Inui Masanori, Kikuchi Yuki, Aoki Naoko, Endo Shota, Maeda Tsutomu, Sugahara-Tobinai Akiko, Fujimura Shion, Nakamura Akira, Kumanogoh Atsushi, Colonna Marco, Takai Toshiyuki
Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo 4-1, Sendai 980-8575, Japan.
Proc Natl Acad Sci U S A. 2009 Mar 24;106(12):4816-21. doi: 10.1073/pnas.0900463106. Epub 2009 Feb 27.
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-kappaB ligand and macrophage-colony stimulating factor and invariably requires a signal initiated by immunoreceptor tyrosine-based activation motif (ITAM)-harboring Fc receptor common gamma 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.
破骨细胞是髓系来源的细胞，在骨吸收过程中发挥独特作用，与成骨的成骨细胞协同维持骨骼稳态。破骨细胞的发育和成熟（破骨细胞生成）由核因子κB受体活化因子配体和巨噬细胞集落刺激因子驱动，并且总是需要由基于免疫受体酪氨酸的活化基序（ITAM）的Fc受体共同γ链或DNAX活化蛋白（DAP）12（也称为KARAP或TYROBP）引发的信号，该信号与同源免疫受体相关联。在此，我们表明，第三个衔接蛋白，即含有YINM共刺激基序的DAP10，可触发破骨细胞生成和骨重塑。随着年龄增长，DAP10缺陷（DAP10(-/-)）小鼠会出现骨质石化，同时破骨细胞数量减少。与DAP10相关的受体被鉴定为髓系DAP12相关凝集素-1（MDL-1），其生理功能尚未明确。MDL-1介导的对破骨细胞前体细胞的刺激导致体外破骨细胞生成增加。在破骨细胞和骨髓来源的巨噬细胞中，MDL-1与DAP12和DAP10均相关联，其中DAP10与MDL-1的关联几乎完全依赖于DAP12，这表明形成了含有ITAM/YINM刺激/共刺激基序的MDL-1-DAP12/DAP10三分子复合物，该复合物可能是骨骼和炎性疾病的新型治疗靶点。
