糖尿病性骨關(guān)節(jié)炎發(fā)病機(jī)制研究進(jìn)展

焦聚陽(yáng) 石晶晟 夏軍 魏亦兵 陳飛雁 趙廣雷 楊元慶

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糖尿病性骨關(guān)節(jié)炎發(fā)病機(jī)制研究進(jìn)展

焦聚陽(yáng) 石晶晟 夏軍 魏亦兵 陳飛雁 趙廣雷 楊元慶

目前骨關(guān)節(jié)炎(OA)發(fā)病機(jī)制尚不明確，大多認(rèn)為是外傷或其他因素刺激誘發(fā)軟骨細(xì)胞使其發(fā)生應(yīng)激反應(yīng)，細(xì)胞外基質(zhì)(ECM)合成分解代謝失衡，繼發(fā)軟骨降解、滑膜炎癥等解剖關(guān)系和生理功能異常。隨著人口老齡化和糖尿病患者人數(shù)的劇增，越來(lái)越多的研究表明糖尿病可破壞關(guān)節(jié)軟骨并誘發(fā)OA。糖尿病可能通過(guò)葡萄糖、胰島素代謝異常影響軟骨代謝，線粒體和微小RNA(miRNA)可能是其影響軟骨代謝的媒介，它們可能成為糖尿病性O(shè)A新的治療靶點(diǎn)。該文從葡萄糖代謝、胰島素代謝、線粒體代謝和miRNA表達(dá)等方面對(duì)糖尿病性O(shè)A發(fā)病機(jī)制研究進(jìn)展作一綜述。

骨關(guān)節(jié)炎;糖尿病;發(fā)病機(jī)制;葡萄糖;胰島素

骨關(guān)節(jié)炎(OA)是一種最常見(jiàn)的關(guān)節(jié)疾病，好發(fā)于中老年人。國(guó)際骨關(guān)節(jié)炎研究協(xié)會(huì)(OARSI)將OA定義為一種累及可動(dòng)關(guān)節(jié)的疾病，因微小損傷或巨大創(chuàng)傷激活適應(yīng)性修復(fù)反應(yīng)(如固有免疫促炎機(jī)制等異常)，誘發(fā)細(xì)胞應(yīng)激和細(xì)胞外基質(zhì)(ECM)降解，引起軟骨降解、骨重建、骨贅形成、滑膜炎癥等解剖結(jié)構(gòu)異常和生理功能紊亂，最終導(dǎo)致OA發(fā)生[1-3]。目前OA發(fā)病機(jī)制尚不明確，可能的危險(xiǎn)因素包括年齡、代謝、外傷、炎癥等，其中代謝與OA的關(guān)系是近年研究熱點(diǎn)。有研究[4-6]表明，OA屬于代謝綜合征，與腹型肥胖、高脂血癥和2型糖尿病(T2DM)密切相關(guān)。 Berenbaum[7]于2001年首次提出糖尿病誘發(fā)骨關(guān)節(jié)炎的概念，認(rèn)為糖尿病很可能是OA的獨(dú)立危險(xiǎn)因素。Schett等[8]對(duì)927例糖尿病患者進(jìn)行長(zhǎng)達(dá)20年的隨訪，結(jié)果顯示T2DM患者中出現(xiàn)晚期OA的比例是非T2DM患者的3.8倍，在排除年齡、體重指數(shù)(BMI)等因素后，該結(jié)果仍有意義。Eymard等[9]每年測(cè)量膝OA患者關(guān)節(jié)間隙狹窄程度，發(fā)現(xiàn)糖尿病性O(shè)A患者關(guān)節(jié)間隙狹窄程度較非糖尿病性O(shè)A患者更明顯，在調(diào)整年齡、BMI等因素后，該結(jié)果亦具有統(tǒng)計(jì)學(xué)意義。Laiguillon等[10]研究提出糖尿病性O(shè)A可能的病理生理學(xué)特點(diǎn)。隨后，越來(lái)越多的臨床研究和系統(tǒng)評(píng)價(jià)[11-13]支持糖尿病可能為OA的獨(dú)立危險(xiǎn)因素這一觀點(diǎn)。本文從葡萄糖代謝、胰島素代謝、線粒體代謝和微小RNA(miRNA)表達(dá)等方面對(duì)糖尿病性O(shè)A可能的發(fā)病機(jī)制作一綜述，旨在為糖尿病性O(shè)A尋找新的治療靶點(diǎn)，為靶向治療和精準(zhǔn)醫(yī)療提供理論依據(jù)。

