于若寒，趙金霞，劉湘源

(北京大學第三醫(yī)院風濕免疫科，北京 100191)

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·綜述·

低氧誘導因子在類風濕關節(jié)炎發(fā)病機制中的作用

于若寒，趙金霞，劉湘源△

(北京大學第三醫(yī)院風濕免疫科，北京 100191)

低氧誘導因子；關節(jié)炎，類風濕；缺氧

類風濕關節(jié)炎(rheumatoid arthritis，RA)是一種系統(tǒng)性自身免疫性疾病，病理特征為異常的滑膜增生伴血管翳形成、軟骨和骨的侵蝕破壞，最終導致關節(jié)畸形。目前RA確切發(fā)病機制未明，環(huán)境和遺傳因素相互作用共同促進了RA的發(fā)病。低氧微環(huán)境是RA重要的病理特點，炎癥滑膜組織的高代謝需求和滑膜的快速增生共同導致了RA關節(jié)內低氧狀態(tài)。研究表明,低氧通過低氧誘導因子(hypoxia-inducible factor，HIF)調控的一系列轉錄因子的活化促進RA的疾病進展[1]。HIF可通過促進RA滑膜細胞(RA fibroblast-like synoviocytes，RA-FLS)增殖和侵襲、調節(jié)炎性細胞因子分泌、誘導血管生成及軟骨破壞參與RA的發(fā)病和病情進展[2-4]。鑒于低氧在RA發(fā)病機制中的重要作用，本文對HIF與RA發(fā)病機制的研究進展進行綜述。

1 HIF信號通路

1.1 HIF的結構

HIF介導多細胞生物對低氧應激的主要轉錄反應在1991年首次被發(fā)現(xiàn)[5]。HIF是一種異源二聚體復合物，由受氧調節(jié)的α亞單位(HIF-1α、HIF-2α和HIF-3α)和穩(wěn)定的β亞單位(HIF-1β)構成，每個亞單位均含一個helix-loop-helix區(qū)域使其識別并結合到低氧誘導基因調節(jié)序列中的HIF DNA結合位點[6-7]。HIF-α的3種亞型中，HIF-1α和HIF-2α在結構和功能上有較大的相似性，而HIF-3α的研究較少，有研究認為HIF-3α可能作為抑制元件對HIF-1α和HIF-2α進行負調控[8]。HIF-α對氧濃度的調節(jié)非常敏感，在氧濃度低于6.0%時，細胞HIF-1α水平以指數(shù)的方式快速增長，在氧濃度為0.5%(相當于PO210～15 mmHg，1 mmHg=0.133 kPa)時達到最高值[2]。大量積累的HIF-α與HIF-1β結合，從胞漿進入胞核內，并結合基因組上的低氧應答元件(hypoxia response elements，HREs)， 從而開啟相關靶基因的轉錄。

1.2 HIF的調節(jié)機制

脯氨酸羥基化酶(prolyl hydroxylase domain proteins，PHDs)在對HIF-α的調節(jié)中發(fā)揮關鍵作用。常氧下，PHDs將HIF-α蛋白上的兩個關鍵位置的脯氨酸進行羥基化修飾[9]，被修飾后的HIF-α可被腫瘤抑制因子vHL(von Hippel-Lindau)所識別和結合，然后進行vHL降解復合物所介導的K48泛素化修飾，最后經26S蛋白酶體途徑將HIF-α降解[10-11]。PHDs的活性受其底物O2的直接調控，低氧下，PHDs酶活力下降，無法完成對HIF-α的羥基化修飾，這時vHL也就無法識別、結合及降解HIF-α，大量積累的HIF-α與HIF-1β結合，由胞漿進入胞核[12]，與HREs結合，上調血管生成、糖酵解、細胞遷移、生長和凋亡基因等的表達。此外，PHDs的活性還受其輔因子Fe2+和α-酮戊二酸的影響[8]。

另外，天門冬氨酸羥基化酶(factor inhibiting HIF，F(xiàn)IH)對HIF-α的調節(jié)也有一定作用，它通過特異性地對HIF-1α的Asn803進行羥基化修飾，從而削弱HIF-1α與其轉錄輔因子p300/CBP的結合能力，降低HIF-1α對其靶基因的轉錄活性[13]。與PHDs一樣，F(xiàn)IH的酶活性也受O2的直接調控，只有在常氧下才對HIF-1α有修飾作用。除此之外，生長因子和炎性因子，如白細胞介素(interleukin，IL)-1β、腫瘤壞死因子-α(tumor necrosis factor-α，TNF-α)均能影響HIF-α的蛋白水平及轉錄活性[14-15]。

