Chinese Journal of Tissue Engineering Research ›› 2021, Vol. 25 ›› Issue (20): 3246-3251.doi: 10.3969/j.issn.2095-4344.3206
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Tong Jie1, 2, Liao Ying1, 2, Chen Zhengyu3, Sun Guanghua1, 2
Received:
2020-08-09
Revised:
2020-09-01
Accepted:
2020-10-09
Online:
2021-07-18
Published:
2021-01-18
Contact:
Sun Guanghua, Master, Attending physician, Department of Rehabilitation Medicine, Rehabilitation Medicine Center, Rehabilitation Medicine Laboratory, the First Affiliated Hospital of University of South China, Hengyang 421001, Hunan Province, China
About author:
Tong Jie, Master candidate, Department of Rehabilitation Medicine, Rehabilitation Medicine Center, Rehabilitation Medicine Laboratory, the First Affiliated Hospital of University of South China, Hengyang 421001, Hunan Province, China
Supported by:
CLC Number:
Tong Jie, Liao Ying, Chen Zhengyu, Sun Guanghua . Osteoarthritic chondrocyte autophagy and regulation of mitogen-activated protein kinase signaling pathway[J]. Chinese Journal of Tissue Engineering Research, 2021, 25(20): 3246-3251.
2.1 骨关节炎的特征及治疗 一项来自于美国的调查表示,2016年肌肉骨骼疾病支出约1 298亿美元,居于医疗总支出第2位[5],而其中骨关节炎支出共800亿美元,骨关节炎常见于中老年人,MRI检查出的无症状骨关节炎患者86%在40岁及以上[6];在中国膝骨关节炎患病率为18%[7]。骨关节炎可见于全身多处关节,其中膝、髋关节最常见,手指远端关节也可发生[8]。骨关节炎关节改变包括关节软骨的进行性退化、滑膜炎症、软骨下骨损伤和软骨下骨的骨赘形成,骨关节炎病理表现为软骨细胞凋亡、软骨细胞外基质合成减少与降解增加[9],临床表现包括关节肿胀、畸形、关节疼痛和残疾等[10],目前还没有开发出能够彻底逆转或改善这种疾病的疗法[11],对乙酰氨基酚、非类固醇抗炎药和阿片类药物可缓解关节疼痛,但不能逆转软骨退变,并且长期服用这些药物会导致许多不良反应;另外类固醇药物能够有效缓解炎症反应并抑制软骨细胞的降解,但是激素半衰期较短,清除迅速,需要频繁给药,此外其长期使用也具有严重的不良反应,例如胃痉挛、恶心、呕吐、消化不良、消化道溃疡和肾脏衰竭或出血等[10,12]。 