Chinese Journal of Tissue Engineering Research ›› 2021, Vol. 25 ›› Issue (26): 4192-4197.doi: 10.12307/2021.120
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Yang Yuchen, Yang Peipei, Huang Biying, Zhang Qiang
Received:
2020-06-28
Revised:
2020-07-04
Accepted:
2020-07-31
Online:
2021-09-18
Published:
2021-05-11
Contact:
Zhang Qiang, MD, Professor, Department of Oral and Maxillofacial Surgery, First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
E-mail:zhq100@aliyun.com
About author:
Yang Yuchen, Master candidate, Department of Oral and Maxillofacial Surgery, First Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, China
Supported by:
CLC Number:
Yang Yuchen, Yang Peipei, Huang Biying, Zhang Qiang. Autophagy regulates osteoclast proliferation, differentiation and function through mitogen-activated protein kinase signaling pathway[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(26): 4192-4197.
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2.1 破骨细胞的增殖与分化 破骨细胞来源于单核造血干细胞,在大多数情况下都存在于骨髓腔内。当骨组织重塑需要破骨细胞时,这些单核细胞会相互融合成多核巨细胞,表现出骨吸收性,并迁移到骨吸收的骨组织表面。破骨细胞进行骨吸收时会通过伪足小体紧紧附着在骨表面,而肌动蛋白丝、肌动蛋白等则是破骨细胞附着的关键蛋白。破骨细胞分泌酸性的蛋白酶和溶酶体,并使其迁移到破骨细胞和骨组织之间的皱褶缘,皱褶缘的形成增加了破骨细胞与骨组织接触的面积,于是酸溶解骨组织中的矿物质,分解胶原基质,完成骨组织的吸收[1]。破骨细胞的分化和功能受多种细胞因子、激素和生长因子的调节[2],其中巨噬细胞集落刺激因子和核因子κB受体活化因子配体(receptor activator of nuclear factor-κB ligand,RANKL)在调节破骨细胞生成的过程中是必不可少的,如破骨细胞前体细胞的增殖、黏附、迁移以及细胞与细胞之间融合继而形成多核细胞,另外还包括成熟破骨细胞的迁移、存活和骨吸收功能[3]。巨噬细胞集落刺激因子和RANKL在破骨细胞分化和骨吸收过程中均可通过MAPK信号传导起作用。巨噬细胞集落刺激因子激活的MAPK信号主要参与破骨前体细胞增殖的调节,而RANKL诱导的MAPK激活主要参与破骨细胞分化[4]。