Endogenous heparan sulfate and heparin modulate bone morphogenetic protein-4 signaling and activity
Endogenous heparan sulfate and heparin modulate bone morphogenetic protein-4 signaling and activity
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DOI：
10.1152/ajpcell.00346.2007
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发表时间：
2008-06-01
影响因子：
5.5
通讯作者：
Gupta, Pankaj
中科院分区：
文献类型：
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作者：
Khan, Shaukat A.;Nelson, Matthew S.;Gupta, Pankaj
骨形态发生蛋白（BMPs）及其内源性拮抗剂对脑和骨的发育以及肿瘤的发生和发展至关重要。硫酸乙酰肝素（HS）蛋白聚糖（HSPG）调节骨形成蛋白（BMP）及其拮抗剂的活性。糖胺聚糖（GAG）如何影响BMP活性在各种恶性肿瘤和遗传性异常的GAG代谢，和结构特征的必需的调节BMP信号，仍然不完全确定。我们研究了化学修饰的可溶性肝素、恶性细胞中的内源性HS和Hurler综合征细胞中积累的HS是否影响BMP-4信号传导和活性。我们表明，外源性（可溶性）和内源性糖胺聚糖调节BMP-4信号和活性，这种效果是依赖于特定的硫酸残基糖胺聚糖。我们的研究表明，内源性硫酸化GAG促进恶性人类细胞的增殖和损害分化，为研究抑制GAG合成或功能的药物是否可能逆转这种作用提供了理论基础。我们证明了人类Hurler综合征多能干细胞中GAG对BMP-4信号传导的损伤，确定了可能导致Hurler综合征和相关粘多糖沉积症中进行性神经和骨骼异常的机制。
Bone morphogenetic proteins (BMPs) and their endogenous antagonists are important for brain and bone development and tumor initiation and progression. Heparan sulfate (HS) proteoglycans (HSPG) modulate the activities of BMPs and their antagonists. How glycosaminoglycans (GAGs) influence BMP activity in various malignancies and in inherited abnormalities of GAG metabolism, and the structural features of GAGs essential for modulation of BMP signaling, remain incompletely defined. We examined whether chemically modified soluble heparins, the endogenous HS in malignant cells and the HS accumulated in Hurler syndrome cells influence BMP-4 signaling and activity. We show that both exogenous (soluble) and endogenous GAGs modulate BMP-4 signaling and activity, and that this effect is dependent on specific sulfate residues of GAGs. Our studies suggest that endogenous sulfated GAGs promote the proliferation and impair differentiation of malignant human cells, providing the rationale for investigating whether pharmacological agents that inhibit GAG synthesis or function might reverse this effect. Our demonstration of impairment of BMP-4 signaling by GAGs in multipotent stem cells in human Hurler syndrome identifies a mechanism that might contribute to the progressive neurological and skeletal abnormalities in Hurler syndrome and related mucopolysaccharidoses.