1 葡萄糖代謝異常

葡萄糖是關(guān)節(jié)軟骨生長(zhǎng)、發(fā)育、維持穩(wěn)態(tài)的重要能量來(lái)源，也是關(guān)節(jié)軟骨基質(zhì)合成的基本原料。關(guān)節(jié)軟骨的葡萄糖水平可隨年齡、體力活動(dòng)、內(nèi)分泌代謝等改變而變化。軟骨細(xì)胞可感知ECM中葡萄糖的濃度并進(jìn)行適應(yīng)性調(diào)節(jié)。

1.1 葡萄糖轉(zhuǎn)運(yùn)蛋白表達(dá)異常

葡萄糖轉(zhuǎn)運(yùn)蛋白(GLUT)可將細(xì)胞外葡萄糖轉(zhuǎn)運(yùn)至細(xì)胞內(nèi)，再通過(guò)無(wú)氧糖酵解等代謝途徑獲取能量或儲(chǔ)存[14]。關(guān)節(jié)軟骨中高表達(dá)的GLUT主要是GLUT1，它可根據(jù)細(xì)胞外葡萄糖濃度、含氧量、胰島素樣生長(zhǎng)因子(IGF)和促炎因子如白細(xì)胞介素(IL)-1水平等進(jìn)行調(diào)節(jié)[14]。Rosa等[15]使用不同濃度葡萄糖溶液刺激OA患者和健康人關(guān)節(jié)軟骨后發(fā)現(xiàn)，正常軟骨細(xì)胞可通過(guò)上調(diào)或下調(diào)GLUT1水平來(lái)適應(yīng)細(xì)胞外低糖或高糖水平，而OA患者軟骨細(xì)胞在高糖刺激下喪失了下調(diào)GLUT1的能力，致使細(xì)胞內(nèi)葡萄糖蓄積過(guò)多。研究發(fā)現(xiàn)，GLUT1在IL-1作用下表達(dá)上調(diào)，亦可增加細(xì)胞內(nèi)糖負(fù)荷[16]；OA軟骨細(xì)胞在高糖刺激下更易增加基質(zhì)金屬蛋白酶(MMP)-13的表達(dá)，這些都會(huì)促進(jìn)軟骨基質(zhì)分解代謝[17]。

1.2 多元醇通路激活

正常情況下，細(xì)胞內(nèi)葡萄糖蓄積過(guò)多可引起無(wú)氧糖酵解增加。研究[18]發(fā)現(xiàn)，雖然OA患者軟骨細(xì)胞內(nèi)葡萄糖蓄積過(guò)多，但參與無(wú)氧糖酵解的3個(gè)關(guān)鍵酶表達(dá)均下調(diào)，糖酵解能力下降。細(xì)胞內(nèi)高糖負(fù)荷會(huì)激活其他糖代謝替代途徑如多元醇通路、氨基己糖通路、蛋白激酶C通路以及產(chǎn)生晚期糖基化終末產(chǎn)物(AGE)等[19]。

多元醇通路指細(xì)胞內(nèi)多余的葡萄糖在醛醣還原酶(AR)作用下被還原成山梨醇，山梨醇在山梨醇脫氫酶的作用下生成果糖。其中，AR是多元醇通路的限速酶。AR的激活在糖尿病慢性并發(fā)癥如糖尿病腎病中起關(guān)鍵作用，AR抑制劑如依帕司他已成功應(yīng)用于臨床[20]。Cheng等[21]在研究糖尿病小鼠椎間盤(pán)退行性變時(shí)發(fā)現(xiàn)，退變椎間盤(pán)軟骨中AR和山梨醇增加，并證明多元醇通路可激活p38絲裂原活化蛋白激酶(p38 MAPK)信號(hào)轉(zhuǎn)導(dǎo)通路而加速椎間盤(pán)軟骨外基質(zhì)的降解。與之類(lèi)似的結(jié)果在關(guān)節(jié)軟骨中也得到了驗(yàn)證。Laiguillon等[10]比較糖尿病性O(shè)A患者與非糖尿病性O(shè)A患者軟骨，發(fā)現(xiàn)IL-1β刺激后糖尿病性O(shè)A患者軟骨中IL-6表達(dá)較非糖尿病性O(shè)A患者高，證實(shí)在IL-1β刺激下，糖尿病性O(shè)A患者軟骨誘發(fā)炎癥的反應(yīng)更劇烈。IL-1β刺激后高糖負(fù)荷的軟骨細(xì)胞攝糖量增加，IL-6表達(dá)水平較在正常葡萄糖濃度下高，這一作用可被GLUT抑制劑和AR抑制劑依帕司他部分抵消(分別可抵消45%和62%)。因此，多元醇通路的激活可能參與糖尿病性O(shè)A的發(fā)生。

