title: DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features.
abstract: 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.
authors.affiliation: Biomedicum/National Public Health Institute, Department of Molecular Medicine, Haartmaninkatu 8, 00290 Helsinki, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Paloneva
authors.forename: Jami
authors.initials: J
authors.lastname: Mandelin
authors.forename: Anna
authors.initials: A
authors.lastname: Kiialainen
authors.forename: Tom
authors.initials: T
authors.lastname: Bohling
authors.forename: Johannes
authors.initials: J
authors.lastname: Prudlo
authors.forename: Panu
authors.initials: P
authors.lastname: Hakola
authors.forename: Matti
authors.initials: M
authors.lastname: Haltia
authors.forename: Yrjo T
authors.initials: YT
authors.lastname: Konttinen
authors.forename: Leena
authors.initials: L
authors.lastname: Peltonen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D001862:Bone Resorption; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D056657:Cathepsin K; D002403:Cathepsins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology*; D048429:Cell Size; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009000:Monocytes / Q000378:metabolism; D009154:Mutation; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D010024:Osteoporosis / Q000378:metabolism*; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000502:physiology; D013577:Syndrome; D000073871:Triggering Receptor Expressed on Myeloid Cells-1
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006023:Glycoproteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D053244:Osteoprotegerin; D018160:Receptors, Cytoplasmic and Nuclear; D011971:Receptors, Immunologic; D018124:Receptors, Tumor Necrosis Factor; C506030:TNFRSF11B protein, human; C408842:TREM1 protein, human; C498715:TREM2 protein, human; C110546:TYROBP protein, human; D000073871:Triggering Receptor Expressed on Myeloid Cells-1; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K