低氧诱导因子在类风湿关节炎发病机制中的作用

于若寒，赵金霞，刘湘源

(北京大学第三医院风湿免疫科，北京 100191)



·综述·

低氧诱导因子在类风湿关节炎发病机制中的作用

于若寒，赵金霞，刘湘源△

(北京大学第三医院风湿免疫科，北京 100191)

低氧诱导因子；关节炎，类风湿；缺氧

类风湿关节炎(rheumatoid arthritis，RA)是一种系统性自身免疫性疾病，病理特征为异常的滑膜增生伴血管翳形成、软骨和骨的侵蚀破坏，最终导致关节畸形。目前RA确切发病机制未明，环境和遗传因素相互作用共同促进了RA的发病。低氧微环境是RA重要的病理特点，炎症滑膜组织的高代谢需求和滑膜的快速增生共同导致了RA关节内低氧状态。研究表明,低氧通过低氧诱导因子(hypoxia-inducible factor，HIF)调控的一系列转录因子的活化促进RA的疾病进展[1]。HIF可通过促进RA滑膜细胞(RA fibroblast-like synoviocytes，RA-FLS)增殖和侵袭、调节炎性细胞因子分泌、诱导血管生成及软骨破坏参与RA的发病和病情进展[2-4]。鉴于低氧在RA发病机制中的重要作用，本文对HIF与RA发病机制的研究进展进行综述。

1 HIF信号通路

1.1 HIF的结构

HIF介导多细胞生物对低氧应激的主要转录反应在1991年首次被发现[5]。HIF是一种异源二聚体复合物，由受氧调节的α亚单位(HIF-1α、HIF-2α和HIF-3α)和稳定的β亚单位(HIF-1β)构成，每个亚单位均含一个helix-loop-helix区域使其识别并结合到低氧诱导基因调节序列中的HIF DNA结合位点[6-7]。HIF-α的3种亚型中，HIF-1α和HIF-2α在结构和功能上有较大的相似性，而HIF-3α的研究较少，有研究认为HIF-3α可能作为抑制元件对HIF-1α和HIF-2α进行负调控[8]。HIF-α对氧浓度的调节非常敏感，在氧浓度低于6.0%时，细胞HIF-1α水平以指数的方式快速增长，在氧浓度为0.5%(相当于PO210～15 mmHg，1 mmHg=0.133 kPa)时达到最高值[2]。大量积累的HIF-α与HIF-1β结合，从胞浆进入胞核内，并结合基因组上的低氧应答元件(hypoxia response elements，HREs)， 从而开启相关靶基因的转录。

1.2 HIF的调节机制

脯氨酸羟基化酶(prolyl hydroxylase domain proteins，PHDs)在对HIF-α的调节中发挥关键作用。常氧下，PHDs将HIF-α蛋白上的两个关键位置的脯氨酸进行羟基化修饰[9]，被修饰后的HIF-α可被肿瘤抑制因子vHL(von Hippel-Lindau)所识别和结合，然后进行vHL降解复合物所介导的K48泛素化修饰，最后经26S蛋白酶体途径将HIF-α降解[10-11]。PHDs的活性受其底物O2的直接调控，低氧下，PHDs酶活力下降，无法完成对HIF-α的羟基化修饰，这时vHL也就无法识别、结合及降解HIF-α，大量积累的HIF-α与HIF-1β结合，由胞浆进入胞核[12]，与HREs结合，上调血管生成、糖酵解、细胞迁移、生长和凋亡基因等的表达。此外，PHDs的活性还受其辅因子Fe2+和α-酮戊二酸的影响[8]。

另外，天门冬氨酸羟基化酶(factor inhibiting HIF，FIH)对HIF-α的调节也有一定作用，它通过特异性地对HIF-1α的Asn803进行羟基化修饰，从而削弱HIF-1α与其转录辅因子p300/CBP的结合能力，降低HIF-1α对其靶基因的转录活性[13]。与PHDs一样，FIH的酶活性也受O2的直接调控，只有在常氧下才对HIF-1α有修饰作用。除此之外，生长因子和炎性因子，如白细胞介素(interleukin，IL)-1β、肿瘤坏死因子-α(tumor necrosis factor-α，TNF-α)均能影响HIF-α的蛋白水平及转录活性[14-15]。