對不同HIF調節(jié)酶(PHD-1、PHD-2、PHD-3和FIH-1)的研究發(fā)現(xiàn)，常氧下PHD-2含量最豐富，低氧可使其水平增加約2倍；而PHD-3含量最少，但對低氧最敏感，低氧下其表達可增加19倍；相反，PHD-1和FIH-1幾乎不受低氧影響。常氧下敲除PHD-2后，HIF-1α和HIF-2α蛋白表達水平與低氧時水平相當；而敲除PHD-3可使HIF-2α與HREs的結合增加，對HIF-1α蛋白表達影響甚小，甚至降低HIF-1α表達水平。以上研究提示，PHD-2是調控RA-FLS中HIF穩(wěn)定性及其下游靶基因的最重要的酶[16]。

2 低氧對RA發(fā)病機制的影響

越來越多的證據(jù)表明低氧調節(jié)RA許多重要的病理生理過程，包括滑膜炎癥、血管生成和軟骨破壞等。

2.1 低氧與滑膜炎癥

滑膜炎是RA最主要的病理特征。低氧下，HIF在細胞核內大量累積。研究表明,HIF是RA滑膜炎癥的重要調節(jié)因素，HIF-α可上調細胞因子[TNF-α、IL-1、IL-6、IL-8、IL-15、IL-17、IL-33、干擾素-γ(interferon，IFN-γ)]、趨化因子[CXCL8(C-X-C motif chemokine ligand 8)、CXCL12、CCL20(CC-chemokine ligand 20)]、血管細胞粘附分子-1(vascular cell adhesion molecule-1，VCAM-1)、促血管生成因子[血管內皮生長因子(vascular endothelial growth factor，VEGF)、血小板反應蛋白-1(thrombospondin-1，TSP-1)]、基質金屬蛋白酶(matrix metalloproteinase，MMP)(MMP-1、MMP-2、MMP-3、MMP-9、MMP-12、MMP-13)和Toll樣受體的表達[1]，從而促進RA的滑膜炎癥、血管生成、軟骨破壞和骨侵蝕[17]。低氧下RA-FLS的遷移、侵襲能力也顯著增加[18]。HIF-1α基因敲除RA小鼠模型臨床表現(xiàn)和病理特征顯著改善，特別是滑膜炎癥、血管翳形成和軟骨破壞[19],同樣，阻斷HIF-1α信號通路顯著降低RA-FLS的遷移和侵襲能力及MMPs分泌[18, 20-21]。Ryu等[22]分別在DBA/1J小鼠膝關節(jié)內注射Ad-HIF-1α或Ad-Epas1(HIF-2α)腺病毒致局部過表達HIF-1α或HIF-2α，3周后局部過表達HIF-2α的關節(jié)組織顯示典型的RA樣改變，如滑膜過度增生、滑膜炎、軟骨破壞、血管生成和血管翳形成。Epas1(HIF-2α)基因敲除顯著減少小鼠膠原誘導性關節(jié)炎的發(fā)生率和嚴重性，致病性細胞因子IL-1β、IL-6、IL-12、IL-17A、IL-17F、TNF-α和IFN-γ的表達顯著下調。但在上述研究中HIF-1α的過表達并沒有引起小鼠關節(jié)結構的任何改變，這可能提示HIF-1α、HIF-2α在RA發(fā)病機制中的作用不同。

盡管與HIF-1α結構有很大的相似性，HIF-2α在RA中的作用與HIF-1α有所不同。首先，HIF-1α和HIF-2α在RA滑膜組織中的表達位置不同，HIF-2α在滑膜襯里層高表達，而HIF-1α則在RA滑膜組織的襯里層下層和更深層表達[22]。其次，HIF-2α在RA發(fā)病機制中的作用似乎是通過炎癥因子介導的，Ryu等[22]的研究發(fā)現(xiàn)IL-1β和TNF-α可上調小鼠FLSHIF-2α的表達，低氧僅可使FLS表達HIF-2α輕度增加，提示炎癥因子可能是HIF-2α表達上調的主要原因。過表達HIF-2α可增加小鼠FLS的增殖能力，上調核因子κB(nuclear factor κB, NF-κB)受體激活蛋白配體(receptor activator of NF-κB ligand，RANKL)的表達和破骨細胞的產生及基質降解酶、趨化因子、炎癥介質水平。敲除HIF-2α后，IL-1β誘導的細胞增殖能力、MMPs、趨化因子和炎癥介質被抑制，還有研究發(fā)現(xiàn)HIF-2α通過上調IL-6的表達而導致RA的發(fā)病。以上結果提示HIF-2α在RA的發(fā)病中起重要作用，且是通過IL-6介導的。