2.2 MAPK信号通路与骨关节炎 MAPKs是一类广泛存在于真核细胞中的蛋白激酶家族,可被细胞外信号、物理刺激、炎性细胞因子(如白细胞介素1和白细胞介素6)、细菌或肿瘤生长因子激活[13]。目前,哺乳动物中,此家族研究最多的MAPKs包括细胞外信号调节蛋白激酶(细胞外信号调节激酶1/2、细胞外信号调节激酶5)、C-JUN氨基酸末端激酶(JNK1/2/3)和p38丝裂原活化蛋白激酶(p38MAPK)[14]。促炎症因子白细胞介素1β和肿瘤诱导因子肿瘤坏死因子α等上游激活作用因子,激活MAPK信号通路,通过MAP激酶激酶(MKK)-MAP激酶激酶激酶(MKKK)-MAPK 3层激酶级联放大刺激[15],一步一步地传递到细胞核,调节转录因子,控制相关基因的表达并进一步引起细胞反应。这种高度保守的模块激活可调节机体内许多生理活动,包括细胞增殖、凋亡、炎症、癌症和肿瘤细胞转移迁徙等[16]。其中,不同的MAPK由特定的MAPKK激活:细胞外信号调节激酶1/2的MKK1/2,p38的MKK3/6,JNK的MKK4/7(JNKK1/2)和细胞外信号调节激酶5的MKK5。但是,每个MAPKK可以被一个以上的MAPKKK激活,从而增加了MAPK信号传导的复杂性和多样性,每个MAPKKK赋予对不同刺激的响应。关节软骨的功能由软骨细胞外基质决定,它富含Ⅱ型胶原纤维,在骨关节炎发生与发展过程中,软骨细胞外基质合成与降解失调,导致软骨功能和结构的改变[17]。MAPKs调控的软骨细胞外基质降解是关键步骤,MAPKs通过激活基质降解酶如基质金属蛋白酶和具有血小板反应蛋白基序的去整合素和金属蛋白酶(a disintegrin like and metalloproteinase with thrombospondin type Ⅰ motifs,ADAMTs)发挥这种作用。软骨细胞外基质由Ⅱ型胶原纤维组成,富含蛋白聚糖,蛋白聚糖与透明质酸2结合形成超分子聚集物,并包裹在Ⅱ/Ⅸ/Ⅺ型胶原网络中[18]。ADAMTs可降解聚集蛋白聚糖[19],其降解使Ⅱ型胶原暴露,并被基质金属蛋白酶破坏,另外ADAMTs也可降解软骨的低聚基质蛋白,这种通过与基质成分如胶原、蛋白聚糖和fibronectin的特定相互作用来稳定细胞外基质的分子丢失能够降低软骨稳定性,而降解的细胞外基质又造成滑膜炎症并且产生更多的炎症因子,进而激活MAPKs诱导关节软骨细胞发生肥大、凋亡、增殖等骨关节炎退行性改变[20-21]。因此抑制激活细胞外基质降解酶的MAPK通路激活,从而抑制软骨细胞外基质降解可以作为治疗骨关节炎的靶点。 2.3 p38 MAPK信号通路与骨关节炎 p38 MAPK通路对骨关节炎的作用机制较复杂,总体上起软骨破坏作用,其具体表现为:刺激软骨细胞的凋亡,抑制软骨细胞外基质的合成,加速软骨细胞的肥大、钙化,促进基质金属蛋白酶的合成和环氧合酶2的表达[22]。KANG等[23]研究发现,细胞传代过程中p38 MAPK磷酸化水平逐渐增高,并且在衰老细胞中达到顶峰。通过环孢素A和他克莫司来抑制p38 MAPK的磷酸化,可以抑制软骨细胞肥大、钙化,证明p38 MAPK的激活是诱导软骨细胞衰老、产生骨关节炎改变的关键。p38 MAPK通路在各种环境和细胞应激、炎症刺激下被激活,有研究发现骨关节炎患者软骨基质金属蛋白酶13蛋白水平高于正常人软骨[2],这种高水平主要由p38 MAPK信号通路激活引起,但激活取决于p38 MAPK的活性而不是p38 MAPK的总水平。SUN等[24]发现骨关节炎模型血清中的促炎症因子增加,抑制p38MAPK的激活可以降低这些因子的表达,并且减少软骨细胞凋亡,抑制软骨退变,因此他们猜测p38MAPK信号通路通过促进软骨细胞凋亡及增加炎症因子来加速骨关节炎进展,然而背后的分子机制尚不明了。