对不同HIF调节酶(PHD-1、PHD-2、PHD-3和FIH-1)的研究发现，常氧下PHD-2含量最丰富，低氧可使其水平增加约2倍；而PHD-3含量最少，但对低氧最敏感，低氧下其表达可增加19倍；相反，PHD-1和FIH-1几乎不受低氧影响。常氧下敲除PHD-2后，HIF-1α和HIF-2α蛋白表达水平与低氧时水平相当；而敲除PHD-3可使HIF-2α与HREs的结合增加，对HIF-1α蛋白表达影响甚小，甚至降低HIF-1α表达水平。以上研究提示，PHD-2是调控RA-FLS中HIF稳定性及其下游靶基因的最重要的酶[16]。

2 低氧对RA发病机制的影响

越来越多的证据表明低氧调节RA许多重要的病理生理过程，包括滑膜炎症、血管生成和软骨破坏等。

2.1 低氧与滑膜炎症

滑膜炎是RA最主要的病理特征。低氧下，HIF在细胞核内大量累积。研究表明,HIF是RA滑膜炎症的重要调节因素，HIF-α可上调细胞因子[TNF-α、IL-1、IL-6、IL-8、IL-15、IL-17、IL-33、干扰素-γ(interferon，IFN-γ)]、趋化因子[CXCL8(C-X-C motif chemokine ligand 8)、CXCL12、CCL20(CC-chemokine ligand 20)]、血管细胞粘附分子-1(vascular cell adhesion molecule-1，VCAM-1)、促血管生成因子[血管内皮生长因子(vascular endothelial growth factor，VEGF)、血小板反应蛋白-1(thrombospondin-1，TSP-1)]、基质金属蛋白酶(matrix metalloproteinase，MMP)(MMP-1、MMP-2、MMP-3、MMP-9、MMP-12、MMP-13)和Toll样受体的表达[1]，从而促进RA的滑膜炎症、血管生成、软骨破坏和骨侵蚀[17]。低氧下RA-FLS的迁移、侵袭能力也显著增加[18]。HIF-1α基因敲除RA小鼠模型临床表现和病理特征显著改善，特别是滑膜炎症、血管翳形成和软骨破坏[19],同样，阻断HIF-1α信号通路显著降低RA-FLS的迁移和侵袭能力及MMPs分泌[18, 20-21]。Ryu等[22]分别在DBA/1J小鼠膝关节内注射Ad-HIF-1α或Ad-Epas1(HIF-2α)腺病毒致局部过表达HIF-1α或HIF-2α，3周后局部过表达HIF-2α的关节组织显示典型的RA样改变，如滑膜过度增生、滑膜炎、软骨破坏、血管生成和血管翳形成。Epas1(HIF-2α)基因敲除显著减少小鼠胶原诱导性关节炎的发生率和严重性，致病性细胞因子IL-1β、IL-6、IL-12、IL-17A、IL-17F、TNF-α和IFN-γ的表达显著下调。但在上述研究中HIF-1α的过表达并没有引起小鼠关节结构的任何改变，这可能提示HIF-1α、HIF-2α在RA发病机制中的作用不同。

