周永飛 宋科官

. 綜述 Review .

磨損顆粒對關(guān)節(jié)假體周圍組織的影響

周永飛 宋科官

人工關(guān)節(jié)置換術(shù)是 20 世紀(jì)外科領(lǐng)域最重要的技術(shù)創(chuàng)新[1]，目前全髖關(guān)節(jié)置換已成為治療髖關(guān)節(jié)嚴(yán)重創(chuàng)傷和骨病的金標(biāo)準(zhǔn)[2]。全球每年約有 150 萬例患者進(jìn)行人工關(guān)節(jié)置換術(shù)[3]。人工關(guān)節(jié)置換術(shù)為廣大終末期骨關(guān)節(jié)病的患者解除病痛，并大大提高了生活質(zhì)量，術(shù)后 10 年優(yōu)良率達(dá)到 90% 甚至更高[4-5]。近年來，我國人工關(guān)節(jié)置換術(shù)發(fā)展迅猛，置換例數(shù)已接近每年 20 萬例。根據(jù)世界衛(wèi)生組織 (WTO ) 估測，到 2015 年我國骨關(guān)節(jié)疾病患者將達(dá)1.5 億例，其中相當(dāng)一部分需要接受關(guān)節(jié)置換術(shù)?？梢灶A(yù)見，在經(jīng)濟(jì)持續(xù)快速發(fā)展的背景下，我國關(guān)節(jié)置換數(shù)量還會不斷增加。然而隨著置換例數(shù)增加和使用時間的延長，人工關(guān)節(jié)假體中晚期松動的問題日益突出[6]。關(guān)節(jié)材料由非生物材料構(gòu)成，具有生物穩(wěn)定性和機(jī)械載荷穩(wěn)定性。此外關(guān)節(jié)界面摩擦，金屬關(guān)節(jié)面與金屬關(guān)節(jié)面，或者金屬關(guān)節(jié)面與超高分子量聚乙烯 (UHMWPE )，產(chǎn)生磨損顆粒是不可避免的。人工關(guān)節(jié)磨損產(chǎn)生的顆粒有大小之分，微米大小的顆粒的生物學(xué)效應(yīng)已經(jīng)有了廣泛的研究。納米顆粒的生物學(xué)作用近年來受到關(guān)注[7-13]。新近假體翻修術(shù)回顧性研究發(fā)現(xiàn)聚乙烯 (PE、UHMWPE )、金屬 (Ti、Co-Cr-Mo ) 和骨水泥 (TCP、PMMA ) 等關(guān)節(jié)假體磨損顆粒誘導(dǎo)的假體周圍骨溶解是假體晚期松動、關(guān)節(jié)置換失敗和二次翻修的主要原因[14-16]。磨損顆粒釋放入關(guān)節(jié)腔后，它能使破骨細(xì)胞分化增多、骨吸收功能增強(qiáng)，同時抑制成骨細(xì)胞的分化和礦化作用，引起假體周圍骨重建失衡而導(dǎo)致骨溶解和松動[17]。

一、磨損顆粒對巨噬細(xì)胞的影響

各類顆粒中，聚乙烯顆粒對巨噬細(xì)胞的趨化作用最明顯，巨噬細(xì)胞不僅本身分泌因子作用于成骨細(xì)胞、破骨細(xì)胞，其本身可能也參與骨溶解過程。近年來，關(guān)節(jié)假體植入后全身和局部炎癥及免疫狀態(tài)的改變引起了廣泛關(guān)注，尤其是 Toll 樣受體 (toll-like receptors，TLRs ) 在假體局部免疫中的重要作用[18-20]。TLRs 主要表于巨噬細(xì)胞表面，參與機(jī)體的固有免疫應(yīng)答，其配體為病原相關(guān)分子模式(pathogen associated molecular pattern，PAMP )。TLRs 結(jié)合PMAP 后，進(jìn)一步激活下游的信號轉(zhuǎn)導(dǎo)分子，對侵入的病原體迅速產(chǎn)生應(yīng)答，發(fā)揮非特異性抗感染免疫應(yīng)答。

