High dose M-CSF partially rescues the Dap12-/-osteoclast phenotype
High dose M-CSF partially rescues the Dap12-/-osteoclast phenotype
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DOI：
10.1002/jcb.10694
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发表时间：
2003-12-01
影响因子：
4
通讯作者：
Ross, FP
中科院分区：
文献类型：
--
作者：
Faccio, R;Zou, W;Ross, FP
破骨细胞是巨噬细胞衍生的细胞，因此受到影响免疫系统其他成员的分子的调节。 Dap12 是 NK 细胞以及 B 和 T 淋巴细胞表达的衔接蛋白。 Dap12 还介导骨髓细胞的成熟，并由破骨细胞表达，如果没有 Dap12，破骨细胞就会出现功能障碍。我们发现 Dap12-/- 破骨细胞前体在体外无法分化，并且高剂量 M-CSF 可以部分挽救这种异常。即使存在高剂量细胞因子，破骨细胞数量也相对较少，其结果是前体细胞的增殖受到抑制，并且它们无法正常地向破骨细胞识别的基质蛋白骨桥蛋白迁移。此外，高剂量 M-CSF 中产生的 Dap12-/- 破骨细胞无法正常组织其细胞骨架。 Dap12 无效细胞无法进行正常破骨细胞分化并不是由于主要 RANK 配体 (RANKL) 或 M-CSF 诱导的信号通路的刺激减弱。另一方面，当铺在骨桥蛋白上时，Dap12-/- 前破骨细胞不会激活酪氨酸激酶 Syk，后者通常与接头蛋白结合并传递下游信号。 Syk 缺陷的巨噬细胞不会进行正常的破骨细胞生成，这证明了 Dap12/Syk 复合物的重要性。此外，铺在骨桥蛋白上的相同细胞粘附不良并且无法磷酸化c-Src或Pyk2，这两种激酶对于破骨细胞细胞骨架的组织至关重要。 (C) 2003 Wiley-Liss, Inc.
Osteoclasts are macrophage derived cells and as such are subject to regulation by molecules impacting other members of the immune system. Dap12 is an adaptor protein expressed by NK cells and B and T lymphocytes. Dap12 also mediates maturation of myeloid cells and is expressed by osteoclasts which are dysfunctional in its absence. We find Dap12-/- osteoclast precursors fail to differentiate, in vitro, and the abnormality is partially rescued by high dose M-CSF. The relative paucity of osteoclast number, even in presence of high dose cytokine, is attended by dampened proliferation of precursor cells and their failure to normally migrate towards the osteoclast-recognized matrix protein, osteopontin. Furthermore, Dap12-/- osteoclasts generated in high dose M-CSF fail to normally organize their cytoskeleton. The incapacity of Dap12 null cells to undergo normal osteoclast differentiation is not due to blunted stimulation of major RANK ligand (RANKL) or M-CSF induced signaling pathways. On the other hand, when plated on osteopontin, Dap12-/- pre-osteoclasts do not activate the tyrosine kinase, Syk, which normally binds to the adaptor protein and transmits downstream signals. Attesting to the importance of the Dap12/Syk complex, Syk deficient macrophages do not undergo normal osteoclastogenesis. Furthermore, the same cells plated onto osteopontin, adhere poorly and fail to phosphorylate c-Src or Pyk2, two kinases central to organization of the osteoclast cytoskeleton. (C) 2003 Wiley-Liss, Inc.