尽管与HIF-1α结构有很大的相似性，HIF-2α在RA中的作用与HIF-1α有所不同。首先，HIF-1α和HIF-2α在RA滑膜组织中的表达位置不同，HIF-2α在滑膜衬里层高表达，而HIF-1α则在RA滑膜组织的衬里层下层和更深层表达[22]。其次，HIF-2α在RA发病机制中的作用似乎是通过炎症因子介导的，Ryu等[22]的研究发现IL-1β和TNF-α可上调小鼠FLSHIF-2α的表达，低氧仅可使FLS表达HIF-2α轻度增加，提示炎症因子可能是HIF-2α表达上调的主要原因。过表达HIF-2α可增加小鼠FLS的增殖能力，上调核因子κB(nuclear factor κB, NF-κB)受体激活蛋白配体(receptor activator of NF-κB ligand，RANKL)的表达和破骨细胞的产生及基质降解酶、趋化因子、炎症介质水平。敲除HIF-2α后，IL-1β诱导的细胞增殖能力、MMPs、趋化因子和炎症介质被抑制，还有研究发现HIF-2α通过上调IL-6的表达而导致RA的发病。以上结果提示HIF-2α在RA的发病中起重要作用，且是通过IL-6介导的。

滑膜炎症的一个重要病理改变是新生血管形成。新生血管为扩增的炎症细胞群提供营养和氧，并促进白细胞的进入，因此导致了滑膜炎的持续。低氧明显促进了血管生成[23]，低氧通过HIF-1α或HIF-2α调控许多血管生成介质的表达，如一氧化氮合成酶、VEGF、CXCL8、CCL20和基质细胞衍生因子-1(stromal cell-derived factor-1，SDF-1)，从而导致血管扩张，增加血管通透性[24]。HIF还可活化血管生成素、Tie-2(tyrosie kinase with Eg and EGF homo-logy domain)、纤维母细胞生长因子(fibroblast growth factor，FGF)和血小板源生长因子(platelet-derived growth factor，PDGF)， 从而导致内皮细胞增殖、迁移和血管重建[25]。

低氧和炎症因子具有协同作用。低氧通过调节HIF-1α和HIF-2α的表达促进滑膜细胞分泌炎症因子，反过来，炎症因子，如IL-1、TNF-α、 高迁移族蛋白-1(high mobility group box-1 protein，HMGB1)和IL-33，能诱导RA-FLS表达HIF-1α和HIF-2α，因此，形成一个调节回路，促进RA滑膜炎症的持续[15, 22, 26]。IL-17A与低氧可协同促进RA-FLS的迁移和侵袭能力，抑制HIF-1α和NF-κB后这种作用显著减弱，另外，抑制NF-κB使HIF-1α的表达显著减弱，提示IL-17A在低氧下通过NF-κB信号通路活化HIF-1α[27]。HMGB1通过促进RA-FLS表达HIF-1α而促进血管形成，从而加重滑膜炎症[28]。

HIF信号通路与其他信号通路之间存在交互作用。信号转导子和转录活化子3(signal transducer and activator transcription factor 3，STAT3)-siRNA和Janus 激酶2(Janus kinase 2，JAK2)的抑制剂(WP1066)可抑制低氧诱导的HIF-1α表达，同样HIF-1α siRNA也可抑制低氧诱导的STAT3的表达，阻断STAT3后炎性细胞因子表达显著减少，提示HIF-1α通路和STAT3通路在RA炎症中存在交互作用[29]。低氧促进RA-FLS Notch信号通路组分的表达，Notch-1 siRNA可抑制低氧诱导的HIF-1α和VEGF表达，提示Notch-1和HIF-1α之间存在交互作用[30]。丝裂原细胞外激酶1/2(mitogen extracellular kinase 1/2，MEK1/2)抑制剂PD98059和磷脂酰肌醇三激酶(phosphoinositide 3-kinase，PI3K)抑制剂LY294002能显著抑制细胞因子诱导的HIF-1α表达，说明PI3K和细胞外信号调节激酶通路在炎症因子诱导的HIF-1α表达中有一定作用[14]。低氧可上调Toll样受体(Toll-like receptor，TLR)配体诱导的RA-FLS炎症性细胞因子、MMPs、VEGF等的释放，过表达HIF-1α可加强聚肌胞苷酸(polyinosinic-polycytidylic acid，polyIC)诱导的IL-6、IL-8和TNF-α的增加，敲除HIF-1α后这种效应可被抑制，提示HIF-1α与TLR刺激的免疫反应协同促进RA的滑膜炎症[31]。另外，过表达NF-κB可促进HIF-1α的表达，而NF-κB亚单位的敲除使HIF-1α的表达下降[32]。NF-kB抑制剂Bay能完全抑制细胞因子诱导的HIF-1α活化[33]。