在假體骨溶解中，磨損顆粒誘發(fā)巨噬細(xì)胞活性起著重要作用。大多數(shù)學(xué)者認(rèn)為，有兩種生物機(jī)制，其一，磨損顆粒引起巨噬細(xì)胞活化，釋放前炎癥因子，增強(qiáng)破骨細(xì)胞的活性，由活化的破骨細(xì)胞完成骨吸收；其二，磨損顆粒增強(qiáng)局部組織中的細(xì)胞浸潤，浸潤的單核細(xì)胞可以作為破骨細(xì)胞的前體，進(jìn)一步分化為破骨細(xì)胞。體外培養(yǎng)發(fā)現(xiàn)，磨損顆?？烧T導(dǎo)巨噬細(xì)胞產(chǎn)生 IL-1，IL-6，TNF-α，PGE2 等破骨細(xì)胞激活因子，針狀的羥基磷灰石顆粒 (HA )比球狀 HA 的使單核細(xì)胞產(chǎn)生更多的 IL-6，TNF-α[21]，TNF-α 是引起假體周圍骨溶解的主要因子。而巨噬細(xì)胞清除病原體以發(fā)揮固有免疫應(yīng)答的機(jī)制包括：溶酶體降解細(xì)菌成分，分泌抗菌肽、防御素、乳鐵蛋白、蛋白酶、組織蛋白酶，以及產(chǎn)生活性氮 (RNS ) 及活性氧 (reactive oxygen species，ROS )。在這些機(jī)制中，NADPH 氧化酶 (NADPH oxidase，NOX ) 活化導(dǎo)致 ROS 的產(chǎn)生出現(xiàn)最早，且最為重要[22]。巨噬細(xì)胞攝取病原體等抗原性異物后，可通過 ROS介導(dǎo)的氧依賴性殺菌途徑殺傷病原體，發(fā)揮固有免疫效應(yīng)。巨噬細(xì)胞中 ROS 的主要來源包括 NADPH 氧化途徑和線粒體途徑[23]。

二、磨損顆粒對成骨細(xì)胞的影響

已有研究發(fā)現(xiàn)，假體磨損產(chǎn)生的顆粒不僅在假體周圍誘發(fā)明顯的破骨細(xì)胞性骨溶解，而且還可抑制假體周圍成骨細(xì)胞的功能。將直徑＜1 μm UHMWPE 顆粒與 MG-63 成骨樣細(xì)胞共同培養(yǎng)發(fā)現(xiàn)，UHMWPE 顆?？梢种瞥晒羌?xì)胞的增殖、分化，減少轉(zhuǎn)化生長因子 (TGF ) -β 及骨基質(zhì)的合成。將鈦磨損顆粒與成骨細(xì)胞共同培養(yǎng)發(fā)現(xiàn)，鈦磨損顆?？梢种瞥晒羌?xì)胞功能，降低纖維連接素、I 型膠原等基因的表達(dá)水平。將不同的顆粒分別于成骨細(xì)胞及巨噬細(xì)胞共同培養(yǎng)發(fā)現(xiàn)，假體磨損顆?？梢悦黠@減少與成骨相關(guān)的堿性磷酸酶、骨鈣素、骨連接素的表達(dá)[24]；將不同大小的鈦顆粒與成骨細(xì)胞共同培養(yǎng)發(fā)現(xiàn)，直徑 1.5～4.0 μm 的鈦顆?？擅黠@抑制成骨細(xì)胞增殖及功能[25]。

