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Advances in Clinical Medicine
Vol. 14  No. 03 ( 2024 ), Article ID: 83877 , 8 pages
10.12677/acm.2024.143974

生长因子衍生肽在骨组织工程中的研究进展

潘卓敏，刘雁鸣*

浙江大学医学院附属第二医院口腔颌面外科，浙江 杭州

收稿日期：2024年2月27日；录用日期：2024年3月24日；发布日期：2024年3月31日

摘要

通过生物支架递送生长因子是骨组织工程中的常用策略，在过去的几十年里取得了大量令人满意的结果。但生长因子存在的一些缺点诸如稳定性差、分子量大、成本高等阻碍了其广泛使用。近年来，一些具有相似生物活性的生长因子衍生肽由于合成简单、性质稳定等有点受到越来越多关注。本文总结了应用于骨组织工程的生长因子衍生肽。

关键词

骨组织工程，生长因子，衍生多肽，骨再生

Research Progress of Peptides Derived from Growth Factors in Bone Tissue Engineering

Zhuomin Pan, Yanming Liu*

Department of Oral and Maxillofacial Surgery, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou Zhejiang

Received: Feb. 27th, 2024; accepted: Mar. 24th, 2024; published: Mar. 31st, 2024

ABSTRACT

The delivery of growth factors through biological scaffolds is a commonly used strategy in bone tissue engineering, which has achieved a large number of satisfactory results in the past few decades. However, some drawbacks of growth factors such as poor stability, high molecular weight and high cost, hinder their widespread use. In recent years, some peptides derived from growth factors with similar biological activities have received increasing attention due to their simple synthesis and stable properties. This article summarizes the application of peptides derived from growth factors in bone tissue engineering.

Keywords:Bone Tissue Engineering, Growth Factors, Derived Peptide, Bone Regeneration

Copyright © 2024 by author(s) and Hans Publishers Inc.

This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).

http://creativecommons.org/licenses/by/4.0/

1. 引言

生长因子在调控骨组织再生方面具有至关重要的功能 [1] 。通过生物材料支架复合生长因子的策略在骨组织工程中被广泛使用，并且也取得了许多令人满意的结果 [2] [3] [4] 。然而，生长因子也存在许多局限性，例如价格昂贵、半衰期短、性质不稳定等，限制了其有效的临床转化 [5] [6] 。近年来，一些生长因子衍生肽被证明具有和生长因子相似的生物活性，由于其合成简单、价格低廉、性质更加稳定等优点受到越来越多关注 [7] [8] 。

2. 骨组织工程与生长因子

骨再生是一个复杂的过程，受到多种生长因子的调控 [9] 。生长因子是一类调节细胞功能的蛋白质，包括细胞增殖、迁移和分化等 [10] ，并且对细胞外基质（ECM）合成有重要意义 [11] 。过去已经研究了多种与骨再生相关的生长因子，包括骨形态发生蛋白(BMP)、血管内皮生长因子(VEGF)、血小板衍生生长因子(PDGF)、成纤维细胞生长因子(FGF)、骨保护素(OPG)、肿瘤坏死因子α (TNFα)等 [12] 。目前，基于生长因子递送的生物材料系统是骨再生研究的最常用策略之一 [13] ，然而，由于生长因子结构复杂、性质不稳定导致其利用率较低，在体内实现长效缓释也是一个巨大挑战 [14] ；同时，直接应用生长因子可能会伴随一些严重后果包括异位成骨、炎症反应等 [15] [16] ，这些局限性阻碍了其在骨组织工程中的进一步应用。因此，寻找理想的生长因子替代品是未来骨组织工程研究面临的巨大挑战之一。

3. 生长因子衍生肽在骨组织工程中的应用

生长因子衍生肽是一类源自生长因子部分氨基酸序列、具有模拟生长因子功能的生物活性多肽 [17] 。生长因子衍生肽多为单链肽形式，可通过多种修饰方式结合于骨组织工程支架上，以实现缓慢释放及促进骨缺损愈合 [18] 。在过去的几十年里，已经开发了多种生长因子衍生肽，包括骨形态发生蛋白衍生肽、血管内皮生长因子衍生肽、骨保护素衍生肽等，并且在多种生物材料系统中实现了有效的骨再生。

