劉繼榮，張一娜

(哈爾濱醫(yī)科大學(xué)附屬第二醫(yī)院老年病科，哈爾濱 150000)

1 炎性衰老的炎癥特征

炎癥是宿主系統(tǒng)對病原體感染或各種類型組織損傷的反應(yīng)，其在炎性衰老過程中不可控[2]。老年人

體內(nèi)促炎因子與抗炎因子此消彼長，最終表現(xiàn)為炎癥穩(wěn)態(tài)失衡，促炎反應(yīng)過度，導(dǎo)致炎性衰老[7]。健康老年人試驗(yàn)研究結(jié)果表明，衰老與促炎癥反應(yīng)水平增高相關(guān)，是促炎癥介質(zhì)包括白細(xì)胞介素-1(interleukin-1，IL-1)、IL-6、腫瘤壞死因子-α(tumor necrosis factor α，TNF-α)和前列腺素E2(prostaglandin E2，PGE2)水平升高所致[8]。Adams等[9]以老年馬為研究對象的研究結(jié)果表明，老年馬外周血中IL-1β、IL-15、IL-18和TNF-α基因表達(dá)水平升高。

2 炎性衰老與骨質(zhì)疏松

在炎性衰老過程中，過度的炎癥可加速骨質(zhì)流失，影響骨代謝，進(jìn)而增加患者骨創(chuàng)傷術(shù)后的死亡率。炎性衰老目前的機(jī)制學(xué)說主要有細(xì)胞因子學(xué)說、自噬學(xué)說、應(yīng)激學(xué)說、氧化-炎癥學(xué)說及DAN損傷學(xué)說等[2]， 一些前瞻性的國外研究結(jié)果表明細(xì)胞

因子學(xué)說、自噬學(xué)說與骨質(zhì)疏松關(guān)系密切。

2.1 細(xì)胞因子學(xué)說與骨質(zhì)疏松

Salvioli等[10]研究發(fā)現(xiàn)，在機(jī)體衰老過程中炎癥細(xì)胞因子發(fā)揮重要的作用。TNF-α、IL-1、IL-6和IL-17等細(xì)胞因子的表達(dá)水平隨年齡增長而升高，它們可作為炎性衰老的血清學(xué)標(biāo)志物。同時(shí)，TNF-α、IL-1、IL-6和IL-17水平增高可導(dǎo)致大量破骨細(xì)胞產(chǎn)生并抑制成骨細(xì)胞活性[11]。

2.1.1 TNF-α與骨質(zhì)疏松 TNF-α可直接或間接促進(jìn)巨噬細(xì)胞集落刺激因子(macrophage-colony stimulating factor，M-CSF)產(chǎn)生。M-CSF是破骨細(xì)胞前體細(xì)胞分化為成熟破骨細(xì)胞過程中一種重要的細(xì)胞因子，M-CSF對破骨細(xì)胞的存活和增殖起重要作用[12]。在任何炎癥過程中，免疫細(xì)胞如T淋巴細(xì)胞、B淋巴細(xì)胞、巨噬細(xì)胞或樹突狀細(xì)胞，都會被激活并產(chǎn)生炎癥細(xì)胞因子，特別是活化的T淋巴細(xì)胞，它主要通過增加骨吸收TNF-α而誘導(dǎo)破骨細(xì)胞生成[13]。D’Amelio等[14]也發(fā)現(xiàn)絕經(jīng)后骨質(zhì)疏松患者T淋巴細(xì)胞和單核細(xì)胞產(chǎn)生TNF-α。TNF-α還可抑制成骨細(xì)胞生成，同時(shí)降低骨基質(zhì)鈣化，最終誘導(dǎo)骨形成和骨吸收失衡。

2.1.2 IL-1與骨質(zhì)疏松 IL-1是骨微環(huán)境中重要的細(xì)胞因子，可影響骨代謝和骨重建活動[15]。IL-1對骨吸收具有較強(qiáng)刺激作用，可直接或間接影響破骨細(xì)胞生成，增強(qiáng)骨吸收能力。Eghbali-fatourechi等[16]也證明絕經(jīng)后骨質(zhì)疏松患者因雌激素缺乏可導(dǎo)致單核細(xì)胞產(chǎn)生的IL-1水平升高。

