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首页> 外文期刊>Nature >Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis
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Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis

机译：由ITAM主题介导的共刺激信号与RANKL协同作用以实现骨稳态

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摘要

Costimulatory signals are required for activation of immune cells, but it is not known whether they contribute to other biological systems. The development and homeostasis of the skeletal system depend on the balance between bone formation and resorption. Receptor activator of NF-κB ligand (RANKL) regulates the differentiation of bone-resorbing cells, osteoclasts, in the presence of macrophage-colony stimulating factor (M-CSF). But it remains unclear how RANKL activates the calcium signals that lead to induction of nuclear factor of activated T cells c1, a key transcription factor for osteoclastogen-esis. Here we show that mice lacking immunoreceptor tyrosine-based activation motif (ITAM)-harbouring adaptors, Fc receptor common γ subunit (FcRγ) and DNAX-activating protein (DAP)12, exhibit severe osteopetrosis owing to impaired osteoclast differentiation. In osteoclast precursor cells, FcRγ and DAP12 associate with multiple immunoreceptors and activate calcium signalling through phospholipase Cγ. Thus, ITAM-dependent costimulatory signals activated by multiple immunoreceptors are essential for the maintenance of bone homeostasis. These results reveal that RANKL and M-CSF are not sufficient to activate the signals required for osteoclastogenesis.
机译：共刺激信号是激活免疫细胞所必需的，但尚不清楚它们是否有助于其他生物系统。骨骼系统的发育和体内平衡取决于骨形成和吸收之间的平衡。在巨噬细胞集落刺激因子（M-CSF）存在下，NF-κB配体的受体激活剂（RANKL）调节骨吸收细胞，破骨细胞的分化。但是，尚不清楚RA​​NKL如何激活钙信号，从而导致活化的T细胞c1（破骨细胞原形成的关键转录因子）的核因子被诱导。在这里我们显示缺乏缺乏基于免疫受体酪氨酸的激活基序（ITAM）的适配器，Fc受体共同的γ亚基（FcRγ）和DNAX激活蛋白（DAP）12的小鼠，由于破骨细胞分化受损而表现出严重的骨质疏松。在破骨细胞前体细胞中，FcRγ和DAP12与多种免疫受体结合，并通过磷脂酶Cγ激活钙信号传导。因此，由多个免疫受体激活的依赖于ITAM的共刺激信号对于维持骨稳态是必不可少的。这些结果表明，RANKL和M-CSF不足以激活破骨细胞形成所需的信号。

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