1.3 AGE生成

AGE是細(xì)胞內(nèi)多余的葡萄糖、蛋白質(zhì)、脂質(zhì)、核苷酸等大分子發(fā)生非酶性糖基化反應(yīng)的終末產(chǎn)物，戊糖素、丙酮醛等都是AGE形成的中間產(chǎn)物。AGE與糖尿病、OA等均有關(guān)聯(lián)[22-23]。AGE一旦形成很難分離，只能隨蛋白降解而消除；而關(guān)節(jié)軟骨中的Ⅱ型膠原蛋白半衰期超過(guò)100年，因此AGE易積聚在關(guān)節(jié)軟骨內(nèi)。AGE可能通過(guò)生物力學(xué)、炎癥和代謝改變參與OA發(fā)生發(fā)展，糖尿病患者更易形成并聚積AGE。體外試驗(yàn)[24]證實(shí)，AGE可與膠原發(fā)生交聯(lián)反應(yīng)，導(dǎo)致關(guān)節(jié)組織僵硬度和脆性增加。但體內(nèi)實(shí)驗(yàn)[25]發(fā)現(xiàn)，軟骨內(nèi)單純的膠原交聯(lián)并不能導(dǎo)致OA發(fā)生，表明AGE引起的生物力學(xué)改變并不是OA發(fā)生的主要機(jī)制，AGE可能通過(guò)炎癥反應(yīng)和氧化應(yīng)激引起基質(zhì)代謝失衡，從而促進(jìn)OA形成。研究[26]發(fā)現(xiàn)，AGE通過(guò)作用于AGE受體(RAGE)來(lái)激活多種信號(hào)轉(zhuǎn)導(dǎo)通路如核因子-κB(NF-κB)信號(hào)轉(zhuǎn)導(dǎo)通路，促進(jìn)MMP-13、IL-1β等生成。此外，AGE還可下調(diào)軟骨細(xì)胞中過(guò)氧化物酶體增殖物激活受體(PPAR)-γ表達(dá)，增加MMP-13表達(dá)，抑制Ⅱ型膠原合成，這一過(guò)程可被PPAR-γ激動(dòng)劑吡格列酮所拮抗[27]。動(dòng)物實(shí)驗(yàn)證實(shí)單純向關(guān)節(jié)腔內(nèi)注射AGE并不能誘導(dǎo)OA發(fā)生。但Li等[28]對(duì)兔OA模型進(jìn)行研究，發(fā)現(xiàn)在過(guò)度體力活動(dòng)下，關(guān)節(jié)腔內(nèi)注射AGE可加速兔關(guān)節(jié)軟骨破壞，而吡格列酮可減輕AGE誘導(dǎo)軟骨破壞的嚴(yán)重程度。Chen等[29]對(duì)糖尿病小鼠進(jìn)行研究，發(fā)現(xiàn)高糖可增加軟骨細(xì)胞中IL-6、MMP-13、AGE等的表達(dá)，同時(shí)減少Ⅱ型膠原和PPAR-γ的表達(dá)；吡格列酮可明顯逆轉(zhuǎn)AGE形成和軟骨損害。由此可見(jiàn)，長(zhǎng)期高血糖可能通過(guò)促進(jìn)AGE生成來(lái)下調(diào)PPAR-γ，導(dǎo)致軟骨內(nèi)炎癥反應(yīng)加劇和分解代謝增加，最終導(dǎo)致OA發(fā)生發(fā)展。