2.2 低氧与软骨破坏

关节软骨的破坏和骨的侵蚀是RA病理的重要表现。随着RA炎症的进展，过度增生的血管翳侵入、破坏关节软骨。低氧下的滑膜细胞可通过分泌大量MMPs破坏关节软骨。HIF-1α和HIF-2α均能显著促进滑膜细胞产生多种MMPs和聚蛋白多糖酶-1(a disintegrin and metalloproteinase with thrombospondin motifs-4，ADAMTS4)[2, 34],HIF-2α可能通过诱导IL-6的产生促进软骨细胞分泌MMP-3和MMP-13，通过诱导TNF-α的产生促进滑膜细胞表达MMPs和炎症性介质[35]。

低氧还可通过活化破骨细胞介导骨的破坏。低氧可使破骨细胞数量、骨吸收及骨质溶解相关酶活性明显增加，HIF-1αsiRNA能完全阻断低氧诱导的这些效应[36]。Zhao等[37]的研究发现低氧可增加破骨细胞的分化，同时伴有一些特异的自噬功能，抑制自噬可显著降低低氧状态下破骨细胞的分化，提示自噬对低氧诱导的破骨细胞分化有重要的作用。他们的研究还发现，低氧状态下自噬的活化是由HIF-1α依赖的BCL2结合蛋白3(BCL-2 interacting protein 3，BNIP3)的上调引起的。将HIF-1α或BNIP3敲除能够显著降低低氧诱导的自噬的活化和破骨细胞的生成增加。低氧下HIF介导的通路还可为破骨细胞提供能量[38]。Hiraga等[39]的研究发现，低氧和HIF-1α通过抑制成骨细胞的分化和促进破骨细胞的形成导致乳腺癌的溶骨性骨转移。以上研究提示低氧可促进骨破坏的发生，并且HIF在其中起重要作用。

2.3 低氧对免疫细胞的影响

T细胞是在RA发病机制中起重要作用的细胞,低氧在T细胞的形成分化和效应功能中起重要作用。Foxp3是调节性T细胞(regulatory T cells，Treg)特异的标志物，低氧可使人Jurkat T细胞表达Foxp3增加，这种效应可被HIF-1αsiRNA抑制，而HIF-1α过表达增加Foxp3的表达[40-41]。同样，人外周血CD4+T细胞转染过表达HIF-1α的慢病毒后Foxp3表达增加，HIF-1αsiRNA能逆转Foxp3的高表达[42]。相反，也有研究发现HIF-1α通过与Foxp3结合，使Treg被蛋白酶体降解而减少其形成[43-44]。造成研究结论不一致的原因可能是HIF-1α对Treg的调节不是直接作用的，低氧对Treg的调节依赖于HIF-1α和转化生长因子β的共同作用及局部微环境的细胞因子[41]。HIF-1α可调节Th17/Treg细胞的平衡，HIF-1α的缺失可影响Th17细胞的分化[43-44]。HIF-1α过表达还可促进RA-FLS介导的Th1和Th17细胞的增加，从而促进IFN-γ和IL-17的产生[31]。相反，HIF-2α对Th17细胞的分化没有影响，但HIF-2α可通过上调IL-6的表达从而影响Th17细胞的分化[22]。总之，这些数据提示HIF对T细胞的分化有重要影响，且对Th17细胞的分化是必要的。