FENG等[25]通过白细胞介素1诱导骨关节炎,随后进行体外实验发现丹参酚这种中药能够通过抑制p38MAPK信号通路来下调软骨破坏相关的基质金属蛋白酶1、基质金属蛋白酶13和Adamsts 5和上调软骨保护相关的Ⅱ型胶原和蛋白聚糖,这进一步解释了p38MAPK信号通路调控骨关节炎的潜在机制。基于细胞实验,CAO等[26]敲减位于细胞中的miR-296-5p,验证发现miR-296-5p能够抑制转化生长因子β1/CTGF/p38MAPK信号通路,直接作用于转化生长因子β,从而抑制软骨细胞凋亡和软骨退变。综上,p38信号通路在炎症因子等的激活下,促进软骨细胞外基质降解酶基质金属蛋白酶及Adamsts 5产生,以及减少软骨成分Ⅱ型胶原和蛋白聚糖的数量,从而起到对软骨的破坏作用,使骨关节炎进一步恶化。 2.4 细胞外信号调节激酶信号通路与骨关节炎 细胞外信号调节激酶是MAPK家族中的一员,它被多种环境应激和炎症细胞因子激活。激活的细胞外信号调节激酶介导细胞对细胞内信号蛋白的反应,并参与包括骨关节炎在内的许多生理和疾病过程。LIU等[27]通过对人正常软骨细胞和骨关节炎软骨细胞的比较,发现人骨关节炎软骨细胞中细胞外信号调节激酶的表达水平低于人类正常关节软骨细胞,并且细胞外信号调节激酶的上调可能会促进基质的合成,具体表现为降低基质金属蛋白酶13水平和增加蛋白聚糖水平,这种作用依赖于其对雷帕霉素的抑制。YU等[28]研究者发现细胞外信号调节激酶通路受生长因子刺激,在关节中主要调节软骨细胞的增殖,从而促进细胞外基质的生成,保护软骨,对骨关节炎有正向调节作用,这也进一步验证了细胞外信号调节激酶对软骨的影响。然而,随着研究深入,细胞外信号调节激酶信号通路决定软骨基质降解或合成的作用开始出现争议。近年来,HOU等[29]认为细胞外信号调节激酶信号通路对骨关节炎有负向调节作用,他们发现血清及关节滑膜中的细胞趋化因子CX3CL1的上调通过激活细胞外信号调节激酶信号通路,可以促进基质金属蛋白酶3的产生。基质金属蛋白酶3一方面降解软骨的蛋白聚糖和Ⅰ、Ⅱ、Ⅲ型胶原纤维等,破坏软骨结构;一方面参与滑膜基质的活化和巨噬细胞、中性粒细胞的浸润造成滑膜炎症[16]。最近,GE等[30]通过雌激素介导细胞外信号调节激酶信号通路抑制雷帕霉素激酶哺乳动物靶蛋白从而激活自噬,达到对软骨细胞的保护作用,这说明雷帕霉素激酶哺乳动物靶蛋白激活的细胞外信号调节激酶信号通路可以作为治疗骨关节炎的靶点。总的来说,仅部分学者认为细胞外信号调节激酶通路对软骨细胞起负面作用,大部分学者接受细胞外信号调节激酶对软骨细胞基质起保护作用。 2.5 JNK信号通路与骨关节炎 作为MAPK信号通路之一,JNK由2种双向特异性MAP激酶激酶(MKK-4和MKK-7)和MAP激酶激酶激酶(MKKKs)激活,骨关节炎动物模型中,JNK及其关键上游活化因子MKK-4和MKK-7均增高。并且JNK活化的效果与时间相关,短期活化促进细胞增殖,而长期活化促进细胞凋亡。炎症信号、活性氧水平改变、紫外线辐射、蛋白质合成抑制剂和多种应激刺激均可激活JNK,这种激活的产生是通过破坏敏感蛋白磷酸酶的构象,而这种特定的磷酸酶通常会抑制JNK本身的活性以及与JNK激活有关的蛋白质的活性 [31]。如肿瘤坏死因子α诱导激活JNK其上游活化因子,进而激活JNK信号通路,激活后的通路上调基质金属蛋白酶1、基质金属蛋白酶3、基质金属蛋白酶13、aggrecanase1和aggrecanase2,这些酶会启动软骨细胞外基质的降解反应[32]。在动物实验中,ISMAIL等[33]发现在JNK基因敲除后,利用半月板失稳手术诱导动物骨关节炎,这种因为手术应激产生的反应因子,相比未敲减的动物组,减少近一半,并且这种反应因子的减少抑制了软骨细胞外基质的降解,其具体机制可能是白细胞介素1通过激活JNK信号通路,产生一种基质金属降解酶ADAMTS-5,来降解软骨基质。