磨损颗粒对关节假体周围组织的影响

周永飞 宋科官

. 综述 Review .

磨损颗粒对关节假体周围组织的影响

周永飞 宋科官

人工关节置换术是 20 世纪外科领域最重要的技术创新[1]，目前全髋关节置换已成为治疗髋关节严重创伤和骨病的金标准[2]。全球每年约有 150 万例患者进行人工关节置换术[3]。人工关节置换术为广大终末期骨关节病的患者解除病痛，并大大提高了生活质量，术后 10 年优良率达到 90% 甚至更高[4-5]。近年来，我国人工关节置换术发展迅猛，置换例数已接近每年 20 万例。根据世界卫生组织 (WTO ) 估测，到 2015 年我国骨关节疾病患者将达1.5 亿例，其中相当一部分需要接受关节置换术。可以预见，在经济持续快速发展的背景下，我国关节置换数量还会不断增加。然而随着置换例数增加和使用时间的延长，人工关节假体中晚期松动的问题日益突出[6]。关节材料由非生物材料构成，具有生物稳定性和机械载荷稳定性。此外关节界面摩擦，金属关节面与金属关节面，或者金属关节面与超高分子量聚乙烯 (UHMWPE )，产生磨损颗粒是不可避免的。人工关节磨损产生的颗粒有大小之分，微米大小的颗粒的生物学效应已经有了广泛的研究。纳米颗粒的生物学作用近年来受到关注[7-13]。新近假体翻修术回顾性研究发现聚乙烯 (PE、UHMWPE )、金属 (Ti、Co-Cr-Mo ) 和骨水泥 (TCP、PMMA ) 等关节假体磨损颗粒诱导的假体周围骨溶解是假体晚期松动、关节置换失败和二次翻修的主要原因[14-16]。磨损颗粒释放入关节腔后，它能使破骨细胞分化增多、骨吸收功能增强，同时抑制成骨细胞的分化和矿化作用，引起假体周围骨重建失衡而导致骨溶解和松动[17]。

一、磨损颗粒对巨噬细胞的影响

各类颗粒中，聚乙烯颗粒对巨噬细胞的趋化作用最明显，巨噬细胞不仅本身分泌因子作用于成骨细胞、破骨细胞，其本身可能也参与骨溶解过程。近年来，关节假体植入后全身和局部炎症及免疫状态的改变引起了广泛关注，尤其是 Toll 样受体 (toll-like receptors，TLRs ) 在假体局部免疫中的重要作用[18-20]。TLRs 主要表于巨噬细胞表面，参与机体的固有免疫应答，其配体为病原相关分子模式(pathogen associated molecular pattern，PAMP )。TLRs 结合PMAP 后，进一步激活下游的信号转导分子，对侵入的病原体迅速产生应答，发挥非特异性抗感染免疫应答。

在假体骨溶解中，磨损颗粒诱发巨噬细胞活性起着重要作用。大多数学者认为，有两种生物机制，其一，磨损颗粒引起巨噬细胞活化，释放前炎症因子，增强破骨细胞的活性，由活化的破骨细胞完成骨吸收；其二，磨损颗粒增强局部组织中的细胞浸润，浸润的单核细胞可以作为破骨细胞的前体，进一步分化为破骨细胞。体外培养发现，磨损颗粒可诱导巨噬细胞产生 IL-1，IL-6，TNF-α，PGE2 等破骨细胞激活因子，针状的羟基磷灰石颗粒 (HA )比球状 HA 的使单核细胞产生更多的 IL-6，TNF-α[21]，TNF-α 是引起假体周围骨溶解的主要因子。而巨噬细胞清除病原体以发挥固有免疫应答的机制包括：溶酶体降解细菌成分，分泌抗菌肽、防御素、乳铁蛋白、蛋白酶、组织蛋白酶，以及产生活性氮 (RNS ) 及活性氧 (reactive oxygen species，ROS )。在这些机制中，NADPH 氧化酶 (NADPH oxidase，NOX ) 活化导致 ROS 的产生出现最早，且最为重要[22]。巨噬细胞摄取病原体等抗原性异物后，可通过 ROS介导的氧依赖性杀菌途径杀伤病原体，发挥固有免疫效应。巨噬细胞中 ROS 的主要来源包括 NADPH 氧化途径和线粒体途径[23]。