3 潜在的治疗作用

越来越多的证据表明低氧和HIF参与了RA许多重要的病理生理过程，包括滑膜炎症、血管生成和软骨破坏，提示HIF可能是RA潜在的治疗靶点。以低氧为靶点的治疗方法多来自低氧对肿瘤的研究，包括应用前体物质、特定的HIF抑制剂或基因治疗，低氧前体物质可在缺氧组织中选择性活化，从而把活性物质运送至缺氧细胞[45]。这些治疗方法应用低氧为靶向机制以运送治疗性物质到特定的疾病部位，但由于低氧不仅是一些疾病的特征,还是正常生理情况下的动态过程，因此，这种治疗方法可能会带来额外的副作用。过去5年中，在肿瘤和HIF相关疾病中报道了很多具有抑制活性的HIF抑制剂[46]。尽管在肿瘤和其他HIF相关疾病中，关于HIF抑制剂的初步临床研究取得了令人欣慰的结果，但由于HIF通路在RA中的复杂性以及服用HIF抑制剂后的药代动力学问题，使得RA中这些抑制剂的研究尚不成熟，还有待于进行临床试验以评估其有效性[47]。有人提出局部应用这些物质(如关节内注射)以减少全身应用带来的药代动力学问题及副作用，但由于RA通常是多关节性的，因此这种方法很难应用于临床。

4 展望

低氧对RA的发病具有重要作用，但具体调控机制甚为复杂，目前尚不完全清楚。研究认为，低氧通过HIF信号通路介导一些靶基因的活化促进RA的病理过程，除此之外，低氧还调节免疫细胞的分化，与RA疾病的炎症状态相互促进，与其他信号通路也存在交互作用，从而促进RA病理的持续。因此，低氧不是通过某单一方面影响RA发病，而是可能在基因转录或蛋白水平对RA发病有着整体的影响作用。未来仍需要对低氧在RA发病机制中的作用进行更深入的研究，对低氧调控机制的更深入理解将有助于以低氧为新的靶点对RA进行治疗。

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(2016-08-11收稿)

(本文编辑：赵 波)

SUMMARY Rheumatoid arthritis (RA) is a destructive chronic autoimmune disease characterized by synovium inflammation, cartilage destruction, bone erosion and the presence of autoantibodies. Hypoxia is a prominent micro-environmental feature in a range of disorders including RA. A combination of increased oxygen consumptionby inflamed resident cells and infiltrating immune cells along with a disrupted blood supply due to vascular dysfunction contribute to tissue hypoxia in RA. Hypoxia in turn regulates a number of key signaling pathways that help adaptation. The primary signaling pathway activated by hypoxia is the hypoxia-inducible factor (HIF) pathway. It has been shown that HIFs are highly expressed in the synovium of RA. HIFs mediate the pathogenesis of RA through inducing inflammation, angiogenesis, cell migration, and cartilage destruction, and inhibiting the apoptosis of synovial cells and inflammatory cells. HIF expressed in RA can be regulated in both oxygen-dependent and independent fashions, like inflammatory cytokines, leading to the aggravation of this disease. Considering the vital role of HIF in the pathogenesis of RA, we reviewed the new advances about hypoxia and RA. In this review, we firstly discussed the hypoxia-inducible factor and its regulation, and then, the pathologic role of hypoxia in RA, mainly elucidating the role of hypoxia in synovitis and cartilage destruction and immune cells. Finally, we provided evidence about the potential therapeutic target for treating RA.

Role of hypoxia-inducible factor in the pathogenesis of rheumatoid arthritis

YU Ruo-han, ZHAO Jin-xia, LIU Xiang-yuan△

(Department of Rheumatology and Immunology, Peking University Third Hospital, Beijing 100191, China)

Hypoxia-inducible factor; Arthritis, rheumatoid; Anoxia

国家自然科学基金(81273293，81471599)资助 Supported by National Natural Science Foundation of China (81273293, 81471599)

时间：2016-11-2 9：01：39

http://www.cnki.net/kcms/detail/11.4691.R.20161102.0901.002.html

R593.22

A

1671-167X(2016)06-1095-05

10.3969/j.issn.1671-167X.2016.06.031

△ Corresponding author’s e-mail, liu-xiangyuan@263.net