3.1. 骨形态发生蛋白(BMP)衍生肽

骨形态发生蛋白(BMP)是TGF-β超家族的成员，具有调节骨髓间充质干细胞成骨分化的作用，据报道，BMP-2、BMP-4、BMP-6、BMP-7和BMP-9都具有很强的成骨能力 [19] ；其中BMP-2和BMP-7已被美国食品药品监督管理局(FDA)批准临床骨再生应用 [6] 。目前研究了多种BMP衍生肽。

BMP-2蛋白具有两个功能结构域，被称为指关节表位和腕表位，指关节表位被认为和BMP-2受体II结合 [20] ，而腕表位则与BMP-2受体I A结合 [21] 。Saito等人开发了一种源自BMP-2指关节表位73-92位氨基酸残基的衍生肽，氨基酸序列为KIPKASSVPTELSAISTLYL (简称KP肽)，被证明可结合BMP-2 II型受体激活BMP通路，提高碱性磷酸酶活性和骨钙素基因表达，从而促进成骨分化 [22] 。这种衍生肽可通过物理或化学结合的形式固定在生物支架上，例如，Park SH等人通过化学反应将KP肽掺入了一种可注射的点击交联透明质酸水凝胶，在体内观察到了多肽的持续释放，并且在体外促进了人牙髓干细胞成骨分化以及体内骨再生 [23] 。另外，KP肽也可通过添加结构域增强与支架的结合，例如，Bain等人设计了具有七谷氨酸结构域(E7)的KP肽，这种源自骨唾液蛋白天然基序结构域显著增强了KP肽和无机牛骨的特异性结合，从而提高了骨再生能力 [24] 。在Weng等人的研究中，具有E7结构域修饰的KP肽也被偶联于一种3D杂化的纳米纤维气凝胶，显著增强了大鼠颅骨缺损愈合 [25] 。KP肽也可与其他生物活性分子共同递送，在最近的一项研究中，一种骨髓间充质干细胞特异性亲和肽(氨基酸序列EPLQLKM)和KP肽被同步偶联到静电纺丝支架上，可以同时促进骨髓间充质干细胞粘附和成骨分化，实现了协同成骨 [26] 。除此之外，源自BMP-2腕表位的30~34位氨基酸残基的DWIVA序列也被证明具有成骨潜力 [27] [28] 。Oliver-Cervelló等人开发了一种含有DWIVA基序和整合素结合序列(RGD)的仿生肽，该肽成功模拟了整合素-BMP信号转导，促进了细胞黏附与成骨分化 [29] ，并且应用于钛仿生涂层后显著促进了大鼠颅骨再生 [30] 。在进一步的研究中，这种含有DWIVA基序和RGD序列的仿生肽被用于一种聚乙二醇(PEG)基水凝胶的功能化，并且联合了基质金属蛋白酶(MMP)可降解序列，显示出理想的可降解性和促成骨分化作用 [31] 。

BFP-1是一种源自BMP-7未成熟区域的衍生肽，对应于BMP-7蛋白序列的第100~114位氨基酸残基，序列为GQGFSYPYKAVFSTQ；体外研究表明，BFP-1可上调成骨标志的显著表达，并且与BMP-7相比，具有更高的成骨分化活性，体内研究也显示了其潜在的成骨活性 [32] 。因此，BFP-1可作为生物活性剂用于骨再生研究。例如，Luo等人将BFP-1掺入了多孔海藻酸盐支架，显示出一定的缓释模式和促成骨活性 [33] 。为了进一步增强BFP-1在海藻酸盐支架中的骨再生能力，该研究团队将BFP-1联合含有RGD序列的粘附肽共同负载于介孔二氧化硅纳米颗粒中，随后掺入海藻酸盐支架中，实现了双功能肽的响应性顺序释放，并且显著改善了药物释放行为，在体内表现出优秀的骨修复效率 [34] 。另外，也可通过共价结合的方式将BFP-1于生物支架结合，在Jing等人的研究中，BFP-1通过交联剂与羧甲基壳聚糖(CMC)共价结合，并最终接枝到脱矿牙本质基质(DDM)表面，结果表明修饰后DDM在体外和体内均显示出更好的骨诱导能力 [35] 。

