Finland
² Institute of Biomedicine, Department of Anatomy
³ Department of Medical Genetics, 00014 University of Helsinki, Helsinki, Finland
⁴ Department of Pathology, Helsinki University Central Hospital, 00014 University of Helsinki, Helsinki, Finland
⁵ Department of Neurology, University Hospital, D-66421 Homburg/Saar, Germany
⁶ Department of Forensic Psychiatry, University of Kuopio, 70240 Kuopio, Finland
⁷ Department of Medicine/Invärtes medicin, 00029 Helsinki University Central Hospital and ORTON Orthopaedic Hospital of the Invalid Foundation, Helsinki, Finland

Address correspondence to Leena Peltonen, Biomedicum/National Public Health Institute, Department of Molecular Medicine, Haartmaninkatu 8, 00290 Helsinki, Finland. Phone: 358-9-47448496; Fax: 358-9-47448480; email: leena.peltonen{at}ktl.fi

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.

Key Words: bone diseases • central nervous system diseases • osteoporosis • monocytes • dementia

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