滑膜炎癥的一個重要病理改變是新生血管形成。新生血管為擴增的炎癥細胞群提供營養(yǎng)和氧，并促進白細胞的進入，因此導致了滑膜炎的持續(xù)。低氧明顯促進了血管生成[23]，低氧通過HIF-1α或HIF-2α調控許多血管生成介質的表達，如一氧化氮合成酶、VEGF、CXCL8、CCL20和基質細胞衍生因子-1(stromal cell-derived factor-1，SDF-1)，從而導致血管擴張，增加血管通透性[24]。HIF還可活化血管生成素、Tie-2(tyrosie kinase with Eg and EGF homo-logy domain)、纖維母細胞生長因子(fibroblast growth factor，F(xiàn)GF)和血小板源生長因子(platelet-derived growth factor，PDGF)， 從而導致內皮細胞增殖、遷移和血管重建[25]。

低氧和炎癥因子具有協(xié)同作用。低氧通過調節(jié)HIF-1α和HIF-2α的表達促進滑膜細胞分泌炎癥因子，反過來，炎癥因子，如IL-1、TNF-α、 高遷移族蛋白-1(high mobility group box-1 protein，HMGB1)和IL-33，能誘導RA-FLS表達HIF-1α和HIF-2α，因此，形成一個調節(jié)回路，促進RA滑膜炎癥的持續(xù)[15, 22, 26]。IL-17A與低氧可協(xié)同促進RA-FLS的遷移和侵襲能力，抑制HIF-1α和NF-κB后這種作用顯著減弱，另外，抑制NF-κB使HIF-1α的表達顯著減弱，提示IL-17A在低氧下通過NF-κB信號通路活化HIF-1α[27]。HMGB1通過促進RA-FLS表達HIF-1α而促進血管形成，從而加重滑膜炎癥[28]。

HIF信號通路與其他信號通路之間存在交互作用。信號轉導子和轉錄活化子3(signal transducer and activator transcription factor 3，STAT3)-siRNA和Janus 激酶2(Janus kinase 2，JAK2)的抑制劑(WP1066)可抑制低氧誘導的HIF-1α表達，同樣HIF-1α siRNA也可抑制低氧誘導的STAT3的表達，阻斷STAT3后炎性細胞因子表達顯著減少，提示HIF-1α通路和STAT3通路在RA炎癥中存在交互作用[29]。低氧促進RA-FLS Notch信號通路組分的表達，Notch-1 siRNA可抑制低氧誘導的HIF-1α和VEGF表達，提示Notch-1和HIF-1α之間存在交互作用[30]。絲裂原細胞外激酶1/2(mitogen extracellular kinase 1/2，MEK1/2)抑制劑PD98059和磷脂酰肌醇三激酶(phosphoinositide 3-kinase，PI3K)抑制劑LY294002能顯著抑制細胞因子誘導的HIF-1α表達，說明PI3K和細胞外信號調節(jié)激酶通路在炎癥因子誘導的HIF-1α表達中有一定作用[14]。低氧可上調Toll樣受體(Toll-like receptor，TLR)配體誘導的RA-FLS炎癥性細胞因子、MMPs、VEGF等的釋放，過表達HIF-1α可加強聚肌胞苷酸(polyinosinic-polycytidylic acid，polyIC)誘導的IL-6、IL-8和TNF-α的增加，敲除HIF-1α后這種效應可被抑制，提示HIF-1α與TLR刺激的免疫反應協(xié)同促進RA的滑膜炎癥[31]。另外，過表達NF-κB可促進HIF-1α的表達，而NF-κB亞單位的敲除使HIF-1α的表達下降[32]。NF-kB抑制劑Bay能完全抑制細胞因子誘導的HIF-1α活化[33]。

2.2 低氧與軟骨破壞

關節(jié)軟骨的破壞和骨的侵蝕是RA病理的重要表現(xiàn)。隨著RA炎癥的進展，過度增生的血管翳侵入、破壞關節(jié)軟骨。低氧下的滑膜細胞可通過分泌大量MMPs破壞關節(jié)軟骨。HIF-1α和HIF-2α均能顯著促進滑膜細胞產生多種MMPs和聚蛋白多糖酶-1(a disintegrin and metalloproteinase with thrombospondin motifs-4，ADAMTS4)[2, 34],HIF-2α可能通過誘導IL-6的產生促進軟骨細胞分泌MMP-3和MMP-13，通過誘導TNF-α的產生促進滑膜細胞表達MMPs和炎癥性介質[35]。

