Attenuated Wnt/β-catenin signalling mediates methotrexate chemotherapy-induced bone loss and marrow adiposity in rats

被引:72
作者
Georgiou, Kristen R. [1 ,2 ]
King, Tristan J. [1 ,2 ]
Scherer, Michaela A. [1 ,3 ]
Zhou, Hong [4 ]
Foster, Bruce K. [3 ]
Xian, Cory J. [1 ,2 ,3 ]
机构
[1] Univ S Australia, Sansom Inst Hlth Res, Sch Pharm & Med Sci, Adelaide, SA 5001, Australia
[2] Univ Adelaide, Discipline Physiol, Adelaide, SA 5005, Australia
[3] Womens & Childrens Hosp, Dept Orthopaed Surg, Adelaide, SA 5006, Australia
[4] Univ Sydney, ANZAC Res Inst, Sydney, NSW 2139, Australia
基金
澳大利亚国家健康与医学研究理事会;
关键词
Cancer chemotherapy; Wnt signalling; Osteogenesis; Adipogenesis; Osteoclastogenesis; DECREASES ADIPOCYTE FORMATION; HEMATOPOIETIC STEM-CELL; LOW-DOSE METHOTREXATE; OSTEOBLAST DIFFERENTIATION; BETA-CATENIN; YOUNG-RATS; SHORT-TERM; WNT; GROWTH; ACTIVATION;
D O I
10.1016/j.bone.2012.03.027
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
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.
引用
收藏
页码:1223 / 1233
页数:11
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