Roles of chemokine receptor CX3CR1 in maintaining murine bone homeostasis through the regulation of both osteoblasts and osteoclasts
Roles of chemokine receptor CX3CR1 in maintaining murine bone homeostasis through the regulation of both osteoblasts and osteoclasts
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DOI：
10.1242/jcs.113910
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发表时间：
2013-02-15
影响因子：
4
通讯作者：
Iimura, Tadahiro
中科院分区：
文献类型：
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作者：
Hoshino, Akiyoshi;Ueha, Satoshi;Iimura, Tadahiro
最近有报道趋化因子参与病理性骨破坏。然而，趋化因子在体内骨代谢中的生理作用还没有很好的记录。我们分析了Cx 3cr 1缺陷小鼠的骨表型。小鼠表现出轻微但显著的骨小梁和皮质厚度增加，破骨细胞数量减少，类骨质形成率增加。虽然形态学参数显示边缘差异，Cx 3cr 1缺陷的骨骼显示Osterix/SP 7的表达升高，其编码成骨细胞的必需转录因子，而基因骨钙素/Bglap，其编码晚期标志物，下调。在Cx 3 cr 1缺陷骨中，各种骨细胞标志物的转录水平显著降低，如NF-κ B受体激活剂（RANK）/TNFRSF 11 A、NF-κ B配体受体激活剂（RANKL）/TNFSF 11、抗酒石酸酸性磷酸酶5 B（TRAP 5 B）/ACP 5 B、组织蛋白酶K（CTSK）、MMP 3和MMP 13。培养的Cx 3cr 1缺陷型成骨细胞显示成骨细胞标志物表达的逆时间模式和减少的钙沉积。此外，体外研究和针对CX 3CR 1和CX 3CL 1的免疫荧光染色表明CX 3CR 1-CX 3CL 1轴在成骨细胞分化的早期阶段中的作用，可能通过它们的反式和顺式相互作用。培养的Cx 3cr 1缺陷的前破骨细胞表现出分化受损，主要是由于骨髓系前体细胞的CD 115（+）CD 11b（10）破骨细胞生成群体的缺陷。在不同时间点用重组CX 3CL 1处理骨髓来源的骨细胞培养物表明CX 3CR 1-CX 3CL 1轴有利于维持骨细胞前体，但不分化破骨细胞。这些观察揭示了CX 3CR 1-CX 3CL 1轴在成骨细胞和破骨细胞分化中的新作用。
Chemokines have recently been reported to be involved in pathological bone destruction. However, the physiological roles of chemokines in bone metabolism in vivo have not been well documented. We analyzed the bone phenotypes in Cx3cr1-deficient mice. The mice exhibited slight but significant increases in trabecular and cortical thickness, reduced numbers of osteoclasts and increased rates of osteoid formation. Although the morphometric parameters showed marginal differences, the Cx3cr1-deficient bones showed an elevated expression of Osterix/SP7, which encodes an essential transcriptional factor for osteoblasts, whereas the gene Osteocalcin/Bglap, which encodes a late marker, was downregulated. The levels of transcripts for various osteoclastic markers, such as receptor activator of NF-kappa B (RANK)/TNFRSF11A, receptor activator of NF-kB ligand (RANKL)/TNFSF11, tartrate-resistant acid phosphatase 5b (TRAP5B)/ACP5B, Cathepsin K(CTSK), MMP3 and MMP13, were significantly decreased in the Cx3cr1-deficient bones. Cultured Cx3cr1-deficient osteoblastic cells showed inverse temporal patterns of osteoblastic marker expression and reduced calcium deposition. Furthermore, in vitro studies and immunofluorescence staining against CX3CR1 and CX3CL1 suggested a role for the CX3CR1-CX3CL1 axis in an early stage of osteoblast differentiation, possibly through their trans and cis interactions. Cultured Cx3cr1-deficient pre-osteoclasts showed impaired differentiation, mainly due to a deficiency of the CD115(+)CD11b(10) osteoclastogenic population ofmyeloid-lineage precursors. The treatment of bone-marrow-derived osteoclastic cultures with recombinant CX3CL1 at different time points suggested that the CX3CR1-CX3CL1 axis favors the maintenance of osteoclastic precursors, but not differentiated osteoclasts. These observations uncovered novel roles of the CX3CR1-CX3CL1 axis in the differentiation of both osteoblasts and osteoclasts.