低氧還可通過活化破骨細胞介導骨的破壞。低氧可使破骨細胞數(shù)量、骨吸收及骨質溶解相關酶活性明顯增加，HIF-1αsiRNA能完全阻斷低氧誘導的這些效應[36]。Zhao等[37]的研究發(fā)現(xiàn)低氧可增加破骨細胞的分化，同時伴有一些特異的自噬功能，抑制自噬可顯著降低低氧狀態(tài)下破骨細胞的分化，提示自噬對低氧誘導的破骨細胞分化有重要的作用。他們的研究還發(fā)現(xiàn)，低氧狀態(tài)下自噬的活化是由HIF-1α依賴的BCL2結合蛋白3(BCL-2 interacting protein 3，BNIP3)的上調引起的。將HIF-1α或BNIP3敲除能夠顯著降低低氧誘導的自噬的活化和破骨細胞的生成增加。低氧下HIF介導的通路還可為破骨細胞提供能量[38]。Hiraga等[39]的研究發(fā)現(xiàn)，低氧和HIF-1α通過抑制成骨細胞的分化和促進破骨細胞的形成導致乳腺癌的溶骨性骨轉移。以上研究提示低氧可促進骨破壞的發(fā)生，并且HIF在其中起重要作用。

2.3 低氧對免疫細胞的影響

T細胞是在RA發(fā)病機制中起重要作用的細胞,低氧在T細胞的形成分化和效應功能中起重要作用。Foxp3是調節(jié)性T細胞(regulatory T cells，Treg)特異的標志物，低氧可使人Jurkat T細胞表達Foxp3增加，這種效應可被HIF-1αsiRNA抑制，而HIF-1α過表達增加Foxp3的表達[40-41]。同樣，人外周血CD4+T細胞轉染過表達HIF-1α的慢病毒后Foxp3表達增加，HIF-1αsiRNA能逆轉Foxp3的高表達[42]。相反，也有研究發(fā)現(xiàn)HIF-1α通過與Foxp3結合，使Treg被蛋白酶體降解而減少其形成[43-44]。造成研究結論不一致的原因可能是HIF-1α對Treg的調節(jié)不是直接作用的，低氧對Treg的調節(jié)依賴于HIF-1α和轉化生長因子β的共同作用及局部微環(huán)境的細胞因子[41]。HIF-1α可調節(jié)Th17/Treg細胞的平衡，HIF-1α的缺失可影響Th17細胞的分化[43-44]。HIF-1α過表達還可促進RA-FLS介導的Th1和Th17細胞的增加，從而促進IFN-γ和IL-17的產生[31]。相反，HIF-2α對Th17細胞的分化沒有影響，但HIF-2α可通過上調IL-6的表達從而影響Th17細胞的分化[22]?？傊?，這些數(shù)據(jù)提示HIF對T細胞的分化有重要影響，且對Th17細胞的分化是必要的。

3 潛在的治療作用

越來越多的證據(jù)表明低氧和HIF參與了RA許多重要的病理生理過程，包括滑膜炎癥、血管生成和軟骨破壞，提示HIF可能是RA潛在的治療靶點。以低氧為靶點的治療方法多來自低氧對腫瘤的研究，包括應用前體物質、特定的HIF抑制劑或基因治療，低氧前體物質可在缺氧組織中選擇性活化，從而把活性物質運送至缺氧細胞[45]。這些治療方法應用低氧為靶向機制以運送治療性物質到特定的疾病部位，但由于低氧不僅是一些疾病的特征,還是正常生理情況下的動態(tài)過程，因此，這種治療方法可能會帶來額外的副作用。過去5年中，在腫瘤和HIF相關疾病中報道了很多具有抑制活性的HIF抑制劑[46]。盡管在腫瘤和其他HIF相關疾病中，關于HIF抑制劑的初步臨床研究取得了令人欣慰的結果，但由于HIF通路在RA中的復雜性以及服用HIF抑制劑后的藥代動力學問題，使得RA中這些抑制劑的研究尚不成熟，還有待于進行臨床試驗以評估其有效性[47]。有人提出局部應用這些物質(如關節(jié)內注射)以減少全身應用帶來的藥代動力學問題及副作用，但由于RA通常是多關節(jié)性的，因此這種方法很難應用于臨床。

4 展望

低氧對RA的發(fā)病具有重要作用，但具體調控機制甚為復雜，目前尚不完全清楚。研究認為，低氧通過HIF信號通路介導一些靶基因的活化促進RA的病理過程，除此之外，低氧還調節(jié)免疫細胞的分化，與RA疾病的炎癥狀態(tài)相互促進，與其他信號通路也存在交互作用，從而促進RA病理的持續(xù)。因此，低氧不是通過某單一方面影響RA發(fā)病，而是可能在基因轉錄或蛋白水平對RA發(fā)病有著整體的影響作用。未來仍需要對低氧在RA發(fā)病機制中的作用進行更深入的研究，對低氧調控機制的更深入理解將有助于以低氧為新的靶點對RA進行治療。

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(2016-08-11收稿)

(本文編輯：趙 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

國家自然科學基金(81273293，81471599)資助 Supported by National Natural Science Foundation of China (81273293, 81471599)

時間：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