Deficiency of Chemokine Receptor CCR1 Causes Osteopenia Due to Impaired Functions of Osteoclasts and Osteoblasts
Deficiency of Chemokine Receptor CCR1 Causes Osteopenia Due to Impaired Functions of Osteoclasts and Osteoblasts
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DOI：
10.1074/jbc.m109.099424
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发表时间：
2010-09-10
影响因子：
4.8
通讯作者：
Yamamoto, Kenji
中科院分区：
文献类型：
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作者：
Hoshino, Akiyoshi;Iimura, Tadahiro;Yamamoto, Kenji
趋化因子的特征在于白细胞对靶向炎症部位的归巢活性。最近的研究表明，趋化因子在发病的各个阶段以及免疫反应中发挥着更加不同的作用。趋化因子受体CCR 1及其配体被认为参与炎症性骨破坏，但它们在体内骨代谢中的生理作用尚未阐明。在本研究中，我们研究了CCR 1在骨代谢中的作用，使用CCR 1缺陷小鼠。Ccr 1（-/-）小鼠的松质骨中骨小梁较少且较薄，骨矿物质密度较低。CCR 1的缺乏影响成骨细胞的分化和功能。Runx 2、Atf 4、骨桥蛋白和骨连接蛋白在Ccr 1（-/-）小鼠中显著上调，尽管Osterix持续表达，骨钙素表达减少，表明分化为成熟成骨细胞的潜力较低。此外，矿化结节的形成显着中断培养成骨细胞分离Ccr 1（-/-）小鼠。从培养的Ccr 1（-/-）骨髓细胞诱导破骨细胞生成产生较少和较小的破骨细胞由于废除细胞融合。Ccr 1（-/-）小鼠破骨细胞没有表现出溶骨活性，同时Rank及其下游靶点表达减少，这意味着破骨细胞生成缺陷参与了Ccr 1（-/-）小鼠的骨表型。野生型破骨细胞前体细胞与Ccr 1（-/-）成骨细胞共培养未能促进破骨细胞生成。这一发现很可能是由于Rankl表达的减少。这些观察结果表明，CCR 1轴及其配体可能通过调节RANK-RANKL介导的相互作用参与破骨细胞和成骨细胞之间的串扰。
Chemokines are characterized by the homing activity of leukocytes to targeted inflammation sites. Recent research indicates that chemokines play more divergent roles in various phases of pathogenesis as well as immune reactions. The chemokine receptor, CCR1, and its ligands are thought to be involved in inflammatory bone destruction, but their physiological roles in the bone metabolism in vivo have not yet been elucidated. In the present study, we investigated the roles of CCR1 in bone metabolism using CCR1-deficient mice. Ccr1(-/-) mice have fewer and thinner trabecular bones and low mineral bone density in cancellous bones. The lack of CCR1 affects the differentiation and function of osteoblasts. Runx2, Atf4, Osteopontin, and Osteonectin were significantly up-regulated in Ccr1(-/-) mice despite sustained expression of Osterix and reduced expression of Osteocalcin, suggesting a lower potential for differentiation into mature osteoblasts. In addition, mineralized nodule formation was markedly disrupted in cultured osteoblastic cells isolated from Ccr1(-/-) mice. Osteoclastogenesis induced from cultured Ccr1(-/-) bone marrow cells yielded fewer and smaller osteoclasts due to the abrogated cell-fusion. Ccr1(-/-) osteoclasts exerted no osteolytic activity concomitant with reduced expressions of Rank and its downstream targets, implying that the defective osteoclastogenesis is involved in the bone phenotype in Ccr1(-/-) mice. The co-culture of wild-type osteoclast precursors with Ccr1(-/-) osteoblasts failed to facilitate osteoclastogenesis. This finding is most likely due to a reduction in Rankl expression. These observations suggest that the axis of CCR1 and its ligands are likely to be involved in crosstalk between osteoclasts and osteoblasts by modulating the RANK-RANKL-mediated interaction.