最近研究表明,巨噬细胞集落刺激因子和RANKL在激活MAPK的程度、持续时间以及MAPK磷酸化的亚型和特异性方面均有不同,从而决定了破骨细胞前体细胞增殖或分化的不同结果[5]。MAPK途径的激活会导致各种生物学结果,包括细胞增殖和存活、凋亡和分化以及细胞应激和细胞自噬反应等。通过MAPK激活将细胞外刺激传递至适当的细胞内分子的信号传导,对于调节破骨细胞分化和骨重塑是必不可少的。探索MAPK在破骨细胞代谢中作用的众多研究表明,ERK、JNK和p38是破骨细胞分化和激活的关键因素。在此次综述中,描述了MAPK在调控破骨细胞自噬中的独特作用。 2.2 自噬在破骨细胞中的作用 任何生命形式都处在一种动态平衡中,在生物体的内部能量不断的产生和消耗,例如蛋白质、脂肪和糖,因此稳定的能量摄入对于任何生命形式的生存和繁殖都是必不可少的。很长一段时间人们都认为外部环境中的能量是支持生物体的唯一来源。后来研究发现,在诸如饥饿等不利的环境下,细胞内部的蛋白质、脂肪等物质可以参与能量循环,成为维持生存所需的最低能量,即使在正常的生理条件下,生物体内大多数细胞内的物质合成过程所需的能量底物主要来源于已有物质的降解、改造或者再利用,这样一种特殊的能量物质循环即称为自噬。 自噬是进化过程中高度保守的细胞分解代谢过程,在生理条件下负责清除受损或过量的细胞器,而在病理条件下促进细胞内营养物质再分配,以满足生存所需的物质和能量。自噬不仅控制单个细胞,还能调控各种组织类型的能量和稳态[6],其主要分为3种类型:微自噬(microautophagy)、分子伴侣介导的自噬和巨自噬(macroautophagy)。在分子伴侣蛋白介导的自噬中,细胞质蛋白不会被溶酶体膜单独隔离,将通过伴侣蛋白被送到溶酶体;微自噬中的溶酶体通过在其膜上形成内凹或突起,直接捕获附近少量细胞质,不需要溶酶体外细胞器的帮助;在巨自噬中,细胞内物质的捕获和传递以自噬体的形成为标志,自噬体由新形成的双层膜组成,可以包裹受损的细胞器、细胞内病原体和蛋白质聚集物,从而实现隔离过程。之后,自噬体被溶酶体吸收,完成传递和消化内容物。与其他两种自噬类型相比,巨自噬的自噬体可以捕获远离溶酶体的细胞质,同时巨自噬也是目前研究的最多的自噬类型,因此本文的讨论均围绕巨自噬展开。 在破骨细胞中,自噬相关蛋白5、自噬相关蛋白7、自噬相关蛋白12、自噬相关蛋白4β、微管相关蛋白1A/1B轻链3(microtubule associated protein 1A/1B light chain 3,LC3)等都是自噬体形成的主要蛋白质,在体内和体外均可促进破骨细胞形成皱褶缘[7]。破骨细胞依靠皱褶缘来增大与骨组织之间的接触面积,在皱褶缘与骨组织之间的间隙里,溶酶体和质膜融合释放组织蛋白酶K吸收骨组织基质。除此之外,当自噬相关蛋白7缺失时,造血干细胞不能分化为破骨细胞[8]。在破骨细胞的分化期间,自噬相关蛋白7的表达降低会抑制破骨细胞标志物抗酒石酸酸性磷酸酶和组织蛋白酶K的表达[9]。 自噬开始时,细胞质内受损的细胞器被双膜小泡隔离,形成自噬体,然后其与溶酶体融合形成自噬溶酶体来降解或回收受损的细胞器、细胞内病原体、糖原、脂质和核苷酸蛋白等物质[10]。随后LC3与磷脂磷脂酰乙醇胺结合转化为LC3-磷脂酰乙醇胺偶联物(LC3-phosphatidyl ethanolamine conjugate,LC3-Ⅱ),并与自噬体膜结合后降解[11],这种从LC3到LC3-Ⅱ的转化是自噬的标志之一。 长期以来,自噬的过程中底物的选择都被认为是非选择性的[12],最近的研究表明在饥饿状态下细胞常表现出非选择性自噬,但维持细胞内稳态的自噬在底物选择上具有高度特异性,这个过程称为选择性自噬,当机体处于疾病状态下表现得更为明显[13]。