pBMP-9是源自BMP-9指关节表位68~87位氨基酸残基的衍生肽，序列为CGGKVGKACCVPTKLSPISVLYK，被证明可通过激活Smad通路，从而上调成骨相关基因的表达，增强碱性磷酸酶活性，促进小鼠前成骨细胞MC3T3-E1成骨分化，并且不会被Noggin抑制，但过高的浓度(400 ng/mL)也会抑制MC3T3-E1细胞的增殖 [36] 。Bergeron等人开发了一种基于I型胶原蛋白凝胶和生物活性玻璃微球的递送系统，掺入了相同浓度的pBMP-9和人重组BMP-2，结果表明掺入pBMP-9能观察到更明显的成骨分化 [37] ；该研究团队随后对递送系统进行了优化，pBMP-9被负载至一种基于壳聚糖的递送系统，实现了10天内的缓慢释放，并且成功诱导了C57BL/6小鼠股四头肌中的异位成骨 [38] 。pBMP-9联合粘附肽也可进一步增强成骨活性，Beauvais等人的研究表明，使用源自纤连蛋白粘合肽(pFibro)功能化的聚己内酯(PCL)膜使小鼠C3H10T1/2细胞中形成了更多的黏附斑点，并且和pBMP-9一起孵育时，观察到更多的Runx2表达 [39] ，表明了基于这两种生物活性肽设计的仿生材料具有良好前景。

3.2. 血管内皮生长因子(VEGF)衍生肽

血管内皮生长因子(VEGF)是具有促血管生成活性的生长因子，对内皮细胞具有促有丝分裂和抗凋亡作用，还可促进细胞迁移，增加血管的通透性等，促进细胞迁移等，因此在调控血管生成方面有重要意义 [40] 。众所周知，血管生成对于骨组织重建非常关键 [9] ，实现有效的血管化骨再生是一种理想的策略。

VEGF衍生肽(QK)是源自VEGF与受体结合区域的一段衍生的氨基酸序列，序列为KLTWQELYQLKYKGI，被证明可通过与VEGF受体结合，导致ERK1/2激活，促进了内皮细胞增殖和迁移，在体外诱导血管生成，并且还可增强内皮细胞对VEGF的反应 [41] 。尽管QK具有很强的诱导血管生成活性，但单独使用QK并不能获得理想的成骨效果，因此QK常作为辅助成分与其他成骨活性肽协同促进骨再生，例如，Li等人将QK和成骨肽KP一起结合在一种基于甲基丙烯酰化明胶(GelMA)和氧化葡聚糖(ODex)的可注射水凝胶上，在植入体内4周后显著促进了大鼠颅骨修复 [42] 。同样地，QK和BMP-7衍生肽BFP-1的组合也加速了牙周骨的再生 [43] 。QK也可通过多种方式以增强其成血管活性，如可通过添加七谷氨酸结构域(E7)加强QK和磷酸钙基支架之间的亲和力，与未修饰的QK相比，E7修饰的QK与磷酸钙基支架的结合增加了4~6倍 [44] ；也可将QK与层粘连蛋白衍生肽AG-73偶联以增强细胞信号转导，更加有效地促进了人脐静脉内皮细胞(HUVECs)的黏附和增殖 [45] 。除此之外，QK在周围神经修复 [46] 、促进伤口愈合 [47] 、治疗心肌梗死 [48] 等方面也具有较强的生物活性。

3.3. 骨保护素(OPG)衍生肽

骨保护素(OPG)是RANK-RANKL-OPG系统的重要成员，是调控破骨细胞分化和骨重塑的关键因子 [49] 。目前已知，核因子κB受体活化因子配体(RANKL)与破骨细胞表面的核因子κB受体活化因子(RANK)结合可促进破骨细胞分化导致骨吸收，而OPG可作为诱导受体与RANKL结合抑制RANK信号转导，从而抑制破骨细胞形成 [50] 。

