International Journal of Molecular Sciences, 2015, 16(8):18293-18311.

Potential Effects of Phytoestrogen Genistein in Modulating Acute Methotrexate Chemotherapy-Induced Osteoclastogenesis and Bone Damage in Rats

Tristan J. King, Tetyana Shandala, Alice M. Lee, et al

Sansom Institute for Health Research, School of Pharmacy and Medical Science, University of South Australia, Adelaide, SA 5001, Australia; et al

Chemotherapy-induced bone damage is a frequent side effect which causes diminished bone mineral density and fracture in childhood cancer sufferers and survivors. The intensified use of anti-metabolite methotrexate (MTX) and other cytotoxic drugs has led to the need for a mechanistic understanding of chemotherapy-induced bone loss and for the development of protective treatments. Using a young rat MTX-induced bone loss model, we investigated potential bone protective effects of phytoestrogen genistein. Oral gavages of genistein (20 mg/kg) were administered daily, for seven days before, five days during, and three days after five once-daily injections (sc) of MTX (0.75 mg/kg). MTX treatment reduced body weight gain and tibial metaphyseal trabecular bone volume (p < 0.001), increased osteoclast density on the trabecular bone surface (p < 0.05), and increased the bone marrow adipocyte number in lower metaphyseal bone (p < 0.001). Genistein supplementation preserved body weight gain (p < 0.05) and inhibited ex vivo osteoclast formation of bone marrow cells from MTX-treated rats (p < 0.001). However, MTX-induced changes in bone volume, trabecular architecture, metaphyseal mRNA expression of pro-osteoclastogenic cytokines, and marrow adiposity were not significantly affected by the co-administration of genistein. This study suggests that genistein may suppress MTX-induced osteoclastogenesis; however, further studies are required to examine its potential in protecting against MTX chemotherapy-induced bone damage.

《国际分子科学杂志》

植物雌激素金雀异黄酮在调节老鼠的急性甲氨蝶呤化疗诱导的破骨细胞形成和骨损伤方面的潜在影响

Sansom健康研究所，南澳大利亚大学药学和医学科学学院，澳大利亚，澳大利亚，SA 5001

化疗诱导的骨损伤是频繁的副作用，其导致骨矿物质密度降低和儿童癌症患者和幸存者中的骨折。抗代谢物甲氨蝶呤（MTX）和其他细胞毒性药物的强化使用导致需要对化疗诱导的骨丢失和用于保护性治疗的发展的机械理解。使用年轻大鼠MTX诱导骨丢失模型，我们调查潜在的骨保护作用的植物雌激素染料木素。在MTX（0.75mg/kg）的五次每日一次注射（sc）之后，五天和三天期间，每日施用染料木黄酮的口服封管（20mg/kg）。MTX治疗减少体重增加和胫骨干al端小梁骨体积（p<0.001），增加小梁骨表面上的破骨细胞密度（p<0.05），并增加骨髓脂肪细胞数在较低的干al端骨（p<0.001）。染料木黄酮补充保持体重增加（p<0.05），并抑制骨髓细胞离体破骨细胞从MTX治疗大鼠（p<0.001）。然而，MTX诱导的骨体积，小梁结构，干al端mRNA表达前破骨细胞生成细胞因子和骨髓肥胖的变化不显着受染料木素的共同施用影响。这项研究表明染料木素可抑制MTX诱导的破骨细胞形成;然而，需要进一步的研究来检查其在防止MTX化疗诱导的骨损伤的潜力。