Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis
Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis
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DOI：
10.1038/nature02444
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发表时间：
2004-04-15
期刊：
影响因子：
64.8
通讯作者：
Takai, T
中科院分区：
文献类型：
--
作者：
Koga, T;Inui, M;Takai, T
共刺激信号是激活免疫细胞所必需的（1），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骨吸收之间的平衡（2，3）。在存在巨噬细胞集落刺激因子（M-CSF）的情况下，NF-κ B配体受体激活剂（RANKL）调节骨吸收细胞、破骨细胞的分化（4，5）。但目前尚不清楚RANKL如何激活钙信号，导致诱导活化T细胞的核因子c1，这是破骨细胞生成的关键转录因子（6）。在这里，我们发现缺乏免疫受体酪氨酸基活化基序（ITAM）（7）-携带衔接子（8-10），Fc受体共同γ亚基（FcR γ）和DNA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硬化症。在破骨细胞前体细胞中，FcR γ和DAP 12与多种免疫受体结合（11-15），并通过磷脂酶C γ激活钙信号传导。因此，由多种免疫受体激活的ITAM依赖性共刺激信号对于维持骨稳态至关重要。这些结果表明，RANKL和M-CSF不足以激活破骨细胞生成所需的信号。
Costimulatory signals are required for activation of immune cells(1), 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(2,3). Receptor activator of NF-kappaB ligand (RANKL) regulates the differentiation of bone-resorbing cells, osteoclasts, in the presence of macrophage-colony stimulating factor (M-CSF)(4,5). 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 osteoclastogenesis(6). Here we show that mice lacking immunoreceptor tyrosine-based activation motif (ITAM)(7)-harbouring adaptors(8-10), Fc receptor common gamma subunit (FcRgamma) and DNAX-activating protein (DAP)12, exhibit severe osteopetrosis owing to impaired osteoclast differentiation. In osteoclast precursor cells, FcRgamma and DAP12 associate with multiple immunoreceptors(11-15) and activate calcium signalling through phospholipase Cgamma. 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.