临床医学进展  >> Vol. 11 No. 10 (October 2021)

激素性股骨头缺血坏死中未折叠蛋白反应的作用和机制
The Role of Unfolded Protein Response in Steroid-Induced Avascular Necrosis of the Femoral Head

DOI: 10.12677/ACM.2021.1110646, PDF, HTML, XML, 下载: 16  浏览: 36 

作者: 刘顺男:内蒙古医科大学研究生学院,内蒙古 呼和浩特;内蒙古医科大学第二附属医院,内蒙古 呼和浩特

关键词: 未折叠蛋白反应内质网应激股骨头坏死糖皮质激素细胞凋亡细胞自噬Unfolded Protein Response Endoplasmic Reticulum Stress Femur Head Necrosis Glucocorticoid Cell Apoptosis Cell Autophagy

摘要: 背景:激素性股骨头缺血坏死发病人数逐年递增,发病机制尚不明确,可能与骨细胞的程序性死亡相关,而内质网应激介导的未折叠蛋白反应及其相关信号通路发挥着重要的作用。目的:综述内质网应激、未折叠蛋白反应的相关信号通路,以及二者与细胞程序性死亡之间的关系,总结未折叠蛋白反应的调控机制及与激素性股骨头缺血坏死发病机制相关的研究进展。方法:检索2000至2021年相关文献,以“未折叠蛋白反应,内质网应激,股骨头坏死,糖皮质激素,细胞凋亡,细胞自噬”为中文检索词检索CNKI、万方、维普数据库;以“unfolded protein response, endoplasmic reticulum stress, femur head necrosis, glucocorticoid, cell autophagy, cell apoptosis”为英文检索词检索PubMed、Web of Science数据库。排除重复和较陈旧的文献及Meta分析,最终共55篇文献符合纳入标准。结果与结论:第一,未折叠蛋白反应通过三条信号通路监测并调节内质网中蛋白质折叠的状态,即肌醇需要酶1a、蛋白激酶R样内质网激酶、激活转录因子6途径,在缓解内质网应激和细胞内环境稳态中发挥重要的作用,若刺激过强或持续存在,未折叠蛋白反应维持蛋白质稳态的能力不堪重负,则会诱发细胞程序性死亡。第二,细胞的程序性死亡可能是通过未折叠蛋白反应特定的信号网络而非单一信号通路来调节的。第三,未折叠蛋白反应可能是激素性股骨头缺血坏死发病过程中的重要环节,但具体发病机制仍不明确。
Abstract: Background: The number of steroid-induced avascular necrosis of the femoral head is increasing year by year, and the pathogenesis is not clear, which may be related to the programmed death of bone cells. The unfolded protein response mediated by endoplasmic reticulum stress and its related signaling pathways play an important role effect. Objective: This review summarizes the signal pathways related to endoplasmic reticulum stress, unfolded protein response, and the relationship between the two and programmed cell death, summarizes the regulation mechanism of unfolded protein response and the pathogenesis of hormonal avascular necrosis of the femoral head Research progress. Methods: Relevant articles published from 2000 to 2021 were retrieved from PubMed, Web of Science, CNKI, WanFang, and VIP databases. The keywords were “unfolded protein response, endoplasmic reticulum stress, femur head necrosis, glucocorticoid, cell autophagy, cell apoptosis” in English and Chinese, respectively. The old and duplicate articles were excluded, and 55 articles were included for analysis and discussion. Results and Conclusion: First, the unfolded protein response monitors and regulates the state of protein folding in the endoplasmic reticulum through three signaling pathways. These three pathways are inositol requiring enzyme 1α (IRE1a), protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6) pathways, which play an important role in relieving endoplasmic reticulum stress and cellular homeostasis. If the stimulus is too strong or persists, the ability of the unfolded protein response to maintain protein homeostasis is overwhelmed, and it will induce programmed cell death. Second, programmed cell death may be regulated by a specific signal network in unfolded protein response rather than a single signal pathway. Third, the unfolded protein response may be an important link in the pathogenesis of steroid-induced avascular necrosis of the femoral head, but the specific pathogenesis is still unclear.

