Takamatsu Y, Simmons P J, Moore R J, Morris H A, To L B, Lévesque J P
Matthew Roberts Laboratory, and the Leukaemia Research Unit, the Division of Haematology, Hanson Centre for Cancer Research, Medical and Veterinary Science, Adelaide, Australia.
Blood. 1998 Nov 1;92(9):3465-73.
The cellular and molecular mechanisms responsible for hematopoietic progenitor cell (HPC) mobilization from bone marrow (BM) into peripheral blood after administration of cytokines such as granulocyte colony-stimulating factor (G-CSF) are still unknown. In this study we show that high concentrations of soluble calcium induce the detachment of BM CD34(+) HPC adherent on fibronectin, a major component of BM extracellular matrix. Because G-CSF has been shown to induce osteoporosis in patients with congenital neutropenia and in G-CSF-overexpressing transgenic mice, we hypothesized that short-term G-CSF administration may be sufficient to induce bone resorption, resulting in the release of soluble calcium in the endosteum leading in turn to the inhibition of attachment to fibronectin and the egress of HPC from the BM. We show herein that in humans, serum osteocalcin concentration, a specific marker of bone formation, is strongly reduced after 3 days of G-CSF administration. Furthermore, in patients mobilized with G-CSF either alone or in association with stem cell factor or interleukin-3, the reduction of serum osteocalcin is significantly correlated with the number of HPC mobilized in peripheral blood. Urine levels of deoxypyridinoline (DPyr), a specific marker of bone resorption, gradually elevated during the time course of G-CSF administration until day 7 after cessation of G-CSF, showing a simultaneous stimulation of bone degradation during G-CSF-induced HPC mobilization. In an in vivo murine model, we found that the number of osteoclasts was dramatically increased paralleling the elevation of DPyr after G-CSF administration. When pamidronate, an inhibitor of osteoclast-mediated bone resorption, was administered together with G-CSF in mice, the G-CSF-induced increase of DPyr levels was completely abolished whereas the numbers of colony-forming cells mobilized in peripheral blood were not decreased, but unexpectedly increased relative to the numbers elicited by G-CSF alone. Collectively, our data therefore show that short-term administration of G-CSF induces bone degradation by a simultaneous inhibition of bone formation and an enhanced osteoclast-mediated bone resorption. This increased bone resorption is inhibited by pamidronate without reducing G-CSF-induced HPC mobilization, suggesting that the activation of bone resorption after G-CSF administration is not the direct cause of HPC mobilization as initially hypothesized, but a parallel event.
粒细胞集落刺激因子（G-CSF）等细胞因子给药后，造血祖细胞（HPC）从骨髓（BM）动员至外周血的细胞和分子机制仍不清楚。在本研究中，我们发现高浓度的可溶性钙会诱导黏附在纤连蛋白（BM细胞外基质的主要成分）上的BM CD34(+) HPC脱离。由于已证明G-CSF会在先天性中性粒细胞减少症患者和G-CSF过表达转基因小鼠中诱导骨质疏松，我们推测短期给予G-CSF可能足以诱导骨吸收，导致骨内膜中可溶性钙的释放，进而抑制与纤连蛋白的黏附以及HPC从BM中逸出。我们在此表明，在人类中，给予G-CSF 3天后，骨形成的特异性标志物血清骨钙素浓度显著降低。此外，在单独使用G-CSF或与干细胞因子或白细胞介素-3联合动员的患者中，血清骨钙素的降低与外周血中动员的HPC数量显著相关。骨吸收的特异性标志物脱氧吡啶啉（DPyr）的尿水平在G-CSF给药期间逐渐升高，直至G-CSF停用后第7天，表明在G-CSF诱导的HPC动员过程中同时刺激了骨降解。在体内小鼠模型中，我们发现给予G-CSF后破骨细胞数量显著增加，与DPyr的升高平行。当在小鼠中与G-CSF一起给予帕米膦酸（一种破骨细胞介导的骨吸收抑制剂）时，G-CSF诱导的DPyr水平升高被完全消除，而外周血中动员的集落形成细胞数量并未减少，反而相对于单独使用G-CSF引起的数量意外增加。因此，我们的数据总体表明，短期给予G-CSF通过同时抑制骨形成和增强破骨细胞介导的骨吸收来诱导骨降解。帕米膦酸可抑制这种增加的骨吸收，而不降低G-CSF诱导的HPC动员，这表明给予G-CSF后骨吸收的激活并非如最初假设的那样是HPC动员的直接原因，而是一个并行事件。
