The enigmatic function of TREM-2 in osteoclastogenesis.
The triggering receptor expressed on myeloid cells 2 (TREM-2) is a member of family of receptors that play a central role in regulating function of myeloid cells. TREM-2 is expressed on macrophages, microglia and pre-osteoclasts and transduces intracellular signals through the adaptor DAP12. In human, genetic defects of TREM-2 and DAP12 result in a rare syndrome characterized by presenile dementia and bone cysts. This syndrome and the tissue distribution of TREM-2 have indicated a role of the TREM-2/DAP12 complex in brain function and bone modeling, particularly osteoclastogenesis. Accordingly, human TREM-2- and DAP12-deficient pre-osteoclast precursors failed to differentiate in vitro into mature osteoclasts endowed with bone resorptive activity. In mouse, DAP12-deficiency also resulted in impaired osteoclastogenesis in vitro and a mild osteopetrosis in vivo although bone cysts were not observed. Surprisingly, TREM-2-deficiency in mouse led to accelerated osteoclastogenesis in vitro without osteopetrosis or bone cysts in vivo, revealing an unexpected inhibitory function of mouse TREM-2. These data demonstrate that TREM-2 function is essential for normal osteoclastogenesis. The conflicting results as to the relationship between TREM-2, DAP12 and osteoclastogenesis and bone modeling in human and mouse suggest that TREM-2 contribution to osteoclast biology may vary depending on the influence of additional DAP12-associated receptors and on the presence of TREM-2 ligands with variable avidity/affinity, which may induce either activating or an inhibitory signals through TREM-2/DAP12.
Colonna
Marco
M
Washington University School of Medicine, St. Louis, Department of Pathology and Immunology, MO, USA. mcolonna@pathology.wustl.edu
Turnbull
Isaiah
I
Klesney-Tait
Julia
J
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001845:Bone Cysts / Q000235:genetics; D002454:Cell Differentiation; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D008954:Models, Biological; D010009:Osteochondrodysplasias / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
D048868:Adaptor Proteins, Signal Transducing; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D053245:RANK Ligand; D011971:Receptors, Immunologic; C505688:TNFSF11 protein, human; C498715:TREM2 protein, human; C110546:TYROBP protein, human