文章引用: 刘顺男. 激素性股骨头缺血坏死中未折叠蛋白反应的作用和机制[J]. 临床医学进展, 2021, 11(10): 4409-4418. https://doi.org/10.12677/ACM.2021.1110646

1. 引言

股骨头坏死的可能危险因素包括长期服用糖皮质激素、酗酒、基因突变和血栓形成/纤溶性疾病等 [1] [2] 。现糖皮质激素在风湿性疾病、自身免疫性疾病和血液系统疾病的治疗当中被广泛应用,而激素的滥用是导致非创伤性股骨头坏死的最常见原因之一,占比约5%~40%。发病人群大多中青年人 [3] ,其主要病理改变为微结构退化和骨组织缺血,主要症状是髋关节疼痛、关节僵硬和活动受限,如果没有及时干预治疗,则会导致关节面塌陷和骨关节炎,最终导致患者出现残疾和畸形 [4] [5] ,最终可能需要通过全髋关节置换术进行治疗 [6] [7] 。但目前激素性股骨头缺血坏死的发病机制仍不明确,而内质网应激介导的未折叠蛋白反应及其相关信号通路扮演着重要的角色。

近年来的研究表明,当内质网内未折叠或错误折叠蛋白异常堆积,引起细胞应激正在成为激素性股骨头缺血坏死的一个可能的驱动因素 [8] ,同时随着研究的深入,我们发现内质网应激介导的细胞程序性死亡即细胞自噬和凋亡与激素性股骨头缺血性坏死的发病机制息息相关,轻度内质网应激时,内质网可通过激活未折叠蛋白反应途径启动自噬以恢复内质网稳态,促使细胞存活;当内质网应激刺激过强且持续存在时,会过度诱导自噬或激活凋亡途径使细胞死亡。在此过程中,未折叠蛋白反应监测内质网蛋白稳态,同时它是一条信号转导通路网络,可以感知内质网管腔内蛋白质折叠的保真度,调节细胞内蛋白质的折叠能力,或者在慢性损伤的情况下,诱导细胞发生凋亡 [8] 。由此可知,未折叠蛋白反应是一个定义明确的过程,在积累过多的错误折叠蛋白后,它在缓解内质网应激和维持细胞稳态方面发挥着关键作用 [9] [10] 。在这里,我们综述了未折叠蛋白反应在内质网应激介导的成骨细胞程序性死亡中的作用机制及相关治疗研究进展,并可能为激素性股骨头缺血性坏死的相关治疗提出新的思路。

2. 资料和方法

2.1. 资料来源

2.1.1. 检索人相关内容

第一作者。

2.1.2. 检索文献时限

2000至2021年。

2.1.3. 检索数据库

CNKI、万方、维普、PubMed、Web of Science等数据库。

2.1.4. 检索词

英文检索词为“unfolded protein response,endoplasmic reticulum stress,femur head necrosis,glucocorticoid,glucocorticoid,cell autophagy,cell apoptosis”,中文检索词为“未折叠蛋白反应,内质网应激,股骨头坏死,糖皮质激素,细胞凋亡,细胞自噬”,将检索词分为组,第一组:未折叠蛋白反应(unfolded protein response);第二组:内质网应激(endoplasmic reticulum stress)、股骨头坏死(femur head necrosis)、糖皮质激素(glucocorticoid);第三组:未折叠蛋白反应(unfolded protein response)、内质网应激(endoplasmic reticulum stress)、股骨头坏死(femur head necrosis);第四组:细胞凋亡(cell apoptosis)、股骨头坏死(femur head necrosis)、内质网应激(endoplasmic reticulum stress);第五组:细胞自噬(cell autophagy)、未折叠蛋白反应(unfolded protein response)、内质网应激(endoplasmic reticulum stress)、股骨头坏死(femur head necrosis);检索出相关文献,提取文献中与激素性股骨头缺血坏死发病机制、未折叠蛋白反应机器信号通路作用机制相关内容,以及未折叠蛋白反应涉及的信号通路与细胞自噬和凋亡之间关系描述的相关内容,进行分析。

2.1.5. 检索文献类型

包括研究原著、综述、病例报告等。

2.2. 纳入和排除标准

2.2.1. 纳入标准

① 论述未折叠蛋白反应信号通路的文章;② 论述未折叠蛋白反应信号通路对激素诱导的细胞程序性死亡调控机制的文章;③ 论述未折叠蛋白反应与激素性股骨头缺血坏死最新研究的文章。

