Signal adaptor DAP10 associates with MDL-1 and triggers osteoclastogenesis in cooperation with DAP12
Signal adaptor DAP10 associates with MDL-1 and triggers osteoclastogenesis in cooperation with DAP12
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DOI：
10.1073/pnas.0900463106
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发表时间：
2009-03-24
影响因子：
11.1
通讯作者：
Takai, Toshiyuki
中科院分区：
文献类型：
--
作者：
Inui, Masanori;Kikuchi, Yuki;Takai, Toshiyuki
破骨细胞是骨髓系细胞，在骨吸收中起着独特的作用，与成骨细胞一起维持骨骼的稳态。破骨细胞发育和成熟（破骨细胞生成）由NF-κ B配体和巨噬细胞集落刺激因子的受体活化剂驱动，并且总是需要由免疫受体酪氨酸基活化基序（ITAM）-携带Fc受体共同γ链或DNA X活化蛋白（DAP）12（也称为KARAP或TYROBP）启动的信号，其与同源免疫受体相关。在这里，我们表明，第三个适配器，YINM共刺激基序窝藏DAP 10，触发破骨细胞生成和骨重建。DAP 10缺陷（DAP 10（-/-））小鼠随着年龄的增长变得骨硬化，伴随着破骨细胞的减少。DAP 10相关受体被鉴定为髓样DAP 12相关凝集素-1（MDL-1），其生理功能尚未被发现，MDL-1介导的破骨细胞前体细胞的刺激导致体外破骨细胞生成增加。MDL-1与破骨细胞和骨髓源性巨噬细胞中的DAP 12和DAP 10都相关，其中DAP 10的相关性几乎完全依赖于DAP 12，这表明在复合物中含有ITAM/YINM刺激/共刺激基序的MDL-1-DAP 12/DAP 10三分子复合物的形成可能是骨骼和炎性疾病的新治疗靶点。
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-kappa B 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.