Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease
Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease
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DOI：
10.1172/jci59987
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发表时间：
2015-06-01
影响因子：
15.9
通讯作者：
Karadimitris, Anastasios
中科院分区：
文献类型：
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作者：
Ersek, Adel;Xu, Ke;Karadimitris, Anastasios
鞘糖脂(GSLS)是细胞膜和脂筏的重要组成部分，可以调节信号转导事件。GSLS在破骨细胞(OC)激活和恶性肿瘤中的溶骨性疾病中的作用尚不清楚，如浆细胞异位症、多发性骨髓瘤(MM)。在这里，我们验证了一种假设，即多发性骨髓瘤中OCS的病理性激活需要从头合成GSL，并被骨髓瘤细胞来源的GSL进一步增强。葡萄糖神经酰胺合成酶(GCS)抑制剂，包括临床批准的N-丁基脱氧诺吉霉素(NB-OND)，通过阻断RANKL诱导的TRAF6和c-SRC在脂筏中的定位和阻止转录激活因子NFATc1的核积聚，阻止OC的发展和激活。GM3是由患者来源的骨髓瘤细胞和MM细胞产生的主要GSL，外源性GM3的加入协同增强了破骨因子RANKL和胰岛素样生长因子1(IGF-1)在前体细胞诱导破骨细胞生成的能力。在WT小鼠中，给予GM3可增加OC数量和活性，这一效应可被NB-DNJ逆转。在小鼠MM模型中，NB-CINJ治疗显著改善了溶骨性骨病症状。综上所述，这些数据表明，肿瘤来源的和从头合成的GSLs都影响破骨细胞的形成，并提示NB-DNI可能减少与MM相关的病理性OC激活和骨破坏。
Glycosphingolipids (GSLs) are essential constituents of cell membranes and lipid rafts and can modulate signal transduction events. The contribution of GSLs in osteoclast (OC) activation and osteolytic bone diseases in malignancies such as the plasma cell dyscrasia multiple myeloma (MM) is not known. Here, we tested the hypothesis that pathological activation of OCs in MM requires de novo GSL synthesis and is further enhanced by myeloma cell-derived GSLs. Glucosylceramide synthase (GCS) inhibitors, including the clinically approved agent N-butyl-deoxynojirimycin (NB-OND, prevented OC development and activation by disrupting RANKL-induced localization of TRAF6 and c-SRC into lipid rafts and preventing nuclear accumulation of transcriptional activator NFATc1. GM3 was the prevailing GSL produced by patient-derived myeloma cells and MM cell lines, and exogenous addition of GM3 synergistically enhanced the ability of the pro-osteoclastogenic factors RANKL and insulin-like growth factor 1 (IGF-1) to induce osteoclastogenesis in precursors. In WT mice, administration of GM3 increased OC numbers and activity, an effect that was reversed by treatment with NB-DNJ. In a murine MM model, treatment with NB-CINJ markedly improved osteolytic bone disease symptoms. Together, these data demonstrate that both tumor-derived and de novo synthesized GSLs influence osteoclastogenesis and suggest that NB-DNI may reduce pathological OC activation and bone destruction associated with MM.