CN107670105B - Igfbp3在制备骨缺损修复材料中的应用 - Google Patents

Igfbp3在制备骨缺损修复材料中的应用 Download PDF

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CN107670105B
CN107670105B CN201710911622.3A CN201710911622A CN107670105B CN 107670105 B CN107670105 B CN 107670105B CN 201710911622 A CN201710911622 A CN 201710911622A CN 107670105 B CN107670105 B CN 107670105B
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邓墨渊
许建中
董世武
侯天勇
罗飞
易绍萱
于博
谭玖琳
罗科宇
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Abstract

本发明涉及一种胰岛素结合蛋白3(IGFBP3)在制备骨缺损修复材料中的应用，利用IGFBP3上调MSCs中TβRII、TβRI和CCR2表达，激活CCR2和TβRI/II‑Smad3信号通路促进MSCs迁移的作用，在体内募集宿主MSCs至骨缺损处，为成骨提供大量前体细胞，促进骨缺损处新生骨的骨量、骨小梁数或骨密度，因此可以作为骨缺损修复材料，对骨缺损修复的治疗提供了新的方向。

Description

IGFBP3在制备骨缺损修复材料中的应用
技术领域
本发明属于生物医药领域，涉及IGFBP3在制备骨缺损修复材料中的应用。
背景技术
肢体大段骨缺损(bone defects)是由创伤、感染、肿瘤等因素造成的临床的常见病。据卫生部有关统计资料，在市级以上医院，骨创伤病人数量占住院病人总量的第一位。在骨创伤中，骨缺损是致残的首要因素，四肢骨折的致残率达20％～30％，是死亡原因的第五位。肢体大段骨缺损的治疗往往因为缺乏大量高成骨活性的植骨材料而使其成为难治病，经久不愈，给患者健康造成严重的损害。
宿主间充质干细胞(Mesenchymal stem cell，MSCs)是中胚层中的主要干细胞，其构成了一个天然的内源性修复系统：一方面更新组织细胞；另一方面作为成骨前体细胞的主要来源分化为成骨细胞促进骨组织再生。现有的损伤修复主要策略是原位组织再生方法，即是利用自身潜力修复组织损伤。据此，当骨缺损发生时，MSCs会定向迁移、聚集、定植于损伤处(即MSCs的募集行为)，随后增殖、分化并参与损伤修复和组织再生，因此MSCs的募集对骨缺损愈合尤为重要。研究表明，趋化因子在MSCs的募集过程发挥着重要作用。MSCs的募集涉及的一个关键步骤就是MSCs的定向迁移，而迁移指的是MSCs在感受到趋化因子类物质的浓度梯度后而产生的趋向移动或运动。
目前，关于胰岛素结合蛋白3(insulin-like growth factor binding protein3，IGFBP3)的研究主要集中在调控癌细胞凋亡和增殖功能，其在IGFBP3招募骨骼系统中MSCs的作用鲜有研究，尚未见关于IGFBP3通过募集宿主MSCs促进骨组织再生，在治疗骨缺损方面的任何报道。
发明内容
有鉴于此，本发明的目的在于提供一种骨缺损修复材料，为达到上述目的，本发明提供如下技术方案：
胰岛素结合蛋白3在制备骨缺损修复材料中的应用。本发明首次发现IGFBP3具有促进hBMSCs迁移，募集宿主MSCs的新功能，主要通过激活CCR2和TβRI/II-Smad信号通路，进而促进MSCs的迁移。在进一步的免疫缺陷(severe combined immunodeficiency，SCID)鼠股骨缺损模型实验中也证实，加载了IGFBP3的骨修复材料能募集宿主MSCs，且IGFBP3材料组骨缺损处新生骨的骨量(BV/TV),骨小梁数(Tb.N)及骨密度(BMD)均显著高于阴性对照材料组，表明了IGFBP3可以用于制备骨缺损修复材料。
本发明的有益效果在于：本发明首次公开了将IGFBP3用于制备骨缺损修复材料，不仅拓宽了IGFBP3的应用领域，还提高了IGFBP3的应用价值，同时本发明方案的实施为治疗肢体大段骨缺损提供了新的方向，对肢体大段骨缺损的治疗具有重要的临床意义。
附图说明
为了使本发明的目的、技术方案和有益效果更加清楚，本发明提供如下附图进行说明：
图1显示了IGFBP3能够有效促进hBMSCs的迁移，****表示与对照组(Vehicle)比较p＜0.001。
图2为qPCR及Westen blot验证IGFBP3对hBMSCs的TβRI/II-Smad和CCR2迁移信号通路的影响(A为IGFBP3对hBMSCs的迁移受体基因表达水平的qPCR实验结果，B为Westernblot验证IGFBP3对TβRI，TβRII和CCR2表达促进作用结果，C为Western blot的TβRI，TβRII和CCR2表达相对密度结果，D为Western blot验证IGFBP3对pSmad2/3和Smad2/3表达促进作用结果，E、F为Western blot验证了抑制剂对IGFBP3上调的TβRI，pSmad2/3、Smad2/3和CCR2表达的抑制作用。G为Western blot的TβRI，pSmad和CCR2表达相对密度结果；图中inhibitors：SB505124为TβR I/II信号通路的抑制剂，BMS CCR2 22为CCR2信号通路的抑制剂；**表示与对照组比较p<0.01，***表示与对照组比较p<0.005，****表示与对照组比较p<0.001。
