Sulfated polysaccharides enhance the biological activities of bone morphogenetic proteins
Sulfated polysaccharides enhance the biological activities of bone morphogenetic proteins
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DOI：
10.1074/jbc.m300937200
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发表时间：
2003-10-31
影响因子：
4.8
通讯作者：
Kamijo, R
中科院分区：
文献类型：
--
作者：
Takada, T;Katagiri, T;Kamijo, R
骨形态发生蛋白（BMP）已被证明是肝素结合蛋白，可诱导间充质细胞中的成骨细胞分化。在本研究中，我们研究了肝素对 C2C12 成肌细胞 BMP 活性的影响。肝素剂量依赖性地增强不仅由BMP-2或BMP-4的同二聚体而且由BMP-2/6或BMP-2/7的异二聚体诱导的成骨细胞分化。然而，由组成型活性 BMPR-IA（一种功能性 BMP I 型受体）诱导的成骨细胞分化不受肝素的影响。硫酸乙酰肝素和硫酸葡聚糖也增强了 BMP-2 活性，尽管化学脱硫的肝素衍生物已经失去了这种刺激能力。肝素剂量依赖性地抑制BMP-2从培养基中积累到细胞层或BMPR-IA中，并在培养基中保留大量BMP-2。 BMP-2 的生物活性（使用 BMP 响应报告基因表达进行评估）在肝素存在下延长。综上所述，这些结果表明，硫酸化多糖通过持续为细胞膜上表达的信号受体提供配体，增强 BMP 同二聚体和异二聚体的生物活性。
Bone morphogenetic proteins (BMPs), which have been shown to be heparin-binding proteins, induce osteoblast differentiation in mesenchymal cells. In the present study, we examined the effects of heparin on the BMP activities in C2C12 myoblasts. Heparin dose dependently enhanced the osteoblast differentiation induced by not only homodimers of BMP-2 or BMP-4 but also heterodimers of BMP-2/6 or BMP-2/7. However, the osteoblast differentiation induced by the constitutively active BMPR-IA, a functional BMP type I receptor, was not affected by heparin. Heparan sulfate and dextran sulfate also enhanced the BMP-2 activity, although the chemically desulfated heparin-derivatives have lost this stimulatory capacity. Heparin dose-dependently suppressed the accumulation of BMP-2 from the culture media into the cell layer or BMPR-IA, and retained a large amount of BMP-2 in the culture media. The biological activity of BMP-2, which was evaluated using a BMP-responsive reporter gene expression, was prolonged in the presence of heparin. Taken together, these results suggest that sulfated polysaccharides enhance the biological activity of both homodimers and heterodimers of BMPs by continuously serving the ligands to their signaling receptors expressed on cell membranes.