二、磨损颗粒对成骨细胞的影响

已有研究发现，假体磨损产生的颗粒不仅在假体周围诱发明显的破骨细胞性骨溶解，而且还可抑制假体周围成骨细胞的功能。将直径＜1 μm UHMWPE 颗粒与 MG-63 成骨样细胞共同培养发现，UHMWPE 颗粒可抑制成骨细胞的增殖、分化，减少转化生长因子 (TGF ) -β 及骨基质的合成。将钛磨损颗粒与成骨细胞共同培养发现，钛磨损颗粒可抑制成骨细胞功能，降低纤维连接素、I 型胶原等基因的表达水平。将不同的颗粒分别于成骨细胞及巨噬细胞共同培养发现，假体磨损颗粒可以明显减少与成骨相关的碱性磷酸酶、骨钙素、骨连接素的表达[24]；将不同大小的钛颗粒与成骨细胞共同培养发现，直径 1.5～4.0 μm 的钛颗粒可明显抑制成骨细胞增殖及功能[25]。

成骨细胞直接暴露于磨损颗粒使成骨细胞黏附到骨基质上的能力下降，而成骨细胞又具有很强的锚定依赖性，不能正常黏附使成骨细胞合成基质的转录与翻译能力下降，新骨形成受抑制而扰乱假体周围的生理性骨转换，人工关节假体周围骨就不能得到良好的整合。骨组织正常结构功能的维持是骨形成代谢和骨吸收代谢动态平衡的结果。假体周围组织细胞吞噬磨损颗粒后。一方面，这些细胞分泌一系列的骨性因子 (IL-6，IL-1，TNF-α，PEG2等 ) 促进破骨细胞前体细胞分化形成成熟的破骨细胞，进而引起邻近骨基质吸收增强，骨量丢失。另一方面，磨损颗粒也可引起成骨细胞本身的功能受到抑制，其增殖能力减弱，胞外基质分泌减少，进而引起邻近骨形成减少。可见引起假体周围骨量丢失的原因，除了破骨细胞性骨吸收外，还可能与骨形成抑制有关。成骨细胞不能维持正常的骨形成代谢，没有足够基质弥补假体周围丢失的骨量，最终导致假体松动。

三、磨损颗粒对破骨细胞的影响

假体周围磨损颗粒激活循环血单核细胞并将其募集至假体周围，破骨细胞前体细胞也聚集在异物单核细胞群周围。破骨细胞是专业的溶骨性细胞，其分化和骨溶解是维护健康的骨骼结构的关键。研究表明人工假体的组件磨损导致的磨损颗粒在骨溶解中发挥重要作用，植入物和骨周围生成界膜组织，界膜组织内含有大量的巨噬细胞、纤维细胞、异物巨细胞和大量的磨损颗粒。颗粒激活和刺激巨噬细胞和其它炎症细胞分泌炎症细胞因子，如 IL-1、TNF、IL-6、PGE2 等，这些因子同时促进破骨细胞形成和假体周围的骨溶解，但是现在的研究表明在颗粒介导的破骨细胞分化成熟过程中，这些因子不是最终的通路，RANKL-RANK-OPG 系统通道是调节骨代谢的最终通路。Sabokar 等[26]研究发现，通过促进 OPG 生成以阻断 RANKL 诱导破骨细胞形成途径时，在磨损颗粒较少的情况下效果较为明显，但当假体周围大量磨损颗粒聚集时，细胞因子巨噬细胞集落刺激因子 (colony stimulating factor，M-CSF ) 和肿瘤坏死因子 (tumor necrosis factor，TNF ) -α 仍足以诱导破骨细胞的分化，TNF-α 和 IL-1 之间也可以协同促进骨溶解，提示当假体周围磨损颗粒较多的情况下，M-CSF、TNF-α 等炎性细胞因子也可能不通过OPG / RANKL / RANK / OPGL 系统直接诱导骨溶解。研究表明[27]TNF-α 在破骨细胞前体聚集和分化为成熟破骨细胞过程中发挥了极其重要的作用，是整个骨溶解反应的上游控制基因，在假体周围骨溶解的生物学现象中具有多重作用。另有实验[28]通过在骨吸收刺激因子存在情况下，将正常小鼠的颅骨细胞与骨髓细胞共同培养可生成破骨细胞，但是如果 M-CSF 缺陷小鼠的颅骨细胞与骨髓细胞共同培养，则不会产生破骨细胞前体细胞和破骨细胞，只有加入外源性 M-CSF 才行，这说明 M-CSF 的存在在破骨细胞的生成过程中发挥了极其重要的作用。M-CSF、TNF-α能募集并激活破骨细胞，进而引起假体周围骨吸收、骨溶解，最终导致假体松动；假体松动后又加重磨损，产生更多微粒，形成恶性循环。