2.1.3 IL-6與骨質(zhì)疏松 研究表明，痛風(fēng)性關(guān)節(jié)炎、類風(fēng)濕性關(guān)節(jié)炎、銀屑病性關(guān)節(jié)炎患者炎性細(xì)胞因子IL-6水平升高[17]。類風(fēng)濕性關(guān)節(jié)炎患者的骨質(zhì)疏松和炎癥存在明顯關(guān)系，即炎癥細(xì)胞因子可造成骨質(zhì)流失和骨轉(zhuǎn)換標(biāo)志物水平升高[18]。IL-6水平升高也可能導(dǎo)致TNF-α和IL-1水平升高，這些細(xì)胞因子可增強(qiáng)破骨細(xì)胞活化、分化與存活，增強(qiáng)核因子-κB受體活化因子配體(receptor activator for nuclear factor-κB ligand，RANKL)表達(dá)和抑制成骨細(xì)胞存活，從而促進(jìn)骨吸收[19]。

2.1.4 IL-17與骨質(zhì)疏松 IL-17是CD4+T淋巴細(xì)胞亞群Th17分泌的細(xì)胞因子。IL-17可加速骨質(zhì)流失，有利于破骨細(xì)胞產(chǎn)生和抑制成骨細(xì)胞分化[20]。IL-17可致RANKL表達(dá)上調(diào)，進(jìn)而促進(jìn)骨吸收增加。IL-17對于類風(fēng)濕性關(guān)節(jié)炎患者的骨破壞也至關(guān)重要[21]。IL-17還可刺激滑膜巨噬細(xì)胞，進(jìn)一步產(chǎn)生大量炎癥因子如 TNF-α、IL-1和IL-6等，這些炎癥因子可作用于破骨細(xì)胞前體，使其分化為破骨細(xì)胞，增加骨吸收，最終導(dǎo)致骨質(zhì)疏松發(fā)生[22]。

無論是炎癥因子還是炎癥細(xì)胞對骨代謝的影響主要是通過核因子-κB受體活化因子(receptor activator for nuclear factor-κB，RANK)/RANKL/護(hù)骨素(osteoprotegerin，OPG)途徑發(fā)揮作用[23]。

2.2 自噬學(xué)說與骨質(zhì)疏松

自噬(autophagy)是利用自身細(xì)胞器來源的膜結(jié)構(gòu)進(jìn)行組裝而吞噬胞質(zhì)內(nèi)的底物，如錯(cuò)誤折疊或衰老蛋白以及受損的細(xì)胞器、再與溶酶體結(jié)合將吞噬物降解并循環(huán)再利用的過程[24]。自噬是細(xì)胞的自我保護(hù)機(jī)制，對細(xì)胞穩(wěn)態(tài)的維持、細(xì)胞分化和增殖以及應(yīng)激發(fā)揮重要的作用[25]。Chen等[26]的研究表明，隨著人體衰老,骨細(xì)胞的自噬水平逐漸下降，使IL-1β等促炎因子分泌增加，加速骨丟失和影響骨代謝，進(jìn)而導(dǎo)致骨質(zhì)疏松[27]。Almeida等[28]證明在骨細(xì)胞中，自噬可防止骨質(zhì)流失，并減少隨著年齡增長骨細(xì)胞發(fā)生的凋亡。

2.2.1 自噬基因與骨質(zhì)疏松 有研究表明，敲除果蠅的自噬基因Atg7后，細(xì)胞內(nèi)有毒蛋白和細(xì)胞器聚集，最終引起細(xì)胞衰老和凋亡[2]。缺乏自噬基因Atg7的小鼠骨量低，易發(fā)生骨折，與破骨細(xì)胞和成骨細(xì)胞數(shù)量減少相關(guān)。自噬在維持細(xì)胞功能和穩(wěn)態(tài)過程中，也需要使細(xì)胞形態(tài)發(fā)生改變，這種改變包括長的細(xì)胞突起以及內(nèi)質(zhì)網(wǎng)和線粒體減少，抑制自噬可減少骨細(xì)胞突起的數(shù)量，導(dǎo)致骨細(xì)胞中線粒體和內(nèi)質(zhì)網(wǎng)滯留。成骨細(xì)胞自噬也有助于骨骼平衡以及骨形成相關(guān)的形態(tài)學(xué)變化[29]。自噬基因BECN-1沉默可致成骨細(xì)胞增殖和分化受抑制，細(xì)胞更易受氧化應(yīng)激損害，增加細(xì)胞凋亡，而過量表達(dá)則增強(qiáng)成骨細(xì)胞抗氧化能力，減少細(xì)胞凋亡[30]。

