Morphogenic Peptides in Regeneration of Load Bearing Tissues.
Morphogenic Peptides in Regeneration of Load Bearing Tissues.
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承重组织再生中的形态发生肽。
DOI：
10.1007/978-3-319-22345-2_6
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发表时间：
2015
影响因子：
--
通讯作者：
Jabbari,Esmaiel
中科院分区：
文献类型：
--
作者：
Moeinzadeh,Seyedsina;Jabbari,Esmaiel
形态发生蛋白的半衰期短，在承载组织的再生过程中需要高剂量的生长因子，这导致了不良的副作用。这些副作用包括骨骼过度生长、肿瘤形成和免疫反应。在再生医学中，减少蛋白质不良反应的另一种方法是使用形态发生蛋白活性区域或矿化承载组织细胞外基质中可溶和不可溶成分的形态多肽来诱导祖细胞分化、矿化、成熟和成骨。在这方面，已经发现了许多具有成骨活性的多肽。这些多肽包括骨形态发生蛋白(BMPs)多肽、与整合素和肝素结合受体相互作用的多肽、胶原多肽、其他可溶性ECM蛋白(如骨唾液蛋白和釉质基质蛋白)的多肽以及血管诱导和神经诱导蛋白的多肽。虽然这些多肽在体外表现出显著的成骨活性，并在动物模型中增加矿化和骨形成，但它们作为形态形成蛋白的替代品并未广泛应用于临床骨科应用。这在一定程度上是由于在生理介质中，特别是在组织工程支架中，有关形态多肽结构和功能的数据有限。由于其两亲性，多肽在生理介质中自发地自组装和聚集成胶束结构。聚集改变了形态多肽中的氨基酸序列，这些氨基酸与细胞表面受体相互作用，从而影响多肽的成骨活性。聚集和胶束的形成可以显著降低形态多肽的活性浓度，使生理介质中的多肽浓度增加数倍。其他影响生物活性的因素包括形态多肽与细胞膜脂质双层的非特异性相互作用，多肽与细胞表面受体的相互作用，而这些受体不能特异性地诱导成骨，从而导致多肽的成骨活性不佳，以及多肽与细胞表面成骨受体的非最佳相互作用。与组织工程基质的共价附着或物理相互作用也可以改变形态多肽的生物活性，导致较低程度的成骨和骨形成。本章综述了形态多肽的发现、结构特征及其在临床应用中作为生长因子在组织工程设备中用于承载组织再生方面的挑战。
Morphogenic proteins due to their short half-life require high doses of growth factors in regeneration of load bearing tissues which leads to undesirable side effects. These side effects include bone overgrowth, tumor formation and immune reaction. An alternative approach to reduce undesirable side effects of proteins in regenerative medicine is to use morphogenic peptides derived from the active domains of morphogenic proteins or soluble and insoluble components of the extracellular matrix of mineralized load bearing tissues to induce differentiation of progenitor cells, mineralization, maturation and bone formation. In that regard, many peptides with osteogenic activity have been discovered. These include peptides derived from bone morphogenic proteins (BMPs), those based on interaction with integrin and heparin-binding receptors, collagen derived peptides, peptides derived from other soluble ECM proteins such as bone sialoprotein and enamel matrix proteins, and those peptides derived from vasculoinductive and neuro-inductive proteins. Although these peptides show significant osteogenic activity in vitro and increase mineralization and bone formation in animal models, they are not widely used in clinical orthopedic applications as an alternative to morphogenic proteins. This is partly due to the limited availability of data on structure and function of morphogenic peptides in physiological medium, particularly in tissue engineered scaffolds. Due to their amphiphilic nature, peptides spontaneously self-assemble and aggregate into micellar structures in physiological medium. Aggregation alters the sequence of amino acids in morphogenic peptides that interact with cell surface receptors thus affecting osteogenic activity of the peptide. Aggregation and micelle formation can dramatically reduce the active concentration of morphogenic peptides with many-fold increase in peptide concentration in physiological medium. Other factors that affect bioactivity are the non-specific interaction of morphogenic peptides with lipid bilayer of the cell membrane, interaction of the peptide with cell surface receptors that do not specifically induce osteogenesis leading to less-than-optimal osteogenic activity of the peptide, and less-than-optimal interaction of the peptide with osteogenic receptors on the cell surface. Covalent attachment or physical interaction with the tissue engineered matrix can also alter the bioactivity of morphogenic peptides and lead to a lower extent of osteogenesis and bone formation. This chapter reviews advances in discovery of morphogenic peptide, their structural characterization, and challenges in using morphogenic peptides in clinical applications as growth factors in tissue engineered devices for regeneration of load bearing tissues.