The immunomodulatory adapter proteins DAP12 and Fc receptor γ-chain (FcRγ) regulate development of functional osteoclasts through the Syk tyrosine kinase
The immunomodulatory adapter proteins DAP12 and Fc receptor γ-chain (FcRγ) regulate development of functional osteoclasts through the Syk tyrosine kinase
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DOI：
10.1073/pnas.0401602101
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发表时间：
2004-04-20
影响因子：
11.1
通讯作者：
Nakamura, MC
中科院分区：
文献类型：
--
作者：
Mócsai, A;Humphrey, MB;Nakamura, MC
破骨细胞是唯一的骨吸收细胞，是骨质疏松症发病机制的核心，但其发育和调控尚不完全清楚。免疫系统的多种受体使用共同的信号传导范例，由此受体相关衔接蛋白内的基于磷酸化免疫受体酪氨酸的激活基序（ITAM）募集Syk酪氨酸激酶。在这里，我们证明了一个类似的机制是需要功能性破骨细胞的发展。缺乏两个ITAM-承载衔接子，DAP 12和Fc受体γ链（FcR γ）的小鼠是严重的骨硬化。DAP 12（-/-）FcR γ（-/-）骨髓细胞在体外不能分化成多核破骨细胞或吸收骨，并显示Syk酪氨酸激酶磷酸化受损。syk（-/-）祖细胞在破骨细胞发育和骨吸收方面也有类似缺陷。通过逆转录病毒转导引入的Syk的完整SH 2结构域是syk（-/-）破骨细胞功能重建所需的，而DAP 12上的完整ITAM结构域是DAP 12（-/-）FcR γ（-/-）细胞重建所需的。这些数据表明，募集Syk磷酸化ITAM是破骨细胞生成的关键。虽然DAP 12似乎是主要负责直接刺激巨噬细胞集落刺激因子和NF-κ B配体细胞因子的受体激活剂的培养物中的破骨细胞分化，DAP 12和FcR γ在支持破骨细胞的发育成骨细胞-破骨细胞共培养物，这反映了它们在体内的重叠功能重叠的作用。这些结果为破骨细胞的生物学提供了新的见解，并为骨重建疾病提供了新的治疗靶点。
Osteoclasts, the only bone-resorbing cells, are central to the pathogenesis of osteoporosis, yet their development and regulation are incompletely understood. Multiple receptors of the immune system use a common signaling paradigm whereby phosphorylated immunoreceptor tyrosine-based activation motifs (ITAMs) within receptor-associated adapter proteins recruit the Syk tyrosine kinase. Here we demonstrate that a similar mechanism is required for development of functional osteoclasts. Mice lacking two ITAM-bearing adapters, DAP12 and the Fc receptor gamma-chain (FcRgamma), are severely osteopetrotic. DAP12(-/-)FcRgamma(-/-) bone marrow cells fail to differentiate into multinucleated osteoclasts or resorb bone in vitro and show impaired phosphorylation of the Syk tyrosine kinase. syk(-/-) progenitors are similarly defective in osteoclast development and bone resorption. Intact SH2-domains of Syk, introduced by retroviral transduction, are required for functional reconstitution of syk(-/-) osteoclasts, whereas intact ITAM-domains on DAP12 are required for reconstitution of DAP12(-/-) FcRgamma(-/-) cells. These data indicate that recruitment of Syk to phosphorylated ITAMs is critical for osteoclastogenesis. Although DAP12 appears to be primarily responsible for osteoclast differentiation in cultures directly stimulated with macrophage-colony stimulating factor and receptor activator of NF-kappaB ligand cytokines, DAP12 and FcRgamma have overlapping roles in supporting osteoclast development in osteoblast-osteoclast cocultures, which mirrors their overlapping functions in vivo. These results provide new insight into the biology of osteoclasts and suggest novel therapeutic targets in diseases of bony remodeling.