成骨細(xì)胞直接暴露于磨損顆粒使成骨細(xì)胞黏附到骨基質(zhì)上的能力下降，而成骨細(xì)胞又具有很強(qiáng)的錨定依賴性，不能正常黏附使成骨細(xì)胞合成基質(zhì)的轉(zhuǎn)錄與翻譯能力下降，新骨形成受抑制而擾亂假體周圍的生理性骨轉(zhuǎn)換，人工關(guān)節(jié)假體周圍骨就不能得到良好的整合。骨組織正常結(jié)構(gòu)功能的維持是骨形成代謝和骨吸收代謝動態(tài)平衡的結(jié)果。假體周圍組織細(xì)胞吞噬磨損顆粒后。一方面，這些細(xì)胞分泌一系列的骨性因子 (IL-6，IL-1，TNF-α，PEG2等 ) 促進(jìn)破骨細(xì)胞前體細(xì)胞分化形成成熟的破骨細(xì)胞，進(jìn)而引起鄰近骨基質(zhì)吸收增強(qiáng)，骨量丟失。另一方面，磨損顆粒也可引起成骨細(xì)胞本身的功能受到抑制，其增殖能力減弱，胞外基質(zhì)分泌減少，進(jìn)而引起鄰近骨形成減少。可見引起假體周圍骨量丟失的原因，除了破骨細(xì)胞性骨吸收外，還可能與骨形成抑制有關(guān)。成骨細(xì)胞不能維持正常的骨形成代謝，沒有足夠基質(zhì)彌補(bǔ)假體周圍丟失的骨量，最終導(dǎo)致假體松動。

三、磨損顆粒對破骨細(xì)胞的影響

假體周圍磨損顆粒激活循環(huán)血單核細(xì)胞并將其募集至假體周圍，破骨細(xì)胞前體細(xì)胞也聚集在異物單核細(xì)胞群周圍。破骨細(xì)胞是專業(yè)的溶骨性細(xì)胞，其分化和骨溶解是維護(hù)健康的骨骼結(jié)構(gòu)的關(guān)鍵。研究表明人工假體的組件磨損導(dǎo)致的磨損顆粒在骨溶解中發(fā)揮重要作用，植入物和骨周圍生成界膜組織，界膜組織內(nèi)含有大量的巨噬細(xì)胞、纖維細(xì)胞、異物巨細(xì)胞和大量的磨損顆粒。顆粒激活和刺激巨噬細(xì)胞和其它炎癥細(xì)胞分泌炎癥細(xì)胞因子，如 IL-1、TNF、IL-6、PGE2 等，這些因子同時促進(jìn)破骨細(xì)胞形成和假體周圍的骨溶解，但是現(xiàn)在的研究表明在顆粒介導(dǎo)的破骨細(xì)胞分化成熟過程中，這些因子不是最終的通路，RANKL-RANK-OPG 系統(tǒng)通道是調(diào)節(jié)骨代謝的最終通路。Sabokar 等[26]研究發(fā)現(xiàn)，通過促進(jìn) OPG 生成以阻斷 RANKL 誘導(dǎo)破骨細(xì)胞形成途徑時，在磨損顆粒較少的情況下效果較為明顯，但當(dāng)假體周圍大量磨損顆粒聚集時，細(xì)胞因子巨噬細(xì)胞集落刺激因子 (colony stimulating factor，M-CSF ) 和腫瘤壞死因子 (tumor necrosis factor，TNF ) -α 仍足以誘導(dǎo)破骨細(xì)胞的分化，TNF-α 和 IL-1 之間也可以協(xié)同促進(jìn)骨溶解，提示當(dāng)假體周圍磨損顆粒較多的情況下，M-CSF、TNF-α 等炎性細(xì)胞因子也可能不通過OPG / RANKL / RANK / OPGL 系統(tǒng)直接誘導(dǎo)骨溶解。研究表明[27]TNF-α 在破骨細(xì)胞前體聚集和分化為成熟破骨細(xì)胞過程中發(fā)揮了極其重要的作用，是整個骨溶解反應(yīng)的上游控制基因，在假體周圍骨溶解的生物學(xué)現(xiàn)象中具有多重作用。另有實(shí)驗(yàn)[28]通過在骨吸收刺激因子存在情況下，將正常小鼠的顱骨細(xì)胞與骨髓細(xì)胞共同培養(yǎng)可生成破骨細(xì)胞，但是如果 M-CSF 缺陷小鼠的顱骨細(xì)胞與骨髓細(xì)胞共同培養(yǎng)，則不會產(chǎn)生破骨細(xì)胞前體細(xì)胞和破骨細(xì)胞，只有加入外源性 M-CSF 才行，這說明 M-CSF 的存在在破骨細(xì)胞的生成過程中發(fā)揮了極其重要的作用。M-CSF、TNF-α能募集并激活破骨細(xì)胞，進(jìn)而引起假體周圍骨吸收、骨溶解，最終導(dǎo)致假體松動；假體松動后又加重磨損，產(chǎn)生更多微粒，形成惡性循環(huán)。