选择性自噬过程中的底物可能包括泛素化蛋白、过氧化物酶和线粒体,自噬体表面的泛素结合蛋白SQSTM1(p62,equestome1)可以捕获泛素化蛋白并与LC3-Ⅱ结合[14]。将目标底物运送到自噬体内部的同时,p62自身也被降解,因此p62的表达增加通常表明自噬的下降。山奈酚通过抑制p62的表达来抑制自噬,引起破骨细胞的骨吸收功能障碍[15]。RANKL诱导产生破骨细胞的过程中,自噬相关蛋白5、自噬相关蛋白7、自噬相关蛋白12以及LC3-Ⅱ/LC3的比值随着p62的降解而增加[16],这种降解在破骨细胞的丝状肌动蛋白环的形成中发挥重要作用。自噬调控不当则会引起各种骨组织疾病,如在类风湿性关节炎患者的破骨细胞中发现肿瘤坏死因子α激活了自噬,在体内和体外实验中均诱导破骨细胞形成并引起骨吸收[17]。破骨细胞中自噬的紊乱还会引起Paget’s病等[18]。 2.3 MAPK信号通路对破骨细胞自噬的调控 MAPK是一类信号转导蛋白酶,在真核细胞中可以将多种细胞外刺激转化为特定的细胞反应,充当信号枢纽,调节细胞增殖、分化、应激反应、自噬以及凋亡等过程[19]。MAPK途径分为3层,由3个分子组成,即MAPK、MAPK激酶和MAPK激酶激酶。在其磷酸化系统中,作为丝氨酸/苏氨酸蛋白激酶的MAPK激酶激酶磷酸化并激活MAPK激酶,随后MAPK激酶将其保守的Thr-X-Tyr基序中的苏氨酸和酪氨酸残基双重磷酸化(其中“X”可代表谷氨酸、脯氨酸或甘氨酸),于是最后激活MAPK信号通路[20]。MAPK信号通路主要包括ERK、JNK、p38激酶和ERK5活化激酶4个亚家族[21],其中ERK的2种亚型ERK1/2和JNK的3种亚型JNK1/2/3与破骨细胞前体细胞增殖和破骨细胞凋亡有关[22],而p38的4亚型p38α、p38β、p38γ、p38δ在破骨细胞前体细胞和成熟的破骨细胞中均有高表达,并且在破骨细胞分化和骨吸收中起关键作用[23]。目前在多种动物和细胞实验中均发现MAPK参与了破骨细胞的自噬。 2.3.1 ERK信号通路对破骨细胞自噬的调控 ERK信号通路可以通过细胞膜上的锚定蛋白受体将细胞外信号转入细胞核内,从而介导细胞内特异性蛋白的表达。在ERK信号通路中ERK1和ERK2是研究最多的信号通路,目前已知ERK有70多种底物,包括调节各种细胞行为的核转录因子[24]。经典的ERK通路激活途径主要是Ras→Raf→MEK1/2激酶(MAPK kinase1/2,MEK1/2)→ERK1/2,Ras/Raf/MEK/ERK级联形成了ERK信号通路的核心结构。Ras→ERK信号通路由3个级联组成,Ras蛋白家族的鸟苷三磷酸亚型与Raf蛋白家族的丝氨酸/苏氨酸激酶结合,激活Raf的双重激酶作用,然后依次激活MEK1/2和ERK1/2来调控细胞的分化、增殖、自噬和凋亡等。被激活的ERK信号通路不仅自身即可激活自噬,并且还能通过上调自噬相关蛋白如LC3、p62来诱导自噬的发生[25]。在糖尿病肾病的小鼠出现严重的肾损伤和纤维化时,肾组织中的促炎因子血管生成素样蛋白2升高,自噬相关蛋白LC3-Ⅱ和Beclin-1下降;而当血管生成素样蛋白2下调时,MEK、LC3-Ⅱ和Beclin-1反而升高,如果抑制MEK/ERK信号通路,则会逆转血管生成素样蛋白2下调产生的变化[26]。姜黄素能增加软骨细胞中ERK1/2、LC3-Ⅱ和Beclin-1的表达,当用ERK1/2抑制剂U0126来孵育软骨细胞后,自噬标志物的表达降低[27]。 ERK信号转导途径与破骨细胞的存活、增殖、凋亡、分化以及伪足小体的分解有关。