2.2.2 自噬相關(guān)性氧化應(yīng)激與骨質(zhì)疏松 隨著年齡增長，自噬被抑制，使得線粒體受損，進(jìn)而增加活性氧(reactive oxygen species，ROS)產(chǎn)生，進(jìn)一步導(dǎo)致氧化應(yīng)激[31]，反過來，氧化應(yīng)激又減少細(xì)胞自噬，這可能是骨質(zhì)疏松發(fā)生過程中骨質(zhì)流失的另一種解釋[32]。同時(shí)，衰老過程中細(xì)胞通過自噬而完成清除的能力逐漸下降，線粒體因功能失調(diào)致蛋白質(zhì)積聚，導(dǎo)致氧化應(yīng)激反應(yīng)和ROS增多，進(jìn)而引發(fā)炎癥反應(yīng)，刺激IL-1β和IL-18分泌，結(jié)果導(dǎo)致炎癥反應(yīng)增強(qiáng)和衰老加快[33]。

2.2.3 自噬相關(guān)藥物與骨質(zhì)疏松 雷帕霉素是一種自噬激活劑，可通過誘導(dǎo)細(xì)胞自噬保持細(xì)胞活力[34]，也可抑制破骨細(xì)胞的骨吸收活性[35]，從而調(diào)節(jié)骨重塑。雷帕霉素也拮抗二甲雙胍，可激活腺苷酸活化的蛋白激酶(AMP-activated protein kinase,AMPK)，AMPK是真核細(xì)胞能量調(diào)節(jié)器。肝激酶B1(liver kinase B1,LKB1)又名絲氨酸-蘇氨酸激酶(serine threonine kinase 1，STK1)，是一種功能性腫瘤抑制因子，LKB1可作用于AMPK的上游，抑癌基因TSC2、p53及p27作為LKB1-AMPK能量感應(yīng)通路的下游底物來調(diào)控自噬，還可通過直接磷酸化自噬相關(guān)基因(autophagy-related gene 1, Atg1)在哺乳動物細(xì)胞中的同源蛋白UNC-51樣激酶(UNC-51 like autophagy activating kinase 1,ULK1)引發(fā)自噬[36]，促進(jìn)成骨細(xì)胞礦化并抑制破骨細(xì)胞分化和成熟[37]。

川芎嗪是一種被認(rèn)可的中藥提取物，具有抗凋亡特性。研究結(jié)果表明，它通過促進(jìn)AMPK和哺乳動物雷帕霉素靶蛋白(mammalian target of rapamycin，mTOR)通路激活而引發(fā)自噬，防止骨髓間充質(zhì)干細(xì)胞(bone marrow mesenchymal stem cells，BMMSCs)凋亡[38]。BMMSCs是位于骨髓腔內(nèi)的具有多向分化和自我更新能力的一類中胚層來源的成體干細(xì)胞，在成人骨骼中主要分化為成骨細(xì)胞和脂肪細(xì)胞。隨著年齡增長，ROS水平升高，BMMSCs也表現(xiàn)一系列變化，如增殖能力下降、細(xì)胞凋亡水平升高、成骨能力下降[39]。激活自噬能降低BMMSCs的ROS水平，衰老BMMSCs的自噬水平較年輕細(xì)胞明顯降低，調(diào)節(jié)自噬可影響細(xì)胞周期和細(xì)胞凋亡[24]。

3 小結(jié)

綜上所述，在衰老過程中，自噬水平下降、ROS增多等多種機(jī)制介導(dǎo)促炎因子產(chǎn)生，進(jìn)而使骨質(zhì)疏松發(fā)生率升高。目前通過對RANKL/RANK/OPG途徑的研究，靶向RANKL的單克隆抗體狄諾塞麥已被開發(fā)，它是被批準(zhǔn)用于骨質(zhì)疏松癥患者的第一個(gè)單克隆抗體。狄諾塞麥可抑制破骨細(xì)胞生成，減少骨吸收和增加骨密度，同時(shí)顯著降低脊椎、非脊椎和髖部骨折風(fēng)險(xiǎn)。TNF-α抗體也已被證明能抑制過度的骨吸收[11]。自噬調(diào)節(jié)骨代謝是骨質(zhì)疏松研究的另一個(gè)里程碑，自噬抑制劑如氯喹(CQ)已在臨床被使用[40]。BECN-1可能是骨質(zhì)疏松抗氧化治療的有效靶點(diǎn)。但炎性衰老與骨質(zhì)疏松的相關(guān)機(jī)制研究目前仍較少，相信以后會有更多研究探索骨平衡的分子機(jī)制，對骨質(zhì)疏松提出新的治療方法。

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