在细胞实验中,WANG等[34]通过体外的原代细胞传代实验发现一种MAPK磷酸酶DUSP19能显著抑制JNK信号通路,而这种抑制作用对细胞凋亡起了抑制效果,进而说明了JNK促进软骨细胞凋亡,从而对关节软骨产生负向调节作用。因此,JNK通路激活可以上调多种基质降解酶,降解软骨细胞外基质,使软骨表面不完整,造成骨关节炎改变,寻找靶点来抑制JNK激活对骨关节炎的治疗有积极意义。 2.6 软骨细胞自噬与骨关节炎 自噬包括宏观自噬、微自噬和伴侣介导的3种最经典的自噬,宏观自噬Macro-autophagy即通常提到的自噬。自噬(autophagy)是真核细胞依靠双膜细胞器即自噬体进行自我吞噬的过程,首先是双膜细胞器自噬体形成,然后是产生的自噬体与溶酶体结合;微自噬是通过溶酶体膜内陷直接吞噬细胞质中的蛋白质;伴侣介导的自噬必须有膜上蛋白识别点,与分子蛋白结合成复合物,随后移动到溶酶体上完成吞噬[35]。自噬是在饥饿等应激条件下,细胞降解失去功能或功能障碍的大分子物质,产生生物合成前体和生命活动所需能源的主要机制,因此,自噬是真核细胞的一种自我保护方式[36],自噬参与机体成骨分化、脂肪生成、血管生成和神经发生等过程[35]。目前研究发现的自噬相关基因有35种,其中自噬相关基因1即ULK1复合体是重要的自噬起始标志物[37]。骨关节炎的发生与促炎症因子及抗炎因子之间的失衡有关 [38],炎症因子,包括白细胞介素1β、肿瘤坏死因子α、环氧合酶2和诱导型一氧化氮合酶等的过度释放,会诱导蛋白水解的表达酶,例如基质金属蛋白酶以及ADAMTs,从而导致软骨损失[39]。而细胞衰老是一种细胞状态,是不可逆型的细胞周期停滞。 衰老软骨细胞会失去维持和修复组织的能力,从而增加了软骨退变的风险[40]。由于软骨中的软骨细胞分化达到成熟,而软骨自身血液循环相对欠缺,且关节受到持续性应力,维持软骨细胞数量和维持软骨的正常功能就尤为重要 [41]。因此,学者们认为自噬这种持续性、活跃的保护作用对于维持软骨代谢、抑制软骨退变具有重要意义[42]。在骨关节炎的发展中,自噬不仅影响着关节的软骨组织形态发生,而且在软骨细胞和细胞外基质的代谢平衡中也有重要作用。如先前的研究报道,小鼠内侧半月板失稳术后,在原位关节腔内注射了雷帕霉素类药物,显示不缺乏自噬相关基因5小鼠的软骨变性得到改善,而缺乏自噬相关基因5的小鼠显示软骨细胞凋亡加剧和关节软骨变性,这些报道提到软骨细胞自噬的激活可以保护细胞免于凋亡并促进骨关节炎中软骨细胞的存活[43]。类似的,BAO等[44]用白细胞介素18处理大鼠模型,发现软骨细胞特异性基因Ⅱ型胶原及蛋白聚糖的mRNA和蛋白水平降低,凋亡相关蛋白(Bax、Bcl-2、半胱氨酸蛋白酶3/9)增高,自噬相关蛋白(自噬相关基因5、自噬相关基因7、Beclin-1、微管相关蛋白轻链3)和雷帕霉素激酶哺乳动物靶蛋白通路相关基因[磷脂酰肌醇-3-激酶(phosphoinositide 3-kinase,PI3K)、Akt、雷帕霉素激酶哺乳动物靶蛋白]均降低,而使用自噬的激活剂雷帕霉素可以通过PI3K/Akt/mTOR信号通路逆转上述情况,起到抑制白细胞介素18产生的作用,达到对软骨保护的目的,因此他们认为自噬对软骨起到了积极作用。DUAN等[45]发现,脂联素受体激动剂可激活自噬,降低碱性磷酸酶的活性,可以抑制软骨下骨内血管及细胞的钙化,遏制软骨细胞减少,从而缓解骨关节炎。LOPEZ等[46]研究者首次提出,自噬可以对抗细胞的氧化应激作用,从而保护线粒体功能障碍患者的软骨细胞,从而延缓骨关节炎的发生与发展。VUPPALAPATI等[47]通过靶向敲除自噬相关基因5、自噬相关基因7抑制细胞自噬,发现软骨细胞凋亡增加,软骨Ⅱ型胶原纤维减少,骨量降低,因此认为自噬水平降低会促进软骨细胞凋亡,自噬负向调节骨关节炎的发生与发展。