TREM2 and b-Catenin Regulate Bone Homeostasis by Controlling the Rate of Osteoclastogenesis

TREM2 is an immunoreceptor expressed on osteoclasts (OC) and microglia that transmits intracellular signals through the adaptor DAP12. Individuals with genetic mutations inactivating TREM2 or DAP12 develop the Nasu–Hakola disease (NHD) with cystic-like lesions of the bone and brain demyelination that lead to fractures and presenile dementia. The mechanisms of this disease are poorly understood. In this study, we report that TREM2-deficient mice have an osteopenic phenotype reminiscent of NHD. In vitro, lack of TREM2 impairs proliferation and b-catenin activation in osteoclast precursors (OcP) in response to M-CSF. This defect results in accelerated differentiation of OcP into mature OC. Corroborating the importance of a balanced proliferation and differentiation of OcP for bone homeostasis, we show that conditional deletion of b-catenin in OcP also results in reduced OcP proliferation and accelerated osteoclastogenesis in vitro as well as osteopenia in vivo. These results reveal that TREM2 regulates the rate of osteoclastogenesis and provide a mechanism for the bone pathology in NHD. S keletal homeostasis is sustained by a balance between bone-forming osteoblasts (OB) and bone-resorbing osteoclasts (OC) (1). Whereas OB are of mesenchymal origin, OC originate from hematopoietic stem cells and belong to the myeloid lineage. OC differentiation and function is controlled by two major signals (2). M-CSF is required for the expansion of OC precursors (OcP) and their differentiation into mature OC. Receptor activator for NF-kB ligand (RANKL) is crucial for OcP differentiation into bone-resorbing OC (3). OC differentiation and function are also controlled by cell surface receptors, including MDL-1, TREM2, and OSCAR, which transmit intracellular signals through associated transmembrane adaptors containing ITAMs (4–11). These adaptors, including FcRg and DAP12, recruit the protein tyrosine kinase Syk, which triggers phosphorylation events ultimately leading to Ca 2+ mobilization and activation of the transcription factors NFAT, NF-kB, and AP-1 (12, 13). Moreover, recent evidence indicates that the receptor for M-CSF, although not physically associated with DAP12, uses this adaptor to transmit certain intracellular signals, particularly to activate Syk and b-catenin (14, 15). FcRg-and DAP12-associated receptors have a critical role in bone homeostasis. Mice lacking FcRg and DAP12 have markedly reduced OC function, resulting in osteopetrosis with increased bone mass and elimination of bone marrow space (16–18). In humans, inactivating mutations of either TREM2 or DAP12 result in a disorder known as Nasu–Hakola disease (NHD) or polycystic lipomembranous osteo-dysplasia with sclerosing leukoencephalopathy (19, 20). NHD patients have progressive loss of white matter in the brain, …