2 胰島素代謝異常

胰島素分泌異常是糖尿病的重要特征之一，T2DM主要表現(xiàn)為高胰島素血癥和胰島素抵抗。胰島素與IGF類(lèi)似，作用于胰島素受體(IR)，繼而激活胰島素受體底物1和蛋白激酶B(AKT)信號(hào)轉(zhuǎn)導(dǎo)通路[30-31]。目前主流觀點(diǎn)認(rèn)為，胰島素或IGF可通過(guò)AKT信號(hào)轉(zhuǎn)導(dǎo)通路促進(jìn)軟骨細(xì)胞Ⅱ型膠原和蛋白聚糖(PG)合成[32-33]。IR在軟骨細(xì)胞和滑膜細(xì)胞中均有表達(dá)。Rosa等[34]研究發(fā)現(xiàn)，OA軟骨細(xì)胞中IR較正常軟骨細(xì)胞表達(dá)下降，這限制了胰島素對(duì)軟骨細(xì)胞的營(yíng)養(yǎng)作用。Hamada等[35]研究發(fā)現(xiàn)，胰島素可通過(guò)抑制滑膜炎癥反應(yīng)來(lái)抑制OA發(fā)生；糖尿病小鼠關(guān)節(jié)內(nèi)出現(xiàn)較明顯的軟骨破壞、滑膜增生和骨贅形成，其中滑膜組織中的腫瘤壞死因子(TNF)-α表達(dá)明顯增加,而胰島素可抑制滑膜中TNF-α的表達(dá)。Griffin等[36]用胰島素刺激糖尿病性O(shè)A患者滑膜，發(fā)現(xiàn)其IR和AKT磷酸化作用均慢于非糖尿病性O(shè)A患者，即糖尿病性O(shè)A患者滑膜組織出現(xiàn)胰島素抵抗。El-Karib等[37]對(duì)糖尿病性O(shè)A小鼠模型進(jìn)行研究，發(fā)現(xiàn)應(yīng)用胰島素和胰島素類(lèi)似物釩可保護(hù)關(guān)節(jié)軟骨，兩者聯(lián)合應(yīng)用效果更佳，這一作用可能是通過(guò)減少炎性介質(zhì)如TNF-α、IL-6等生成及增加超氧化物歧化酶的產(chǎn)生而實(shí)現(xiàn)的。Al-Jarallah等[38]研究發(fā)現(xiàn)，經(jīng)胰島素治療的糖尿病性O(shè)A患者骨贅較未使用胰島素治療的糖尿病性O(shè)A患者小。與之相矛盾的是，Ribeiro等[39]研究認(rèn)為高胰島素血癥是破壞軟骨的危險(xiǎn)因素，其主要通過(guò)抑制自噬作用實(shí)現(xiàn)，此結(jié)論可能與實(shí)驗(yàn)設(shè)計(jì)及胰島素濃度有關(guān)。關(guān)于胰島素對(duì)關(guān)節(jié)組織的影響，有待進(jìn)一步研究。

3 線粒體代謝異常

線粒體代謝異常主要包括線粒體氧化磷酸化水平下降及氧化應(yīng)激。線粒體的主要功能是通過(guò)氧化磷酸化產(chǎn)生三磷酸腺苷(ATP)，雖然關(guān)節(jié)軟骨主要通過(guò)無(wú)氧糖酵解進(jìn)行能量代謝，但線粒體在軟骨代謝中也扮演著重要角色[40]。研究[41]發(fā)現(xiàn)，線粒體代謝異?？芍萝浌呛铣赡芰ο陆怠④浌羌?xì)胞凋亡增加及炎癥、分解代謝增加，與OA發(fā)生有關(guān)。OA軟骨細(xì)胞的線粒體生物合成能力和氧化磷酸化能力受損，導(dǎo)致軟骨分解代謝加劇[42]。氧化應(yīng)激損傷在代謝綜合征，尤其是糖尿病和胰島素抵抗中扮演著重要作用[4]。OA關(guān)節(jié)中的軟骨細(xì)胞、滑膜成纖維細(xì)胞等在外界刺激下也可產(chǎn)生大量活性氧簇(ROS)和活性氮簇(RNS)，造成細(xì)胞損傷和凋亡。ROS可通過(guò)激活NF-κB信號(hào)轉(zhuǎn)導(dǎo)通路促進(jìn)IL-1β、TNF-α等炎性介質(zhì)生成，增加MMP-3、MMP-13表達(dá)[43]。有學(xué)者[44]提出氧化應(yīng)激亦可通過(guò)調(diào)控磷脂酰肌醇-3-羥激酶(PI3K)/AKT信號(hào)轉(zhuǎn)導(dǎo)通路來(lái)抑制IGF誘導(dǎo)的軟骨PG合成。Rosa等[15]研究認(rèn)為，OA軟骨細(xì)胞中的高糖負(fù)荷引起ROS生成增多、存在時(shí)間延長(zhǎng)，進(jìn)而誘發(fā)軟骨細(xì)胞凋亡。Laiguillon等[10]研究發(fā)現(xiàn)，高糖條件下軟骨細(xì)胞對(duì)炎性刺激的高反應(yīng)性可被線粒體氧化應(yīng)激抑制劑部分抵消(38%)，證實(shí)氧化應(yīng)激可能參與糖尿病性O(shè)A的發(fā)生，甚至成為葡萄糖異?；蛞葝u素異常與軟骨炎癥反應(yīng)之間的媒介。