四、磨損顆粒對骨髓間充質(zhì)干細(xì)胞的影響

磨損顆粒可以進(jìn)入骨髓腔，會作用于骨髓間充質(zhì)干細(xì)胞 (MSCs )，MSCs 是骨組織中成骨細(xì)胞、脂肪細(xì)胞等共同的前體細(xì)胞，在不同誘導(dǎo)條件下，MSCs 可分別向成骨細(xì)胞和脂肪細(xì)胞分化，MSCs 在體外培養(yǎng)時具有成骨分化的能力，特異表達(dá)堿性磷酸酶、骨鈣素、I 型膠原以及細(xì)胞外基質(zhì)的礦化。鈦顆粒抑制 MSCs 的成骨表型的表達(dá)，抑制 BSP 基因表達(dá)，細(xì)胞增殖，基質(zhì)礦化及 I 型膠原的產(chǎn)生[29]，能直接和間接誘導(dǎo) MSCs 的凋亡[30]，MSCs 不能完全表達(dá)成骨表型，增殖分化能力受到抑制，從質(zhì)上影響了成骨細(xì)胞來源骨髓祖細(xì)胞的數(shù)量和質(zhì)量，這是關(guān)節(jié)周圍骨量減少的原因之一。

五、磨損顆粒對成纖維細(xì)胞的影響

磨損顆粒作用于成纖維細(xì)胞，增加纖維化過程，促進(jìn)假體周圍纖維界膜的形成，成纖維細(xì)胞受到刺激，能夠釋放基質(zhì)金屬蛋白酶 (matrix metalloproteinases，MMPs )。MMPS 是結(jié)構(gòu)中含有 ZN2+和 Ca2+的蛋白水解酶家族，目前已至少發(fā)現(xiàn) 20 個成員，根據(jù)其作用底物不同至少可分為間質(zhì)膠原酶、明膠酶、基質(zhì)溶解素、膜型金屬蛋白酶四大類[31]。細(xì)胞外基質(zhì)金屬蛋白酶誘導(dǎo)劑 (extracellular matrix metalloproteinase inducer，EMMPRIN )，屬于免疫球蛋白超家族 (IgSF ) 的跨膜糖蛋白，是 MMPs 最主要的上游調(diào)節(jié)因子，可刺激多種細(xì)胞表達(dá) MMPs[32]。目前有研究表明胞膜或可溶性的 EMMPRIN 分子通過形成同源或異源低聚體激活細(xì)胞信號轉(zhuǎn)導(dǎo)通路[33-34]，EMMPRIN 在惡性腫瘤[35-36]、動脈粥樣硬化[37]、心肌缺血性疾病[32]等領(lǐng)域被廣泛研究。惡性腫瘤細(xì)胞高表達(dá) EMMPRIN ，誘導(dǎo)腫瘤間質(zhì)細(xì)胞大量表達(dá) MMPs，對腫瘤骨破壞、轉(zhuǎn)移過程的研究已證實(shí)[38-39]。MMPs 通過降解類骨質(zhì)層和細(xì)胞外基質(zhì)，解除類骨質(zhì)層對破骨細(xì)胞與骨的黏附，協(xié)助破骨細(xì)胞遷移至骨吸收部位，最終導(dǎo)致和促進(jìn)假體無菌性松動的產(chǎn)生[40]。研究表明鈦顆粒還可以通過 Cox-2 通路刺激成纖維細(xì)胞產(chǎn)生 IL-6，PEG2[41]。