四、磨损颗粒对骨髓间充质干细胞的影响

磨损颗粒可以进入骨髓腔，会作用于骨髓间充质干细胞 (MSCs )，MSCs 是骨组织中成骨细胞、脂肪细胞等共同的前体细胞，在不同诱导条件下，MSCs 可分别向成骨细胞和脂肪细胞分化，MSCs 在体外培养时具有成骨分化的能力，特异表达碱性磷酸酶、骨钙素、I 型胶原以及细胞外基质的矿化。钛颗粒抑制 MSCs 的成骨表型的表达，抑制 BSP 基因表达，细胞增殖，基质矿化及 I 型胶原的产生[29]，能直接和间接诱导 MSCs 的凋亡[30]，MSCs 不能完全表达成骨表型，增殖分化能力受到抑制，从质上影响了成骨细胞来源骨髓祖细胞的数量和质量，这是关节周围骨量减少的原因之一。

五、磨损颗粒对成纤维细胞的影响

磨损颗粒作用于成纤维细胞，增加纤维化过程，促进假体周围纤维界膜的形成，成纤维细胞受到刺激，能够释放基质金属蛋白酶 (matrix metalloproteinases，MMPs )。MMPS 是结构中含有 ZN2+和 Ca2+的蛋白水解酶家族，目前已至少发现 20 个成员，根据其作用底物不同至少可分为间质胶原酶、明胶酶、基质溶解素、膜型金属蛋白酶四大类[31]。细胞外基质金属蛋白酶诱导剂 (extracellular matrix metalloproteinase inducer，EMMPRIN )，属于免疫球蛋白超家族 (IgSF ) 的跨膜糖蛋白，是 MMPs 最主要的上游调节因子，可刺激多种细胞表达 MMPs[32]。目前有研究表明胞膜或可溶性的 EMMPRIN 分子通过形成同源或异源低聚体激活细胞信号转导通路[33-34]，EMMPRIN 在恶性肿瘤[35-36]、动脉粥样硬化[37]、心肌缺血性疾病[32]等领域被广泛研究。恶性肿瘤细胞高表达 EMMPRIN ，诱导肿瘤间质细胞大量表达 MMPs，对肿瘤骨破坏、转移过程的研究已证实[38-39]。MMPs 通过降解类骨质层和细胞外基质，解除类骨质层对破骨细胞与骨的黏附，协助破骨细胞迁移至骨吸收部位，最终导致和促进假体无菌性松动的产生[40]。研究表明钛颗粒还可以通过 Cox-2 通路刺激成纤维细胞产生 IL-6，PEG2[41]。

六、磨损颗粒对 RANKL / RANK / OPG 系统的影响

成骨细胞、骨髓基质细胞表达两个破骨细胞分化所必须的分子：一个是巨噬细胞集落刺激因子 (M-CSF )，另一个是 NF-KB 受体激活剂 (RANK ) 的配体 (RANKL )。它们结合于破骨细胞前体细胞 (单核、巨噬细胞系统 ) 上的M-CSF 受体 c-fms 和 RANK，发出使巨噬细胞变为破骨细胞的信号，使其存活并增殖。