4 miRNA表達(dá)異常

miRNA通過(guò)完全或不完全互補(bǔ)方式與靶mRNA配對(duì)，進(jìn)而在轉(zhuǎn)錄后對(duì)靶基因表達(dá)進(jìn)行負(fù)調(diào)控，它可調(diào)節(jié)多種細(xì)胞功能包括細(xì)胞發(fā)育、增殖、分化、凋亡、糖代謝等[45]。miRNA因其獨(dú)特的組織特異性和時(shí)序性，在疾病的早期診斷及早期治療中具有無(wú)可比擬的應(yīng)用前景。糖尿病可引起多種miRNA表達(dá)異常，繼而參與一系列并發(fā)癥的發(fā)生，其中包括骨和關(guān)節(jié)損傷[46-47]。有研究[48]發(fā)現(xiàn)，胰島素抵抗患者脂肪細(xì)胞中miRNA-223明顯過(guò)度表達(dá)，且miRNA-223可直接作用于GLUT4，引起GLUT4水平降低及糖攝取能力下降。Kim等[49]比較糖尿病性O(shè)A患者與非糖尿病性O(shè)A患者過(guò)氧化物酶體生物合成因子(PEX)-16基因表達(dá)，發(fā)現(xiàn)糖尿病性O(shè)A患者PEX-16基因表達(dá)明顯低于非糖尿病性O(shè)A患者；體外實(shí)驗(yàn)證實(shí)，抑制PEX-16可致miRNA-223過(guò)度表達(dá)，并引起軟骨細(xì)胞凋亡。有學(xué)者[50]研究發(fā)現(xiàn)，miRNA-223在成骨細(xì)胞中可直接負(fù)調(diào)控IGF-1受體，介導(dǎo)AGE引起的成骨細(xì)胞凋亡。目前關(guān)于miRNA在糖尿病性O(shè)A中的研究較少。因此，代謝/miRNA/炎癥/凋亡反應(yīng)網(wǎng)絡(luò)可能是參與糖尿病性O(shè)A發(fā)生發(fā)展的重要機(jī)制。

5 結(jié)語(yǔ)

隨著人口老齡化和糖尿病患者的日益劇增，研究糖尿病性O(shè)A發(fā)生機(jī)制意義重大。越來(lái)越多的證據(jù)支持糖尿病可能通過(guò)糖代謝和胰島素代謝改變軟骨、滑膜等關(guān)節(jié)組織細(xì)胞代謝、炎癥反應(yīng)，甚至基因表達(dá)，從而導(dǎo)致關(guān)節(jié)內(nèi)環(huán)境紊亂，參與OA發(fā)生發(fā)展。此外，糖尿病可能會(huì)加重OA患者臨床癥狀如疼痛等，使患者更早地需要進(jìn)行關(guān)節(jié)置換。同時(shí)，糖尿病可能會(huì)增加關(guān)節(jié)置換術(shù)后并發(fā)癥發(fā)生率，降低患者生活質(zhì)量。目前OA尚無(wú)特效治療藥物，通過(guò)研究糖尿病性O(shè)A可能的分子機(jī)制，探索特殊分子靶點(diǎn)如RAGE、PPAR-γ、miRNA等以及新的分子標(biāo)記物、靶向治療藥物，可為糖尿病性O(shè)A患者的早期篩查和治療提供更好的切入點(diǎn)。此外，現(xiàn)有的糖尿病治療藥物如二甲雙胍、吡格列酮等對(duì)糖尿病性O(shè)A的早期干預(yù)也是較好的研究方向。進(jìn)一步建立相關(guān)動(dòng)物實(shí)驗(yàn)?zāi)Ｐ停晟拼x/miRNA/炎癥/凋亡反應(yīng)網(wǎng)絡(luò)，明確相互之間的聯(lián)系，仍需進(jìn)一步研究。

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(收稿：2016-08-15；修回：2016-10-09)

(本文編輯：李圓圓)

國(guó)家自然科學(xué)基金(8140090243)

復(fù)旦大學(xué)附屬華山醫(yī)院骨科

夏軍 E-mail: dr.xiajun@139.com

10.3969/j.issn.1673-7083.2016.06.007