Syndecan-1 is a multifunctional regulator of myeloma pathobiology: Control of tumor cell survival, growth, and bone cell differentiation
Syndecan-1 is a multifunctional regulator of myeloma pathobiology: Control of tumor cell survival, growth, and bone cell differentiation
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DOI：
10.1182/blood.v91.8.2679.2679_2679_2688
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发表时间：
1998-04-15
期刊：
影响因子：
20.3
通讯作者：
Sanderson, RD
中科院分区：
文献类型：
--
作者：
Dhodapkar, MV;Abe, E;Sanderson, RD
多发性骨髓瘤的特征在于骨髓中恶性浆细胞的积累，伴随破骨细胞和成骨细胞的平衡改变，导致溶骨性疾病。尽管驱动该过程的一些细胞因子已被表征，但关于负调节因子知之甚少。我们发现，syndecan-1（CD 138），硫酸乙酰肝素蛋白聚糖，表达和主动脱落的大多数骨髓瘤细胞的表面，诱导细胞凋亡，抑制骨髓瘤肿瘤细胞的生长，也介导减少破骨细胞和增加成骨细胞分化。向培养的骨髓瘤细胞系中加入完整纯化的多配体蛋白聚糖-1胞外域（1至6 nmol/L）导致诱导凋亡和剂量依赖性生长抑制，同时下调细胞周期蛋白D1。向培养的骨髓细胞中添加皮摩尔浓度的纯化的多配体蛋白聚糖-1导致破骨细胞生成的剂量依赖性减少和成骨细胞生成的较小增加。与对骨髓瘤细胞的作用相反，多配体蛋白聚糖-1对破骨细胞生成的作用仅需要多配体蛋白聚糖-1硫酸乙酰肝素链而不是完整的胞外域，这表明多配体蛋白聚糖对骨髓瘤和骨细胞的作用通过不同的机制发生。当注射到严重的联合免疫缺陷（scid）小鼠中时，对照转染的骨髓瘤细胞（ARH-77细胞）几乎不表达syndecan-1，很容易形成肿瘤，导致后肢瘫痪和溶骨性疾病。然而，注射syndecan-1转染的ARH-77细胞后，疾病相关的发病率和溶骨性疾病的发展被显著抑制。总之，我们的数据表明，无论是在体外和体内，syndecan-1有一个显着的有益效果的骨髓瘤和骨细胞的行为，因此可能代表在骨髓瘤病理生物学的调节的中心分子之一。(C)1998年，美国血液学会。
Multiple myeloma is characterized by an accumulation of malignant plasma cells in the bone marrow coupled with an altered balance of osteoclasts and osteoblasts, leading to lytic bone disease, Although some of the cytokines driving this process have been characterized, little is known about the negative regulators. We show that syndecan-1 (CD 138), a heparan sulfate proteoglycan, expressed on and actively shed from the surface of most myeloma cells, induces apoptosis and inhibits the growth of myeloma tumor cells and also mediates decreased osteoclast and increased osteoblast differentiation. The addition of intact purified syndecan-1 ectodomain (1 to 6 nmol/L) to myeloma cell lines in culture leads to induction of apoptosis and dose-dependent growth inhibition, with concurrent downregulation of cyclin D1. The addition of purified syndecan-1 in picomolar concentrations to bone marrow cells in culture leads to a dose-dependent decrease in osteoclastogenesis and a smaller increase in osteoblastogenesis. In contrast to the effect on myeloma cells, the effect of syndecan-1 on osteoclastogenesis only requires the syndecan-1 heparan sulfate chains and not the intact ectodomain, suggesting that syndecan's effect on myeloma and bone cells occurs through different mechanisms. When injected in severe combined immune deficient (scid) mice, control-transfected myeloma cells (ARH-77 cells) expressing little syndecan-1 readily form tumors, leading to hind limb paralysis and lytic bone disease. However, after the injection of syndecan-1-transfected ARH-77 cells, the development of disease-related morbidity and lytic bone disease is significantly inhibited. Taken together, our data demonstrate, both in vitro and in vivo, that syndecan-1 has a significant beneficial effect on the behavior of both myeloma and bone cells and therefore may represent one of the central molecules in the regulation of myeloma pathobiology. (C) 1998 by The American Society of Hematology.