研究表明低剂量的奥巴克拉(Obatoclax)就足以阻断RANKL对ERK的激活并抑制破骨前体细胞的增殖和融合,使其凋亡数量明显增加[28]。在研究ERK1基因敲除的小鼠发现,ERK1在调节破骨细胞的分化、迁移和骨吸收功能中起重要作用[29]。破骨细胞中的许多细胞因子、生长因子等物质均能调控ERK信号通路,甘草酸能够抑制ERK信号通路的磷酸化,从而抑制破骨细胞的成熟和骨吸收功能,不影响骨量和骨小梁的形成[30];同样,香紫苏醇也能抑制RANKL介导的ERK信号通路的活化,导致破骨细胞形成和功能障碍[31],因此ERK信号通路的活化对于破骨细胞的分化和功能来说是必不可少的。破骨细胞在降解骨组织基质时需要释放含有组织蛋白酶K的溶酶体,而组织蛋白酶K的分泌活性取决于LC3的脂化水平。瞬变感受器电位蛋白4能够激活Ca2+/NFATc1通路,上调破骨细胞分化相关基因和自噬相关蛋白如Beclin-1、LC3-Ⅱ,从而促进破骨细胞的自噬和分化[32]。白细胞介素1β能够与RANKL协同作用,以Ca2+依赖的方式激活ERK信号通路,上调LC3的裂解和脂化水平,使其与LC3-Ⅱ结合并分泌到溶酶体内,促进破骨前体细胞分泌组织蛋白酶K。此外自噬相关蛋白7缺失的破骨前体细胞中的LC3脂化功能受损,白细胞介素1β不能介导组织蛋白酶K分泌增加[33]。 另外,之前研究较少的MEK5/ERK5信号通路的功能渐渐引起人们的关注[34-35]。研究表明,在小鼠的前列腺中条件性敲除ERK5基因会导致脊柱的严重变形和弯曲,这与破骨细胞的活性增加有关,将液体剪切应力施加在RAW264.7细胞上会抑制ERK5信号通路,从而使破骨细胞特异性基因表达下降[36]。此外,诱导ERK5磷酸化的是巨噬细胞集落刺激因子而不是RANKL,巨噬细胞集落刺激因子/MEK5/ERK5信号通路的激活能够介导破骨细胞的分化[37]。 2.3.2 JNK信号通路对破骨细胞自噬的调控 JNK是MAPK中的应激活化丝氨酸苏氨酸蛋白激酶家族。目前已经发现JNK有3种不同的基因:JNK1、JNK2、JNK3,其中JNK1有4个亚型,JNK2有4个亚型,JNK3有2个亚型。JNK1/2在机体各种组织中广泛表达,而JNK3在中枢神经系统、心脏平滑肌和睾丸中特异性表达。JNK在不同的应激刺激下,如环境应激、炎症因子、G蛋白偶联受体和生长因子等通过一系列的磷酸化作用被激活。炎症细胞因子受体或凋亡受体通过肿瘤坏死因子相关受体因子的适配蛋白激活JNK。肿瘤坏死因子受体的激活途径包括肿瘤坏死因子受体相关因子2、肿瘤坏死因子受体1相关死亡域蛋白、受体相互作用蛋白和死亡相关蛋白6,这些受体蛋白与凋亡信号调节激酶1结合,激活并磷酸化MAPK激酶4/7(MAP kinase kinase 4/7,MKK4/7),MKK4/7进一步激活JNK[38]。JNK磷酸化并激活转录因子激活蛋白1,该蛋白由Jun蛋白与线粒体中Bcl-2家族的Fos蛋白二聚形成,随后激活转录因子2、c-myc、p53等。 JNK信号在调节破骨细胞的凋亡、形成和分化中发挥重要作用[39]。JNK1的激活诱导转录因子激活蛋白1活化,进而破骨细胞的形成。在RANKL的作用下形成的成熟的破骨细胞伴随着JNK1的活化,缺乏JNK1基因或携带JNK基因但却不能磷酸化的突变小鼠中分离出来的骨髓巨噬细胞表现出破骨细胞的骨吸收功能和细胞活性降低[40]。低浓度的白细胞介素17A能促进破骨前体细胞的自噬和破骨细胞形成,但无法使缺失RANKL和JNK基因的破骨前体细胞分化为破骨细胞;氯喹作为自噬抑制剂能显著抑制低浓度白细胞介素17A的促破骨形成效果,表明低浓度的白细胞介素17A能通过上调JNK1/RANKL信号通路水平诱导破骨细胞的自噬并促进破骨细胞形成[41]。 