G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow
G-CSF potently inhibits osteoblast activity and CXCL12 mRNA expression in the bone marrow
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DOI：
10.1182/blood-2004-01-0272
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发表时间：
2005-11-01
期刊：
影响因子：
20.3
通讯作者：
Link, DC
中科院分区：
文献类型：
--
作者：
Semerad, CL;Christopher, MJ;Link, DC
越来越多的证据表明，基质细胞衍生因子1（SDF-1/CXCL 12 [CXC基序，配体12]）与其同源受体CXCR 4（CXC基序，受体4）的相互作用产生调节骨髓中造血祖细胞（HPC）运输的信号。在粒细胞集落刺激因子（G-CSF）诱导的HPC动员过程中，骨髓中的CXCL 12蛋白表达减少。在此，我们表明，在一系列转基因小鼠携带有针对性的突变的G-CSF受体，并显示显着不同的G-CSF诱导的HPC动员反应，骨髓CXCL 12蛋白表达的减少密切相关的HPC动员的程度。G-CSF治疗诱导骨髓CXCL 12 mRNA的减少，这密切反映了CXCL 12蛋白的下降。细胞分选实验表明，成骨细胞和较小程度的内皮细胞是骨髓中产生CXCL 12的主要来源。有趣的是，成骨细胞的活性，通过组织形态计量学和骨钙素的表达，强烈下调G-CSF治疗期间。然而，G-CSF受体在成骨细胞上不表达;因此，G-CSIF对成骨细胞功能没有直接影响。总的来说，这些数据表明了一种模型，其中G-CSF通过间接机制有效地抑制成骨细胞活性，导致骨髓中CXCL 12表达降低。随后CXCR 4信号传导的减弱最终导致HPC动员。
Accumulating evidence indicates that interaction of stromal cell-derived factor 1 (SDF-1/CXCL12 [CXC motif, ligand 12]) with its cognate receptor, CXCR4 (CXC motif, receptor 4), generates signals that regulate hematopoietic progenitor cell (HPC) trafficking in the bone marrow. During granulocyte colony-stimulating factor (G-CSF)-induced HPC mobilization, CXCL12 protein expression in the bone marrow decreases. Herein, we show that in a series of transgenic mice carrying targeted mutations of their G-CSF receptor and displaying markedly different G-CSF-induced HPC mobilization responses, the decrease in bone marrow CXCL12 protein expression closely correlates with the degree of HPC mobilization. G-CSF treatment induced a decrease in bone marrow CXCL 12 mRNA that closely mirrored the fall in CXCL12 protein. Cell sorting experiments showed that osteoblasts and to a lesser degree endothelial cells are the major sources of CXCL12 production in the bone marrow. Interestingly, osteoblast activity, as measured by histomorphometry and osteocalcin expression, is strongly down-regulated during G-CSF treatment. However, the G-CSF receptor is not expressed on osteoblasts; accordingly, G-CSIF had no direct effect on osteoblast function. Collectively, these data suggest a model in which G-CSF, through an indirect mechanism, potently inhibits osteoblast activity resulting in decreased CXCL12 expression in the bone marrow. The consequent attenuation of CXCR4 signaling ultimately leads to HPC mobilization.