六、磨損顆粒對 RANKL / RANK / OPG 系統(tǒng)的影響

成骨細(xì)胞、骨髓基質(zhì)細(xì)胞表達(dá)兩個破骨細(xì)胞分化所必須的分子：一個是巨噬細(xì)胞集落刺激因子 (M-CSF )，另一個是 NF-KB 受體激活劑 (RANK ) 的配體 (RANKL )。它們結(jié)合于破骨細(xì)胞前體細(xì)胞 (單核、巨噬細(xì)胞系統(tǒng) ) 上的M-CSF 受體 c-fms 和 RANK，發(fā)出使巨噬細(xì)胞變?yōu)槠乒羌?xì)胞的信號，使其存活并增殖。

RANKL / RANK / OPG 系統(tǒng)是近年來破骨細(xì)胞研究領(lǐng)域中的一個重要發(fā)現(xiàn)。RANK 是位于破骨細(xì)胞及其前體細(xì)胞表面的 I 型跨膜受體蛋白，與 RANKL 結(jié)合后可激活前體細(xì)胞內(nèi)的信號轉(zhuǎn)導(dǎo)系統(tǒng)，使前體細(xì)胞分化為成熟的破骨細(xì)胞，成骨細(xì)胞及骨髓基質(zhì)細(xì)胞分泌骨保護(hù)素(OPG )，與 RANK 競爭性結(jié)合，阻止 RANK 與 RANKL 之間的結(jié)合。成骨細(xì)胞及骨髓基質(zhì)細(xì)胞分泌在生理狀態(tài)下表達(dá)一定量的 RANKL，促進(jìn)破骨細(xì)胞的分化和骨吸收，同時又分泌相應(yīng)數(shù)量的 OPG，防止骨的過度吸收，因此RANKL / OPG 的比例平衡是維持局部骨代謝平衡的關(guān)鍵。RANK 激活后可使分化中的破骨細(xì)胞表達(dá)特異性基因，如c-fos，c-src，CATK，TRAP，CTR 等。還可使成熟的破骨細(xì)胞執(zhí)行骨吸收功能并維持破骨細(xì)胞的存活。松動的人工關(guān)節(jié)的周圍組織內(nèi) RANKL / RANK / OPG 系統(tǒng)的表達(dá)呈失衡狀態(tài)。在松動的人工關(guān)節(jié)的周圍界膜內(nèi)可以檢測到 RANKL，RANK，OPG 的 mRNA 和蛋白質(zhì)的表達(dá)[42]。界膜內(nèi) RANKL / RANK 的含量明顯高于骨性關(guān)節(jié)炎 (OA )滑膜內(nèi)的含量，而 OPG 的含量與正常及 OA 滑膜內(nèi)的含量相比無顯著性差異[43-44]。且 OPG mRNA 僅在界膜內(nèi)的血管內(nèi)皮細(xì)胞中少量表達(dá)。這說明松動的人工關(guān)節(jié)周圍的RANKL / OPG 比例失衡。

松動的人工關(guān)節(jié)周圍出現(xiàn)骨溶解的部位一般都有大量含磨損顆粒的多核巨細(xì)胞存在，而原位雜交顯示 RANKL / RANK mRNA 也主要有這些細(xì)胞表達(dá)，說明 RANKL / RANK 增多與細(xì)胞顆粒吞噬有關(guān)。UHMWPE 等顆粒與外周單核細(xì)胞共同培養(yǎng)后可刺激細(xì)胞表達(dá)較高水平 RANKL / RANK[41]，進(jìn)一步證實(shí) RANKL / RANK 的增多是顆粒誘導(dǎo)的結(jié)果。人工關(guān)節(jié)周圍組織內(nèi)的 RANKL / OPG 比例失衡將導(dǎo)致局部骨代謝不平衡和骨溶解。

顆粒可以誘導(dǎo)前體細(xì)胞分化為成熟的破骨細(xì)胞，體外實(shí)驗(yàn)發(fā)現(xiàn)鈦顆粒增強(qiáng)成骨細(xì)胞 RANKL 和 CSF-1 基因表達(dá)，促進(jìn)破骨細(xì)胞的形成[45]。聚乙烯顆粒和成骨細(xì)胞的條件培養(yǎng)液促進(jìn)單核細(xì)胞分化成破骨細(xì)胞[46]，生成的破骨細(xì)胞的 c-src 基因表達(dá)增強(qiáng)[47]。PMMA 刺激 OA 患者成骨細(xì)胞產(chǎn)生 M-CSF，sRANKL 增多，OPG 減少，sRANKL / OPG 增高[48]。