另外,最近有研究表明,JNK1能通过Beclin-1介导的自噬通路诱导破骨前体细胞自噬,从而调控由RANKL介导的破骨细胞的生成。Beclin‐1是哺乳动物中的酵母自噬相关蛋白6同源物,是与自噬最直接相关的分子,作为磷脂酰肌醇3-激酶多蛋白复合物中的核心亚基,在促进自噬体成熟和自噬功能起重要作用,因此也被看做是自噬起始的标志。研究表明,破骨细胞中Beclin‐1水平的下降将会通过活化T细胞核因子1降低细胞的分化和功能[42]。Beclin-1能与囊泡分选蛋白34和Bcl-2结合形成复合物,当Beclin-1与囊泡分选蛋白34结合时能在自噬体形成过程和调控囊泡蛋白分选发挥重要作用,而当其与Bcl-2结合则会阻断与囊泡分选蛋白34的结合作用,从而抑制自噬。JNK的促破骨细胞形成作用依赖于其下游信号Bcl-2的磷酸化,抑制了Bcl-2与Beclin-1结合,从而促进破骨前体细胞的自噬[43]。 2.3.3 p38信号通路对破骨细胞自噬的调控 p38是一类酪氨酸激酶,具有4种不同的亚型:p38α(MAPK14)、p38β(MAPK11)、p38 γ(MAPK12)、p38δ(MAPK13),p38α在脂多糖的刺激下,其酪氨酸被迅速磷酸化。p38信号通路主要在破骨细胞形成和成熟的调控中起关键作用,从而影响骨组织的重塑[44]。p38可以被许多细胞因子和生长因子激活,如RANKL、转化生长因子β1、骨形成蛋白、肿瘤坏死因子α等。 p38信号通路既能促进自噬也能抑制自噬。自噬始于自噬相关蛋白同源物1复合物的形成,它由自噬相关蛋白同源物1、自噬相关蛋白13、自噬相关蛋白101和自噬相关蛋白17组成。自噬相关蛋白同源物1复合物与动物雷帕霉素复合物1有关,自噬启动时,自噬相关蛋白同源物1去磷酸化,自噬相关蛋白同源物1复合物与动物雷帕霉素复合物1分 离[45]。在小胶质细胞中,脂多糖能够激活p38α导致其磷酸化,使自噬相关蛋白同源物1磷酸化从而阻止了自噬相关蛋白同源物1与自噬相关蛋白13相结合,抑制小胶质细胞的自噬[46]。骨桥蛋白能抑制人结直肠癌细胞HCT116细胞的自噬,但阻断p38信号通路可逆转这种抑制,说明p38信号通路的激活抑制了细胞自噬[47]。在顺铂诱导的急性肾损伤中,发现经顺铂给药后的小鼠肾脏中转化生长因子Β活化激酶1的水平增加,转化生长因子β活化激酶1于是增加了p38信号通路的表达,使得管状上皮细胞过度自噬,加重了肾损伤[48]。经由DHA处理的U937细胞p38信号通路表达增加,巨噬细胞极化转录因子上调,LC3-Ⅱ的表达也增加,加入自噬抑制剂后p38信号通路也被抑制,表明DHA能通过p38信号通路促进细胞自噬和极化,在先天免疫中发挥作用[49]。 在破骨细胞形成过程中,破骨细胞因子刺激MAPK激酶激酶,如转化生长因子β活化激酶1,接着将信号传递给MAPK激酶3和MAPK激酶6使其磷酸化,随后通过激活核因子κB信号和活化T细胞核因子1诱导破骨细胞形成[50]。在巨噬细胞的发育过程中,巨噬细胞集落刺激因子诱导p38活化[51]。RANKL与RANK相结合通过TRAF6也可以使p38活化,从而诱导破骨细胞分化。骨保护素则可以直接激活p38信号通路,通过基质金属蛋白酶9调控破骨细胞的黏附作用,从而增强破骨细胞的功能[52]。p38基因缺失的幼年小鼠骨量增加,破骨细胞数量减少从而导致骨吸收减少。小鼠若去除Nbr1基因,将会导致p38信号通路被抑制,使得破骨细胞分化能力下降,成骨细胞分化增多,小鼠的骨密度和骨组织矿化程度随年龄增长[53]。"
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