2.2.2. 排除标准

重复性研究,较陈旧的文献,Meta分析文章。

2.3. 质量评估

通过上述计算机检索与手工检索,共检索到2600余篇相关文献。通过阅读标题选出280篇与该综述相关文献,通过阅读文章摘要或全文排除与主题相关性差及重复、陈旧的文献,最终纳入55篇文献。文献检索流程见图1

Figure 1. Document retrieval process

图1. 文献检索流程

3. 结果

3.1. 未折叠蛋白反应的发生机制

内质网是一个复杂的、动态的细胞器,其功能主要包括蛋白质的折叠、Ca2+的储存以及脂肪和碳水化合物的代谢,广泛参与细胞应激和凋亡过程,在维持细胞稳态中发挥重要作用 [11] 。内质网中蛋白质的正确折叠是维持细胞稳态和存活的必需条件;然而,这个过程非常敏感,即使是细胞环境中的微小改变也可能导致蛋白质的错误折叠 [12] ,当细胞面对不同的刺激时,比如缺氧、病毒感染、Ca2+平衡紊乱、氧化还原失衡、蛋白质糖基化或存在蛋白质折叠缺陷,这种情况被称为内质网应激 [8] [13] ,此时大量未折叠或错误折叠蛋白在内质网腔内积聚,从而发生未折叠蛋白反应以恢复内质网稳态并起到保护细胞的作用 [14] 。

未折叠蛋白反应是一种细胞过程,由复杂的传感器网络和下游靶基因组成,主要包括三个传感器:肌醇需要酶1a (inositol requiring enzyme 1α, IRE1α)、蛋白激酶R样内质网激酶(protein kinase R (PKR)-like endoplasmic reticulum kinase, PERK)、激活转录因子6 (ATF6) [4] [15] ,它们能够监测内质网中蛋白质折叠的状态,内质网发生应激时,这些传感器就会直接靶向激活或特定翻译下游靶基因。然而,触发未折叠蛋白反应的具体机制仍在讨论中 [16] [17] [18] ,这些过程共同协同作用决定了内质网应激的程度,从而决定了细胞是否会重新建立内环境稳态或激活细胞程序性死亡 [19] 。

3.2. 未折叠蛋白反应与其相关信号通路的调控

在哺乳动物中,内质网通过调节蛋白质合成和折叠过程来维持细胞内环境的平衡,未折叠蛋白反应由三种关键的跨膜蛋白介导:肌醇需要酶1a (IRE1a)、蛋白激酶R样内质网激酶(PERK)、激活转录因子6 (ATF6) [4] ,如图2所示。这些参与未折叠蛋白反应的关键分子蛋白一直是疾病机制研究的重点,实际上,三种跨膜传感器触发的信号事件会互相影响、互相调节,信号网络中任意一个分支的中断都会导致其他分支的过度活动,从而引起细胞对外界刺激的不适应甚至引起细胞死亡 [20] 。它们在内质网腔内与伴侣蛋白(BiP)之间的相互作用,使未折叠蛋白反应保持在未激活状态。当内质网应激时,这三种跨膜传感器并使伴侣蛋白发生解离并激活,从而首先启动下游PERK信号通路传导。

Figure 2. Schematic diagram of the mechanism of unfolded protein response and related signaling pathways