七、磨損顆粒引起假體周圍生物學(xué)反應(yīng)的結(jié)果

人工關(guān)節(jié)面臨的難題之一是使用壽命問題，影響使用壽命并導(dǎo)致假體失敗主要原因是假體松動。而假體松動的發(fā)生、發(fā)展主要為假體活動產(chǎn)生的各種磨損顆粒介導(dǎo)假體周圍骨溶解所致[49]。假體周圍磨損顆粒激活循環(huán)血單核細(xì)胞并將其募集至假體周圍，破骨細(xì)胞前體細(xì)胞也聚集在異物單核細(xì)胞群周圍。骨性關(guān)節(jié)炎患者血清中炎癥介質(zhì)在關(guān)節(jié)置換前后不同，炎癥原因不同循環(huán)血單核細(xì)胞接觸不同的炎癥信號，循環(huán)血單核細(xì)胞在血液循環(huán)過程中已經(jīng)開始募集分化和轉(zhuǎn)化。關(guān)節(jié)假體磨損產(chǎn)生的顆粒刺激假體周圍吞噬細(xì)胞，成纖維細(xì)胞等產(chǎn)生多種細(xì)胞因子誘導(dǎo)破骨細(xì)胞生成及骨吸收。磨損顆粒也影響骨髓間充質(zhì)干細(xì)胞向成骨細(xì)胞的分化和成骨細(xì)胞的功能，抑制骨形成，結(jié)果引起假體周圍骨溶解，最終形成假體松動。所以假體失效的發(fā)生、發(fā)展主要為假體活動產(chǎn)生的各種磨損顆粒介導(dǎo)假體周圍骨溶解所致[49-50]。

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(本文編輯：李貴存 )

Effects of wear particles on periprosthetic tissues

ZHOU Yong-fei, SONG Ke-guan. Department of Orthopaedics, the frst affliated Hospital of Harbin Medical University, Harbin, Heilongjiang, 150001, PRC

Artifcial joint replacement is the most important technical innovation in the feld of surgery in the 20th century, and at present total hip replacement has become the gold standard in the treatment of severe hip joint trauma and bone diseases. However, with the increase in the number of cases of replacement and the extension of the usage time, the problem of advanced loosening of artifcial prostheses has become more and more prominent. Wear particle-mediated osteolysis is a major cause of aseptic loosening of artifcial prostheses, but the mechanism is unclear. Circulating blood mononuclear cells can be activated by wear particles, and also be recruited around the prostheses. While the differentiation and transformation of the mononuclear cells have begun in the circulation process. At the same time, osteoclast precursor cells will also gather around the foreign body monocytes. The periprosthetic phagocytic cells are stimulated by wear particles of the joint prostheses, and the osteoclast formation and bone resorption are induced by various cytokines that are produced by fbroblast cells. Wear particles not only exist around the prostheses, but also could enter the marrow cavity and further affect the differentiation of bone marrow mesenchymal stem cells into osteoblasts and the function of osteoblasts. The osteoclast differentiation will be increased and the bone resorption will be enhanced. In the meanwhile, the osteoblast differentiation and mineralization and the bone formation will be inhibited. Wear particles may be swallowed by many cells in the periprosthetic tissues. Finally, a series of biological reactions of the periprosthetic tissues will occur, which are induced by wear particles, with the results of periprosthetic osteolysis. So the occurrence and development of prosthetic failure are mainly caused by the periprosthetic osteolysis that is mediated by various wear particles produced in the prosthetic activities. In the paper, the recent research progress of biological changes of the periprosthetic tissues caused by wear particles are reviewed.

Joint prosthesis; Arthroplasty; Osteoblast; Osteoclast

10.3969/j.issn.2095-252X.2014.06.011

R687.4

國家自然科學(xué)基金 (81272016 )

150001 哈爾濱醫(yī)科大學(xué)第一附屬醫(yī)院骨三科

宋科官，Email: songkeguan@sohu.com

2013-10-23 )