ZHENG等[48]在人类骨关节炎和内侧半月板失稳小鼠软骨中发现一种代表自噬空泡降解水平的蛋白质p62大量出现,这表明骨关节炎软骨细胞的自噬降解被阻断,进而说明自噬对软骨退变有抑制作用。QIAO等[49]通过高浓度胰岛素诱导抑制细胞内自噬关键通路,即PI3K/AKT/mTOR、核因子κB、雷帕霉素激酶哺乳动物靶蛋白等信号通路,加重炎症反应,恶化软骨退变,因此促进细胞的自噬可以保护软骨,作为骨关节炎的一种治疗方式。 2.7 MAPKs家族与细胞自噬 MAPK家族的细胞外信号调节激酶、JNK、p38 MAPK调节自噬的作用及机制各不相同。Wang等[50]研究者通过胡桃醌(Juglone)激活MAPKs信号通路从而诱导自噬,证明了MAPKs是一种自噬激活相关信号通路。自噬的吞噬再利用功能为细胞生存提供了一定量的能源,同时也保证了细胞内稳态。因此,自噬有助于消除细胞病理反应及维持细胞的生理功能,例如作为抗衰老、肿瘤抑制和抗原呈递等其关键蛋白包括雷帕霉素激酶哺乳动物靶蛋白、ULK1/2、CaMKKβ、PI3K、AKT、TBK1、PKG、PKA、PDK1、JNK、RAF1和RTKs等。据目前研究,自噬反应是由许多事件调控的,其中雷帕霉素激酶哺乳动物靶蛋白是自噬调节通路PI3K和Akt途径的下游靶点[51]。作为自噬的负调节因子,雷帕霉素激酶哺乳动物靶蛋白阻止了细胞自噬通过磷酸化转录因子表达溶酶体和自噬基因,通过抑制Unc51样激酶复合物激活,从而抑制自噬。活化的Unc51样激酶1复合物与自噬相关基因1蛋白结合成自噬相关基因1-Unc51样激酶,接收细胞营养状态信号并招募下游自噬相关蛋白进入自噬体形成位点,从而启动自噬反应[52]。周睿曦等[53]通过p38MAPK特异性抑制剂抑制p38MAPK信号通路发现自噬过程激活进一步增强,证明了其对自噬的抑制作用,随后发现p38MAPK通路甚至可以不用依赖雷帕霉素激酶哺乳动物靶蛋白途径,独立负向调节自噬相关蛋白。JNK对自噬的调节是通过增加自噬相关基因5和Beclin-1的表达,从而激活自噬相关信号通路[54],其特征是自噬空泡的积聚,伴随微管相关蛋白轻链3-Ⅰ降解转化为微管相关蛋白轻链3-Ⅱ。用JNK抑制剂处理过的细胞和本身缺乏JNK1/2的小鼠胚胎成纤维细胞自噬水平均降低,证明了JNK对自噬的正向调节作用。此外,JNK激活可促进Bcl-2磷酸化,破坏Beclin-1-Bcl-2复合物并刺激自噬[55]。在MAPKs家族中,细胞外信号调节激酶信号通路对自噬的调节作用尚存在争议。WANG等[56]认为细胞外信号调节激酶1/2蛋白通过抑制PI3K-AKT-mTOR途径,增强对凋亡信号的抵抗从而减少凋亡细胞,并且减少裂解的半胱氨酸蛋白酶3、半胱氨酸蛋白酶9最终促进细胞自噬。LI等[57]研究者发现在白细胞介素1β刺激下,软骨细胞膜上受体磷酸化激活细胞外信号调节激酶1/2蛋白,促进Beclin-1和bcl-2自噬相关物质的形成,自噬蛋白微管相关蛋白轻链Ⅱ增加,证明细胞外信号调节激酶信号通路对自噬的调节作用,因此,激活细胞外信号调节激酶信号通路提高软骨细胞自噬水平可能成为治疗骨关节炎的策略。而FAN等[58]通过二氢青蒿素DC32抑制细胞外信号调节激酶信号通路,发现自噬标志物微管相关蛋白轻链Ⅱ/微管相关蛋白轻链Ⅰ比值增高,促进自噬蛋白p62形成,证明了细胞外信号调节激酶信号通路对自噬的抑制作用。YUE等[59]通过半月板失稳构建骨关节炎动物模型,随后关节内注射MgCl2,在一定程度上促进了自噬,延缓软骨变性及软骨下骨的骨赘形成,而这种作用是通过抑制细胞外信号调节激酶信号通路达到的,与FAN等[58]的 研究结果一致。"
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