图2. 未折叠蛋白反应及其相关信号通路作用机制示意图

第一条信号通路是蛋白激酶R样内质网激酶(PERK)信号通路。在人体内,真核翻译起始因子2α激酶3 (EIF2AK3)基因编码蛋白激酶R样内质网激酶。在稳态条件下,蛋白激酶R样内质网激酶与伴侣蛋白相互作用,该蛋白也被称为葡萄糖调节蛋白78 (GRP78),而非以活性单体状态存在,内质网应激时,二者发生解离,从而激活蛋白激酶R样内质网激酶 [21] 。PERK的重要调节功能之一是对蛋白质翻译的监测作用 [22] ,它是磷酸化真核翻译起始因子2α (eIF2α)的激酶,通过可逆的共价修饰一方面引起蛋白质合成的瞬时衰减,停止错误折叠蛋白的堆积 [23] ;另一方面磷酸化eIF2α启动一组特定的mRNA进行翻译,这些mRNA的5'非翻译区具有一个或多个上游开放阅读框,其中一个用来编码激活转录因子4 (ATF4),它是一种应激诱导转录因子,可激活参与氧化还原反应、氨基酸代谢、蛋白质合成、细胞凋亡和自噬的相关基因表达,在成骨细胞分化中起重要作用 [24] ;激活转录因子4上调诱导蛋白34 (GADD34),与蛋白磷酸酶1 (PP1)形成复合物,使eIF2α去磷酸化,来恢复蛋白质合成 [25] [26] 。近年来,PERK信号通路在激素性股骨头缺血坏死中的研究正日渐增多,Saito等 [27] 发现,在骨形成蛋白2 (BMP2)处理的成骨细胞中,PERK-eIF2a-ATF4信号通路确实被激活,而在成骨细胞中特异性敲除PERK后,激活转录因子4的表达显著降低。

第二条信号通路是肌醇需要酶1a (IRE1α)信号通路。IRE1α是一种I型内质网跨膜蛋白激酶,也是一种内切核糖核酸酶,在内质网应激时,发生寡聚化和自动磷酸化从而改变其核糖核酸酶活性 [8] [28] [29] ,而X盒结合蛋白1 (XBP1)是保护细胞免受内质网应激信号转导网络中的重要组成部分。当IRE1α被激活时,它会从编码多细胞生物转录因子X盒结合蛋白1的mRNA中切除一个26核苷酸的内含子,从而改变其进行翻译的开放阅读框,这种加工在多细胞生物中称为“XBP1s”剪接形式,能够导致活性X盒结合蛋白1转录因子的表达,该因子上调参与内质网内蛋白易位、折叠和分泌基因的表达,以及错误折叠蛋白的降解 [8] [29] [30] 。当出现X盒结合蛋白1的靶向丢失时,细胞中的内质网应激反应会随之增强,最终可能导致细胞死亡和相关炎症发生。在一种称为受调节的肌醇需要酶1a依赖性衰减(RIDD)过程中,肌醇需要酶1a切割一组mRNA或前体microRNA (miRNA),导致它们降解,降低mRNA丰度 [31] [32] ,从而降低内质网中的蛋白质堆积负荷。还有研究表明,肌醇需要酶1a在促细胞生存和死亡的转变过程中,RIDD是其众多分子信号组成中的一部分 [33] 。

第三条信号通路是激活转录因子6 (ATF6)信号通路。当内质网应激时,全长激活转录因子6 (ATF6p90)从内质网内转移到高尔基体,在那里被位点1蛋白酶(S1P)和位点2蛋白酶(S2P)裂解,释放出含有碱性亮氨酸拉链片段(bZIP)转录因子,称为“ATF6p50”,其易位至细胞核以诱导其基因表达。ATF6p50和XBP1s平行起作用,但也有重叠的途径来调节编码内质网分子伴侣和酶的基因转录,这些酶促进内质网中蛋白易位、折叠、成熟和分泌,以及错误折叠蛋白的降解 [34] [35] 。此外,XBP1s和ATF6p50促进内质网和高尔基体生物发生,以增加细胞在内质网应激下的分泌能力 [36] 。研究表明,激活转录因子6信号通路是一种新兴的促细胞生存途径,显示出对缺血相关疾病的巨大治疗潜力,当其缺乏时器官更容易受到缺血性应激的影响,激活转录因子6特异性缺失的小鼠更容易发生心肌缺血或脑缺血 [37] [38] 。因此,本文中所涉及的激素性股骨头坏死的缺血病理性改变相关机制可能也与此信号通路息息相关。

