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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >CD200 and its receptor, CD200R, modulate bone mass via the differentiation of osteoclasts
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CD200 and its receptor, CD200R, modulate bone mass via the differentiation of osteoclasts

机译：CD200及其受体CD200R通过破骨细胞的分化来调节骨量

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Fusion of macrophages is an essential step in the differentiation of osteoclasts, which play a central role in the development and remodeling of bone. Osteoclasts are important mediators of bone loss, which leads, for example, to osteoporosis. Macrophage fusion receptor/signal regulatory protein α (MFR/SIRPα) and its ligand CD47, which are members of the Ig superf amily (IgSF), have been implicated in the fusion of macrophages. We show that CD200, which is not expressed in cells that belong to the myeloid lineage, is strongly expressed in macrophages at the onset of fusion. By contrast, the CD200 receptor (CD200R), which, like CD200, belongs to the IgSF, is expressed only in cells that belong to the myeloid lineage, including osteoclasts, and in CD4~+ T cells. Osteoclasts from CD200~(-/-) mice differentiated at a reduced rate. Activation of the NF-κB and MAP kinase signaling pathways downstream of RANK, a receptor that plays a central role in the differentiation of osteoclasts, was depressed in these cells. A soluble recombinant protein that included the extracellular domain of CD200 rescued the fusion of CD200~(-/-) macrophages and their activation downstream of RANK. Conversely, addition of a soluble recombinant protein that included the extracellular domain of CD200R or short-hairpin RNA-mediated silencing of the expression of CD200R prevented fusion. Thus CD200 engagement of the CD200R at the initiation of macrophage fusion regulated further differentiation to osteoclasts. Consistent with in vitro observations, CD200~(-/-) mice contained fewer osteoclasts and accumulated more bone than CD20~(+/+) mice. The CD200-CD200R axis is therefore a putative regulator of bone mass, via the formation of osteoclasts.
机译：巨噬细胞融合是破骨细胞分化的重要步骤，破骨细胞在骨的发育和重塑中起着核心作用。破骨细胞是骨质流失的重要介质，例如导致骨质疏松。作为Ig超家族（IgSF）成员的巨噬细胞融合受体/信号调节蛋白α（MFR /SIRPα）及其配体CD47与巨噬细胞融合有关。我们表明，CD200在属于髓样谱系的细胞中不表达，在融合开始时在巨噬细胞中强烈表达。相反，CD200受体（CD200R）与CD200一样，属于IgSF，仅在属于骨髓谱系的细胞（包括破骨细胞）和CD4〜+ T细胞中表达。 CD200〜（-/-）小鼠的破骨细胞分化速度降低。这些细胞抑制了RANK下游的NF-κB和MAP激酶信号通路的激活，RANK是在破骨细胞分化中起关键作用的受体。包含CD200细胞外结构域的可溶性重组蛋白挽救了CD200-（-/-）巨噬细胞的融合及其在RANK下游的活化。相反，添加包含CD200R胞外结构域或短发夹RNA介导的CD200R表达沉默的可溶性重组蛋白可防止融合。因此，巨噬细胞融合开始时CD200R的CD200参与调节了向破骨细胞的进一步分化。与体外观察一致，与CD20〜（+ / +）小鼠相比，CD200〜（-/-）小鼠包含更少的破骨细胞并积累了更多的骨骼。因此，CD200-CD200R轴通过破骨细胞的形成是假定的骨量调节剂。

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