图3为TGFβ信号途径和CCR2信号途径阻断对IGFBP3引起的hBMSCs迁移的影响(****表示与对照组(Vehicle)比较p＜0.001)，SB505124为TβR I/II信号通路的抑制剂，BMS CCR2 22为CCR2信号通路的抑制剂。
图4为加载IGFBP3的修复材料招募宿主MSCs引起骨缺损的骨再生。A为流式细胞术检测募集MSCs的细胞的Scar-1及PDGFR-α的阳性细胞点，B为在术后3、7及10天移植材料中招募的宿主MSCs的细胞百分比；C为在术后4及8周DBM，Igfbp3组的股骨缺损处再生骨组织的Micro CT的3D and 2D图；D为在术后4及8周DBM，Igfbp3组的股骨缺损处再生骨组织Micro CT的BV/TV，Tb.N及BMD结果；Scale bar:5mm；*P<0.05,**P<0.01,****P<0.001。
具体实施方式
下面将结合附图，对IGFBP3招募宿主MSCs以促进骨再生的作用及机制进行详细的描述，其中IGFBP3氨基酸序列如SEQ ID NO.1所示。
实施例1、IGFBP3促进hBMSCs迁移
通过Transwell法检测hBMSCs的迁移能力，确定IGFBP3对hBMSCs趋化作用的影响。
Transwell法具体步骤如下：50μL hBMSCs悬液按1×104cells/chamber接种到Boyden chambers of 24-well plates(8mm，Millipore，Darmstadt，Germany)上层，不同浓度(0-10ng/ml)IGFBP3加入下层孔板中，经24小时孵育，上层小室用于迁移检测。小室经4％多聚甲醛固定后，结晶紫染色，用棉签擦去未迁移至薄膜下层的hBMSCs。迁移hBMSCs细胞数目是在光镜下(×100)五个连续视野的计数，值为三个平行样的平均计数，以迁移细胞数评价IGFBP3的迁移能力，结果见图1。结果显示，IGFBP3能够有效地促进hBMSCs的迁移，IGFBP3对hBMSCs的促迁移作用在25ng/mL最为显著。
实施例2、IGFBP3通过TGFβ及CCR2信号途径促进hBMSCs迁移
通过qPCR实验和Western blot实验评价IGFBP3活化hBMSC的信号途径。
qPCR实验：将hBMSCs接种于6孔细胞培养板，用含10％胎牛血清的DMEM/F12培养基培养，待细胞融合80％后，加入25ng/mL IGFBP3作为实验刺激组，相应地PBS作为对照组，培养1、2及3天后分别收集各组细胞，提取总RNA，按常规操作流程反转录合成cDNA，设计并合成针对细胞迁移特异基因TβR I等的Real-time PCR引物，并以GAPDH为内参，具体引物如表1所示：
表1、迁移相关受体基因引物序列
通过荧光实时定量PCR检测迁移相关基因的表达丰度，每组做独立实验5复孔，结果图如2中A所示。qPCR实验结果显示，25ng/mL IGFBP3处理hBMSCs 2天时，CCR2和TβRI表达上调显著。
Western blot实验：将hBMSCs接种于6孔细胞培养板，用含10％胎牛血清的DMEM/F12培养基培养，待细胞融合80％后，加入25ng/mL IGFBP3作为实验刺激组，相应地PBS作为对照组，培养6、12小时，以及1、2和3天后，收集细胞，培养6、12小时的样品与pSmad2/3抗体和Smad2/3抗体进行免疫杂交，计算Smad 3蛋白的磷酸化水平；1、2和3天的细胞样品TβR I、TβR II及CCR2抗体进行免疫杂交，计算这3个蛋白的表达水平，结果见图2中B～D。结果显示，25ng/mL IGFBP3处理hBMSCs 1天时，TβRII、CCR2和TβRI表达显著上调；25ng/mL IGFBP3处理hBMSCs 2天时，CCR2和TβRI表达显著上调。3天时，IGFBP3对hBMSCs的作用不显著。25ng/mL IGFBP3处理hBMSCs 6小时，能促进Smad2/3的磷酸化水平。分子水平的结果提示，IGFBP3活化TGFβ以及CCR2信号通路。
采用信号通路特异性抑制剂SB505124和BMSCCR2 22分别阻断TGFβ以及CCR2信号通路，检测hBMSCs的迁移率，评价IGFBP3的迁移通路，结果如图3所示。结果显示，25ng/mLIGFBP3增加64％hBMSCs迁移数，而5μM浓度SB505124和100nM BMSCCR2 22处理后的细胞穿过transwell微孔的数量比IGFBP3组分别少了33％和43％。
经Western blot检测TβRI/II，pSmad2/3和CCR2表达，结果如图2中E～G所示。结果显示，hBMSCs中Smad2/3蛋白的磷酸化水平及TβRI、CCR2表达随着抑制剂的处理发生了显著的下降，表明TGFβ以及CCR2信号通路的阻断直接使hBMSCs迁移受到抑制。
