Attenuated Wnt/β-catenin signalling mediates methotrexate chemotherapy-induced bone loss and marrow adiposity in rats
Attenuated Wnt/β-catenin signalling mediates methotrexate chemotherapy-induced bone loss and marrow adiposity in rats
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DOI：
10.1016/j.bone.2012.03.027
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发表时间：
2012-06-01
期刊：
影响因子：
4.1
通讯作者：
Xian, Cory J.
中科院分区：
文献类型：
--
作者：
Georgiou, Kristen R.;King, Tristan J.;Xian, Cory J.
癌症化疗通常会导致显著的骨质流失、骨髓肥胖和造血缺陷，但其潜在机制和恢复潜力仍不清楚。Wnt/β-catenin信号传导是骨生成、脂肪生成和造血调控不可或缺的;使用大鼠模型，目前的研究调查了该信号传导途径在用甲氨蝶呤（MTX）（一种常用的抗代谢药）化疗后骨髓基质细胞和造血细胞分化变化中的作用。先前已发现大鼠MTX治疗（每日5次，0.75 mg/kg）可减少骨体积并增加骨髓脂肪，这与造血细胞中破骨细胞生成增加以及治疗大鼠骨髓基质细胞中骨生成向脂肪生成转换相关。在本研究中，在第一次MTX给药后第6天，我们发现伴随着这些变化以及抑制的造血细胞但增加的粒细胞/巨噬细胞分化潜力，骨中Wnt拮抗剂sFRP-1和Dkk-1的mRNA表达增加，骨髓基质细胞中核β-连环蛋白减少，β-连环蛋白靶基因lef-1的mRNA水平降低，细胞周期蛋白D1和生存素，表明在MTX诱导的损伤过程中，骨中Wnt/β-连环蛋白信号的激活减少。同时给予BIO（一种稳定β-连环蛋白的GSK-3 β抑制剂），部分消除了MTX诱导的成骨/成脂定型、粒细胞/巨噬细胞谱系分化和破骨细胞数量的瞬时变化。这些发现表明，Wnt/β-连环蛋白信号转导在MTX化疗诱导的骨髓微环境细胞变化中具有潜在的重要作用。(C)2012 Elsevier Inc. All rights reserved.
Cancer chemotherapy often causes significant bone loss, marrow adiposity and haematopoietic defects, yet the underlying mechanisms and recovery potential remain unclear. Wnt/beta-catenin signalling is integral to the regulation of osteogenesis, adipogenesis and haematopoiesis; using a rat model, the current study investigated roles of this signalling pathway in changes to bone marrow stromal and haematopoietic cell differentiation after chemotherapy with methotrexate (MTX), a commonly used antimetabolite. MTX treatment in rats (5 daily administrations at 0.75 mg/kg) has previously been found to decrease bone volume and increase marrow fat, which was associated with increased osteoclastogenesis in haematopoietic cells and with an osteogenesis to adipogenesis switch in bone marrow stromal cells of treated rats. In the current study, on day 6 after the first MTX dose we found that accompanying these changes as well as a suppressed haematopoietic cellularity but increased granulocyte/macrophage differentiation potential, there was an increase in mRNA expression of Wnt antagonists sFRP-1 and Dkk-1 in bone, a reduction in nuclear beta-catenin protein in bone marrow stromal cells, and decreased mRNA levels of beta-catenin target genes lef-1, cyclin D1 and survivin, suggesting reduced activation of Wnt/beta-catenin signalling in the bone during MTX-induced damage. Concurrent administration of BIO, a GSK-3 beta inhibitor that stabilises beta-catenin, partially abrogated the MTX-induced transient changes in osteogenic/adipogenic commitment, granulocyte/macrophage lineage differentiation and osteoclast number. These findings demonstrate a potentially important role of Wnt/beta-catenin signalling in MTX chemotherapy-induced cellular changes to the bone marrow microenvironment. (C) 2012 Elsevier Inc. All rights reserved.