总体而言,未折叠蛋白反应代表了一系列信号通路的组合,这些信号通路通过动态调整内质网折叠能力来维持内质网内的稳定,并在内质网应激时维持细胞功能。

3.3. 未折叠蛋白反应与细胞凋亡

当未折叠蛋白反应维持蛋白质稳态的能力不堪重负时,则会应触发经典细胞凋亡途径 [39] ,包括B淋巴细胞瘤-2基因(BCL-2)家族中促凋亡成员的激活,以及凋亡小体的生成和半胱天冬酶-3 (caspase3)的激活。然而,细胞内将内质网应激传递给线粒体以诱导细胞凋亡的信号备受争议。第一,BCL-2家族的BH3-only蛋白合成增加,它是BCl-2蛋白家族中启动和调节细胞凋亡的重要成员,能识别不同的细胞刺激形式并被活化,是参与内质网应激介导的细胞凋亡的重要组成部分 [40] [41] 。第二,一旦细胞凋亡程序启动,激活转录因子4和CCAAT/增强子结合蛋白同源蛋白(CHOP)激活编码相关蛋白翻译部分的基因,使细胞内蛋白质合成增加,增强内质网应激反应,导致细胞内活性氧产生增加、蛋白毒性增强,最终引起细胞死亡 [26] 。

肌醇需要酶1a依赖性衰减途径(RIDD)在持续的内质网应激介导的细胞凋亡中发挥重要作用。第一,持续的内质网应激状态引起未折叠蛋白反应相关的肌醇需要酶1a信号通路持续激活,硫氧还蛋白互作蛋白(TXNIP)是一种细胞凋亡抑因子,此信号通路中的RIDD过程可以降解其miRNA,使半胱天冬酶2相对水平升高,而半胱天冬酶2是位于线粒体上的早期凋亡启动开关,从而启动细胞凋亡程序 [32] [42] ;第二,持续过度磷酸化的IRE1α还可能通过 RIDD途径消耗内质网的重要成分,例如伴侣蛋白,使其与三种未折叠蛋白反应相关的跨膜蛋白解离,持续激活未折叠蛋白反应,使细胞对凋亡更加敏感,同时PERK和IRE1α信号通路的激活可以作为触发细胞凋亡的开关 [8] ;第三,RIDD途径可以降解由CCAAT/增强子结合蛋白同源蛋白51诱导编码的死亡受体5 (DR5)的mRNA,现已证实死亡受体5和半胱天冬酶8在细胞凋亡过程中起到关键作用 [43] [44] ,持续的内质网应激下,RIDD在某些细胞中的降解能力被减弱,从而相对加强了死亡受体5的表达并激活了凋亡程序 [45] 。

3.4. 细胞凋亡与激素性股骨头缺血坏死之间的关联

在过去的十年中,随着分子生物学的发展,成骨细胞凋亡理论受到了越来越多学者的关注,目前已知成骨细胞的凋亡在激素性股骨头缺血性坏死的发病中起到重要作用。

宏观来讲,激素性股骨头缺血坏死发病相关的细胞凋亡理论包括一氧化氮代谢异常与脂质代谢异常等。第一,Bai等人的研究发激素可以损伤产生一氧化氮的血管内皮细胞,抑制一氧化氮合酶的活性,从而使一氧化氮含量降低,出现血管痉挛、血管壁增生、狭窄、血小板聚集、白细胞粘附以及血栓形成,当这些病理变化发生在股骨头及其周围血管系统中,就会诱发股骨头缺血性坏死,在此过程中,一氧化氮含量和骨细胞凋亡指数均有所增加,并且呈正相关关系,表明一氧化氮能够诱导细胞凋亡,是成骨细胞凋亡的重要调节因子 [46] 。第二,Hu等 [47] 的研究表明大剂量地塞米松可能影响骨髓间充质干细胞的脂质代谢,引起细胞应激状态,启动细胞凋亡,抑制成骨过程,最终导致股骨头坏死。

微观来讲,细胞自噬诱导或调节细胞凋亡以及内质网应激介导的未折叠蛋白反应相关通路在激素性股骨头坏死的发病机制中是不可或缺的一部分。第一,细胞自噬可以诱导细胞凋亡,糖皮质激素可以调节细胞自噬相关蛋白Beclin-1、LC3B-II、P62以及内质网应激相关蛋白(ATF4和CHOP)的表达,细胞自噬的过度激活最终引起细胞凋亡,Peng等 [48] 的研究发现糖皮质激素诱导成骨细胞凋亡的过程中,p-JNK、p-c-Jun、Bax、半胱天冬酶3、半胱天冬酶9、细胞色素C、Beclin和LC3水平显著升高,诱导成骨细胞启动自噬及凋亡。第二,长期或大量使用糖皮质激素,使骨髓间充质干细胞发生内质网应激,从而引起未折叠蛋白反应下游相关信号通路的持续激活,最终启动细胞凋亡程序,Cheng等人实验研究表明,当激素浓度加大时,未折叠蛋白反应相关信号通路中磷酸化PERK的表达增加最显著,而核因子E2相关因子2是PERK信号通路的一个重要的下游因子,继而磷酸化核因子E2相关因子2水平升高,诱导细胞凋亡,成骨减少,骨量丢失,最终发生股骨头缺血坏死 [4] 。