OP3-4是一种OPG的衍生肽，氨基酸序列为YCEIEFCYLIR，其作用机制是模拟OPG与RANKL结合，导致RANK信号转导减弱，从而抑制破骨细胞形成以减少骨质流失 [51] 。骨再生过程中成骨与破骨是同时存在的 [17] ，因此通过减少破骨的方式来增加成骨也是一种合理的策略，例如，Uehara等人通过将OP3-4加入到含有BMP-2的可注射明胶水凝胶中，在注射体内4周后显著促进了BMP-2诱导的上颌骨再生 [52] 。OP3-4也可与其他活性分子协同作用，如OP3-4联合抗CXCL9抗体，同时抑制了破骨细胞分化和促血管生成，从而加速股骨缺损的愈合 [53] 。由于肽的聚集可能会导致其失去生物活性，因此Xie等人将OP3-4引入了含胆固醇的支链淀粉(CHP)纳米凝胶支架，改善了OP3-4的释放模式，并获得更佳的骨修复效果 [54] 。

3.4. 肿瘤坏死因子受体(TNFR)衍生肽

TNF-α是一种细胞因子，可促进多种生物学效应，TNF-α诱导的破骨细胞募集被认为是与炎症性骨吸收相关疾病(如牙周病)发病机制的核心 [8] 。WP9QY肽(简称W9)是一种肿瘤坏死因子α (TNF-α)拮抗剂，是一种以TNF 1型受体上的TNF-α结合位点为模板设计的环肽，序列为YCWSQYLCY，其作用机制和OP3-4相似，主要通过与RANKL和TNF-α结合来抑制破骨细胞形成，从而减少骨吸收 [55] 。W9对炎症也有一定的抑制作用，尽管弱于抗TNF抗体，但W9对骨破坏的抑制作用与抗TNF抗体相似甚至更强 [56] 。同样地，W9也被证明可以直接促进骨再生 [57] 或者增强BMP-2诱导的骨形成 [58] 。利用W9的免疫调控作用，也可实现促成骨效果，如Ma等人 [59] 开发的封装有W9肽和抗菌肽LL37的猪小肠黏膜下层(SIS)水凝胶，不仅表现出良好的抗菌能力，还通过W9调控巨噬细胞向M2型极化，促进骨髓间充质干细胞成骨分化，表明了其在免疫调控和骨再生方面的优势。

3.5. 成纤维细胞生长因子(FGF)衍生肽

成纤维细胞生长因子(FGF)是骨骼发育的重要调节因子，其中FGF-2是软骨内骨形成和骨膜内成骨的关键调节剂 [60] 。据报道，FGD-2和肝素/硫酸乙酰肝素蛋白聚糖(HSPG)的相互作用可调控细胞生长和迁移 [61] ，因此，FGF-2中的肝素结合位点在调节其生物活性方面起着重要作用。F105和F119是源自FGF-2肝素结合位点的两段衍生肽，分别对应于第105-111 (F105, YKRSRYT)和119-135 (F119, KRTGQYKLGSKTGPGQK)位氨基酸残基，体外结果表明F105和F119与肝素有很高的结合亲和力，并且促进了骨髓间充质干细胞黏附和铺展；进一步研究表明，F105和F119通过提高细胞外调节蛋白激酶(ERK)的磷酸化水平，最终导致了骨髓间充质干细胞碱性磷酸酶过表达和钙沉积的增加 [62] 。目前尚无体内研究证据表明这两种肝素结合肽具有成骨活性，未来有望用于生物支架材料的功能化，以增强骨再生。

4. 总结

对生长因子的研究推动了骨组织工程技术的应用和进一步拓展，但生长因子潜在的免疫原性、大分子量、复杂的递送模式以及体内的不稳定性等缺点阻碍了它们的广泛使用。大量的研究表明，生长因子衍生肽同样具有较强的生物活性。肽作为小分子药物，合成简单，克服了成本问题，多样化的修饰及释放模式也是其优势之一。未来值得探索更多具有成骨活性的多肽序列；多种肽组合以实现不同药物调控的复杂再生过程也值得进一步探索。总而言之，生长因子衍生肽有望作为理想的生长因子替代品，在骨组织工程领域具有良好的应用前景。

文章引用

潘卓敏,刘雁鸣. 生长因子衍生肽在骨组织工程中的研究进展
Research Progress of Peptides Derived from Growth Factors in Bone Tissue Engineering[J]. 临床医学进展, 2024, 14(03): 2290-2297. https://doi.org/10.12677/acm.2024.143974

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    63. NOTES

    *通讯作者。

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