The identification of a heparin binding domain peptide from bone morphogenetic protein-4 and its role on osteogenesis
The identification of a heparin binding domain peptide from bone morphogenetic protein-4 and its role on osteogenesis
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DOI：
10.1016/j.biomaterials.2010.05.022
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发表时间：
2010-10-01
期刊：
影响因子：
14
通讯作者：
Park, Yoon Jeong
中科院分区：
文献类型：
--
作者：
Choi, Yoon Jung;Lee, Jue Yeon;Park, Yoon Jeong
肝素结合的存在在发挥生长因子相关的组织形成中已变得至关重要。骨形态发生蛋白（BMP）-4受体介导的成骨细胞分化及其与肝素结合的支持作用已被提出，但BMP-4的肝素结合位点在成骨中的直接作用尚未完全研究。如果结合位点本身在骨生成中起作用，则位点结构域可以与生物材料组合用于骨形成。本文中，我们合成了对应于BMP-4（HBD，RKKNPNCRRH）的残基15-24的肽序列，作为潜在的肝素结合序列。HBD肽通过激活细胞外信号调节激酶（ERK 1/2）诱导成骨分化，ERK 1/2是hMSC中的关键调节因子之一。此外，用肝素酶处理培养的hMSCs阻断了HBD肽诱导的成骨分化和GAG链检测，同时消除了磷酸化ERK水平的增加。这些结果表明，所鉴定的肝素结合域肽（HBD）通过与肝素和ERK信号转导相互作用刺激成骨细胞分化。体内实验结果进一步证明，HBD与藻酸盐凝胶形成复合物，能够诱导骨缺损处的成骨。(C)2010爱思唯尔有限公司版权所有。
The presence of heparin binding has been become crucial in exerting growth factor related tissue formation. Receptor-mediated osteoblastic differentiation by bone morphogenetic protein (BMP)-4 and supportive function of its heparin binding has been proposed, direct role of the heparin binding site of BMP-4 on osteogenesis has not yet been fully investigated. If the binding site itself plays role on osteogenesis, the site domain can be useful in bone formation in combination with biomaterial. Herein, we synthesized a peptide sequence corresponding to residues 15-24 of BMP-4 (HBD, RKKNPNCRRH), as potential heparin binding sequence. The HBD peptide-induced ostoegenic differentiation by activating extracellular signal-regulated kinase (ERK1/2), one of the key regulators in hMSC. Also, treatment of cultured hMSCs with heparinase blocked both HBD peptide-induced osteogenic differentiation and GAG chain detection while abolishing the increased phospho-ERK level. These results suggest that the identified heparin binding domain peptide (HBD) stimulated osteoblastic differentiation via interaction with heparin and the ERK signaling. In vivo results further demonstrated that HBD, as a form of complex with alginate gel, was able to induce bone formation in the bone defect. (C) 2010 Elsevier Ltd. All rights reserved.