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首页> 外文期刊>Rheumatology >Effects of methotrexate on human bone cell responses to mechanical stimulation.
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Effects of methotrexate on human bone cell responses to mechanical stimulation.

机译：甲氨蝶呤对人骨细胞对机械刺激的反应的影响。

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OBJECTIVES: Methotrexate (MTX), which is prescribed in the treatment of malignancy and autoimmune disease, has detrimental effects on a number of organ systems, including bone. At present, the exact mechanism of action of MTX on bone at the cellular level is unclear. Mechanical stimuli imparted by stretch, pressure, fluid flow and shear stress result in a variety of biochemical responses that are important in bone metabolism. Cyclical mechanical stimulation at 0.33 Hz induces rapid cell membrane hyperpolarization of human bone cells (HBC) via an integrin-mediated pathway which includes an IL-1beta autocrine/paracrine loop. This study was undertaken to investigate the effect of MTX on responses of HBC to 0.33 Hz mechanical stimulation. METHODS: Electrophysiological responses of HBC were measured before and after mechanical stimulation at 0.33 Hz in the presence or absence of MTX. Semiquantitative RT-PCR was used to investigate effects of MTX on relative levels of type-1 collagen and bone morphogenetic protein-4 (BMP-4) following 0.33 Hz mechanical stimulation. RESULTS: MTX dose-dependently inhibited HBC hyperpolarization in response to 0.33 Hz mechanical stimulation. Production/release of IL-1beta was inhibited by MTX, whereas its effects on target cells were not. Mechanical stimulation of HBC at 0.33 Hz caused a significant decrease in relative levels of BMP-4 mRNA, whereas relative levels of type-1 collagen mRNA were consistently increased, although these increases did not reach statistical significance. These trends were unaffected by MTX. CONCLUSIONS: These studies show that MTX affects HBC mechanotransduction by interfering with integrin-mediated signalling. The data also suggest that the mechanotransduction pathway responsible for the regulation of type-1 collagen and BMP-4 gene expression may be distinct from the IL-1beta-mediated signalling pathway.
机译：目的：甲氨蝶呤（MTX）是治疗恶性肿瘤和自身免疫性疾病的处方药，对包括骨骼在内的许多器官系统都具有有害作用。目前，尚不清楚MTX在细胞水平上对骨骼的确切作用机理。拉伸，压力，流体流动和剪切应力赋予的机械刺激导致对骨骼代谢至关重要的多种生化反应。在0.33 Hz的循环机械刺激下，通过整合素介导的途径（包括IL-1β自分泌/旁分泌环），诱导人骨细胞（HBC）的细胞膜超极化迅速。进行该研究以研究MTX对HBC对0.33Hz机械刺激的响应的作用。方法：在存在或不存在MTX的情况下，在0.33 Hz的机械刺激前后测量HBC的电生理反应。半定量RT-PCR用于研究0.33 Hz机械刺激后MTX对1型胶原和骨形态发生蛋白4（BMP-4）相对水平的影响。结果：MTX剂量依赖性抑制HBC超极化响应0.33 Hz机械刺激。 IL-1β的产生/释放受到MTX的抑制，而其对靶细胞的作用却没有。机械刺激HBC在0.33 Hz时会导致BMP-4 mRNA相对水平的显着降低，而1型胶原mRNA的相对水平持续升高，尽管这些升高并未达到统计学显着性。这些趋势不受MTX的影响。结论：这些研究表明MTX通过干扰整联蛋白介导的信号传导影响HBC机械转导。数据还表明，负责调节1型胶原和BMP-4基因表达的机械传导途径可能与IL-1beta介导的信号传导途径不同。

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