DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features - PubMed (original) (raw)
DAP12/TREM2 deficiency results in impaired osteoclast differentiation and osteoporotic features
Juha Paloneva et al. J Exp Med. 2003.
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.
Figures
Figure 1.
Impaired multinucleation and bone resorption capability of genetically deficient osteoclasts. (A) The number of multinucleated (three or more nuclei) DAP12- or TREM2-deficient (open bars) osteoclastic cells per 106 adherent PBMCs calculated at day 1 was lower than that of controls (solid bars; P < 0.01) after stimulation with M-CSF and RANKL for 7 and 14 d. (B) The total surface area per dentine slice resorbed by DAP12-deficient osteoclasts (p) after incubation on dentine for 7 d was significantly reduced compared with the controls (c; P < 0.01). (C) The resorbed surface area per DAP12-deficient osteoclast (p) was markedly smaller than that of the controls (c; P < 0.05). (D) The resorption pits generated by DAP12-deficient osteoclasts were significantly deeper compared with the controls (P < 0.0001). The error bars indicate the standard error of the mean.
Figure 2.
TRAP staining of DAP12-, TREM2-deficient, and control osteoclastic cells differentiated from PBMCs. DAP12- (A) and TREM2-deficient (B) osteoclastic cells are intensely TRAP+ and much smaller than the control osteoclasts (C) after stimulation for 7 d. Only occasional genetically deficient cells contain two to three nuclei. Note the numerous processes in DAP12-deficient osteoclastic cells.
Figure 3.
Morphological characteristics of DAP12- and TREM2-deficient osteoclastic cells and control osteoclasts after stimulation for 14 d. (A–C, same visual field) DAP12-deficient osteoclastic cells are small and cathepsin K+ (A). Staining for DAPI demonstrates that only occasional cells have a few nuclei (B). Phalloidin staining for actin demonstrates numerous small unorganized actin clusters in DAP12-deficient osteoclastic cells (C). (D–F, same visual field) TREM2-deficient osteoclastic cells are small and cathepsin K+ (D). Majority of the cells are mononuclear (E) and show a single granular ring-like actin staining pattern (F). (G–I, same visual field) The control cells are large and cathepsin K+ (G), contain multiple nuclei (H), and a single large actin ring (I). (J) A high magnification of two DAP12-deficient mononuclear osteoclastic cells demonstrates several granular, unorganized actin clusters. (K) A high magnification of a mononuclear TREM2-deficient cell shows a single granular ring-like actin staining pattern.
Figure 4.
DAP12-deficient osteoclasts are capable of bone resorption in vitro. (A) Control osteoclasts generated long continuous resorption pits. (B) The average surface area per resorption pit generated by DAP12-deficient osteoclasts is similar to controls. The resorption pits generated by genetically deficient osteoclasts are deeper compared with controls (toluidine blue staining).
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