Osteoclasts, cells of myeloid lineage, play a unique role in bone resorption, maintaining skeletal homeostasis in concert with bone-producing osteoblasts. Osteoclast development and maturation (osteoclastogenesis) is driven by receptor activator of NF-κB ligand and macrophage-colony stimulating factor and invariably requires a signal initiated by immunoreceptor tyrosine-based activation motif (ITAM)-harboring Fc receptor common γ chain or DNAX-activating protein (DAP)12 (also referred to as KARAP or TYROBP) that associates with the cognate immunoreceptors. Here, we show that a third adaptor, YINM costimulatory motif-harboring DAP10, triggers osteoclastogenesis and bone remodeling. DAP10-deficient (DAP10−/−) mice become osteopetrotic with age, concomitant with a reduction in osteoclasts. The DAP10-associating receptor was identified as myeloid DAP12-associating lectin-1 (MDL-1), whose physiologic function has not been found. MDL-1-mediated stimulation of osteoclast precursor cells resulted in augmented osteoclastogenesis in vitro. MDL-1 associates with both DAP12 and DAP10 in osteoclasts and bone marrow-derived macrophages, where DAP10 association depends almost entirely on DAP12, suggesting a formation of MDL-1–DAP12/DAP10 trimolecular complexes harboring ITAM/YINM stimulatory/costimulatory motifs within a complex that could be a novel therapeutic target for skeletal and inflammatory diseases
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