实施例3、IGFBP3募集宿主MSCs促进骨缺损修复
制备骨移植材料：设置IGFBP3实验组骨移植材料(2×2mm，DBM-1μg IGFBP3)和对照组材料(2×2mm，DBM-PBS)。
动物建模：采用48只8周大SCID鼠(重约25-30克)，分成IGFBP3组和对照组两组，每组24只，并建立股骨缺损模型。待SCID鼠麻醉后，固定股骨，截取2-mm长的股骨缺损，并剥去骨皮质，并将相应的支架材料植入骨缺损处，关闭伤口。术后3、7及10天，采用流式细胞术检测宿主MSCs募集情况，术后4及8周，采用micro CT评价骨形成效果。
细胞流式术检测MSCs募集实验：术后7天，取移植材料，剪碎后，采用Trypleexpress和0.1％typeΙ胶原酶，收集支架材料中募集到的宿主细胞。收集到的细胞经Ratanti-Mouse CD45(APC,clone 30-F11)，Rat anti-Mouse Sca-1(FITC,Clone D7)及Ratanti-Mouse PDGFR-α(PE,clone APA5)标记鼠MSCs。经FACS Calibur flow cytometer检测，计数Sca-1+PDGFR-α+CD45-MSCs，结果如图4中A和B所示。结果显示，术后3、7天，IGFBP3组的Sca-1+PDGFR-α+CD45-MSCs数目约为对照组的10倍。
micro CT评价：术后4及8周，每组分别取3只，4％多聚甲醛固定48小时，行microCT检测，计算相对骨量(BV/TV),骨小梁数(Tb.N)及骨密度(BMD)，图4中C和D所示。结果显示，术后4周，micro CT的二维及三维图显示，对照组小鼠的股骨缺损无新生骨桥接，而IGFBP3组则大量骨新生；术后8周，IGFBP3组缺损处已由新生骨组织桥接，部分髓腔已通。Micro CT统计结果显示，术后4及8周，IGFBP3组骨缺损处新生骨的骨量(BV/TV),骨小梁数(Tb.N)及骨密度(BMD)均显著高于对照组。上述结果说明IGFBP3可通过募集MSCs促进骨缺损修复。
最后说明的是，以上优选实施例仅用以说明本发明的技术方案而非限制，尽管通过上述优选实施例已经对本发明进行了详细的描述，但本领域技术人员应当理解，可以在形式上和细节上对其作出各种各样的改变，而不偏离本发明权利要求书所限定的范围。
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<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 8
tgaaggcagg cacatttaca tcta 24
<210> 9
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 9
tacaggagtc tcgggatcag ttg 23
<210> 10
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 10
ggggacaggg aggtggatt 19
<210> 11
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 11
attcccgatc acaatgcaca 20
<210> 12
<211> 23
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 12
cagctccctg gaaatcaaca ttc 23
<210> 13
<211> 24
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 13
cagtcttggc agagcacaaa aagg 24
<210> 14
<211> 19
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 14
acccggagta cttcagcgc 19
<210> 15
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 15
cacagaagct tcgttgagaa 20
<210> 16
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 16
cttcaacagc gacacccact 20
<210> 17
<211> 20
<212> DNA
<213> 人工序列(Artificial Sequence)
<400> 17
gtggtccagg ggtcttactc 20

Claims (2)

1.胰岛素结合蛋白3在制备促进MSCs迁移、招募MSCs归巢的材料中的应用。
2.胰岛素结合蛋白3在制备上调MSCs 中TβRII、TβRI和CCR2表达的材料中的应用。
CN201710911622.3A 2017-09-29 2017-09-29 Igfbp3在制备骨缺损修复材料中的应用 Expired - Fee Related CN107670105B (zh)

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