RANKL / RANK / OPG 系统是近年来破骨细胞研究领域中的一个重要发现。RANK 是位于破骨细胞及其前体细胞表面的 I 型跨膜受体蛋白，与 RANKL 结合后可激活前体细胞内的信号转导系统，使前体细胞分化为成熟的破骨细胞，成骨细胞及骨髓基质细胞分泌骨保护素(OPG )，与 RANK 竞争性结合，阻止 RANK 与 RANKL 之间的结合。成骨细胞及骨髓基质细胞分泌在生理状态下表达一定量的 RANKL，促进破骨细胞的分化和骨吸收，同时又分泌相应数量的 OPG，防止骨的过度吸收，因此RANKL / OPG 的比例平衡是维持局部骨代谢平衡的关键。RANK 激活后可使分化中的破骨细胞表达特异性基因，如c-fos，c-src，CATK，TRAP，CTR 等。还可使成熟的破骨细胞执行骨吸收功能并维持破骨细胞的存活。松动的人工关节的周围组织内 RANKL / RANK / OPG 系统的表达呈失衡状态。在松动的人工关节的周围界膜内可以检测到 RANKL，RANK，OPG 的 mRNA 和蛋白质的表达[42]。界膜内 RANKL / RANK 的含量明显高于骨性关节炎 (OA )滑膜内的含量，而 OPG 的含量与正常及 OA 滑膜内的含量相比无显著性差异[43-44]。且 OPG mRNA 仅在界膜内的血管内皮细胞中少量表达。这说明松动的人工关节周围的RANKL / OPG 比例失衡。

松动的人工关节周围出现骨溶解的部位一般都有大量含磨损颗粒的多核巨细胞存在，而原位杂交显示 RANKL / RANK mRNA 也主要有这些细胞表达，说明 RANKL / RANK 增多与细胞颗粒吞噬有关。UHMWPE 等颗粒与外周单核细胞共同培养后可刺激细胞表达较高水平 RANKL / RANK[41]，进一步证实 RANKL / RANK 的增多是颗粒诱导的结果。人工关节周围组织内的 RANKL / OPG 比例失衡将导致局部骨代谢不平衡和骨溶解。

颗粒可以诱导前体细胞分化为成熟的破骨细胞，体外实验发现钛颗粒增强成骨细胞 RANKL 和 CSF-1 基因表达，促进破骨细胞的形成[45]。聚乙烯颗粒和成骨细胞的条件培养液促进单核细胞分化成破骨细胞[46]，生成的破骨细胞的 c-src 基因表达增强[47]。PMMA 刺激 OA 患者成骨细胞产生 M-CSF，sRANKL 增多，OPG 减少，sRANKL / OPG 增高[48]。

七、磨损颗粒引起假体周围生物学反应的结果

人工关节面临的难题之一是使用寿命问题，影响使用寿命并导致假体失败主要原因是假体松动。而假体松动的发生、发展主要为假体活动产生的各种磨损颗粒介导假体周围骨溶解所致[49]。假体周围磨损颗粒激活循环血单核细胞并将其募集至假体周围，破骨细胞前体细胞也聚集在异物单核细胞群周围。骨性关节炎患者血清中炎症介质在关节置换前后不同，炎症原因不同循环血单核细胞接触不同的炎症信号，循环血单核细胞在血液循环过程中已经开始募集分化和转化。关节假体磨损产生的颗粒刺激假体周围吞噬细胞，成纤维细胞等产生多种细胞因子诱导破骨细胞生成及骨吸收。磨损颗粒也影响骨髓间充质干细胞向成骨细胞的分化和成骨细胞的功能，抑制骨形成，结果引起假体周围骨溶解，最终形成假体松动。所以假体失效的发生、发展主要为假体活动产生的各种磨损颗粒介导假体周围骨溶解所致[49-50]。

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(本文编辑：李贵存 )

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

国家自然科学基金 (81272016 )

150001 哈尔滨医科大学第一附属医院骨三科

宋科官，Email: songkeguan@sohu.com

2013-10-23 )