4. 讨论

激素性股骨头缺血坏死是最常见的非创伤性股骨头坏死,自2010年“非典型肺炎”以来,由于激素的使用,出现了大量病例。2019年新冠状病毒肺炎流行至今,感染患者早期出现急性呼吸窘迫综合征,但又合并严重的肾功能不足时,需要使用激素进行治疗 [49] ,但长期或大量使用则会引起成骨细胞病理性改变,最终导致激素性股骨头缺血坏死的发生,其主要病理过程包括脂质代谢异常、血管内皮细胞损伤、凝血功能障碍、凋亡、自噬等 [50] [51] [52] ,但至今没有完整明确的研究证其具体发病机制。因此,为能够预防、早期诊断及治疗并逆转此病理过程,探究其发病机制是十分必要的,也可针对其靶向治疗提出有效的指导和建议。

当激素刺激成骨细胞引起内质网应激时,未折叠蛋白反应通过PERK、ATF6和IRE1三条信号通路网络来缓解内质网应激包括以下三个途径,第一,抑制蛋白质的翻译,防止更多未折叠或错误折叠蛋白质的产生;第二,通过调节内质网分子伴侣蛋白诱导并促进蛋白质的重新折叠;第三,激活内质网相关降解,去除内质网中积累过多的未折叠蛋白。短期内未折叠蛋白反应可以通过减少未折叠蛋白质的堆积来恢复正常的内质网功能,起到促细胞生存的作用,但如果持续存在,则会激活促凋亡信号通路,最终导致细胞死亡 [53] ,引起股骨头发生病理性改变。因此,未折叠蛋白反应在维持成骨细胞稳态过程中发挥着重要作用。

近年来,未折叠蛋白反应与各类疾病发病机制类之间的关系成为广大学者的研究热点。但是在激素性股骨头缺血坏死中未折叠蛋白反应及其相关信号通路的作用及机制研究鲜有报道。类固醇激素已被证明可以诱导细胞凋亡,它们可以通过促进成骨细胞和骨细胞的凋亡来减少骨细胞的数量,影响成骨细胞的功能,也可以通过干扰骨髓间充质干细胞的分化,从而延缓或减少成骨并诱导细胞凋亡,从而导致骨丢失。对于激素性股骨头缺血坏死的治疗研究也取得了很多成果,如Nrf2抑制剂ML385、阿托伐他汀均可抑制成骨细胞凋亡,延缓疾病进展 [4] [54] ;草药中骨碎补提取物总黄酮(TFRD)具有抗氧化特性和抗骨质疏松活性,能够保护成骨细胞免受类固醇激素的损伤 [55] ;总的来说,针对激素性股骨头缺血坏死的靶向治疗方法仍然是十分有限的。此次综述通过对内质网应激介导的未折叠蛋白反应以及相关信号通路对细胞凋亡影响的介绍,有助于将未折叠蛋白反应作为激素性股骨头缺血坏死发病机制中重要环节进行研究,其关系可能是:激素作为刺激因素持续作用于成骨细胞,引发持续的内质网应激同时持续激活未折叠蛋白反应,未折叠蛋白反应相关通路过度激活,不堪重负,启动成骨细胞程序性死亡,进而股骨头发生病理性改变,最终导致股骨头缺血坏死。上述结论还需要进一步的实验去验证,来明确激素性股骨头缺血坏死的发病机制,达到预防和靶向治疗的效果。

缩略词

蛋白激酶R样内质网激酶:protein kinase R (PKR)-like endoplasmic reticulum kinase,PERK

肌醇需要酶1α:inositol requiring enzyme 1α,IRE1α

激活转录因子6:Activating Transcription Factor 6,ATF6

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