姜黄素保护关节软骨抑制骨关节炎的作用和机制

doi:10.3969/j.issn.2095-4344.2015.02.022

摘要/Abstract

摘要：

背景：研究证实姜黄素具有抗炎抗氧化抗凋亡作用。
目的：综合阐述姜黄素保护关节软骨及抑制骨关节炎等方面的机制和作用。
方法：作者检索 1973至2014 年 PubMed、Embase、Elseveir数据库文献。检索词为“Osteoarthritis，curcumin，chondrocyte，articular cartilage”，按照事先制定的标准逐一评价纳入研究的文献，提取有效资料进行综合分析。
结果与结论：姜黄素可通过抑制氧化作用酶，清除自由基，完成抗氧化作用，从而防止骨关节炎的发生和进展。姜黄素抑制基质金属蛋白酶的对软骨基质的消耗，增加Ⅱ型胶原的产生。姜黄素通过抑制胞浆型磷脂酶A2，环氧化酶2，脂氧合酶5，从而完成抗炎反应。姜黄素抑制白细胞介素1β导致的线粒体肿胀和凋亡，完成抗凋亡作用。临床研究提示，姜黄素或者其衍生物骨关节炎患者膝关节功能、关节疼痛等均有改善。高浓度姜黄素对体外培养的细胞和组织有毒性作用。

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

全文链接：

关键词: 组织构建, 骨组织工程, 姜黄素, 骨关节炎, 软骨细胞, 关节软骨

Abstract:

BACKGROUND: Curcumin is proved to possess anti-inflammatory, antioxidant and anti-apoptotic roles.
OBJECTIVE: To summarize and discuss the mechanisms and effects of curcumin used for the treatment of osteoarthritis
METHODS: PubMed, Embase, Elseveir databases were retrieved for relevant articles published from 1973 to 2014, with the key words of “osteoarthritis, curcumin, chondrocyte, articular cartilage” in English. After the quality of the included studies was evaluated, valid data were extracted and analyzed.
RESULTS AND CONCLUSION: Curcumin prevents the occurrence and development osteoarthritis by inhibiting oxidative enzyme and scavenging free radicals. Curcumin increases production of collagen type 2 through suppressing the reduction of cartilage matrix by matrix metalloproteinases. Anti-inflammatory reaction of curcumin can be achieved by inhibiting cytosolic phospholipase A2, cyclooxygenase-2, and 5-lipoxygenase. Curcumin inhibits interleukin-1β-induced apoptosis of chondrocytes and mitochondrial swelling. Results from clinical trials suggest that curcumin or its derivatives can reduce joint pain and improve the function of knee joints in patients with osteoarthritis. High-concentration curcumin in vitro have been demonstrated toxic effects.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

全文链接：

Key words: Osteoarthritis, Curcumin, Chondrocytes

中图分类号:

R318

张锐，刘世清. 姜黄素保护关节软骨抑制骨关节炎的作用和机制[J]. 中国组织工程研究, 2015, 19(2): 277-282.

Zhang Rui, Liu Shi-qing. Curcumin prevents against osteoarthritis[J]. Chinese Journal of Tissue Engineering Research, 2015, 19(2): 277-282.

图/表（结果） 5

2.1 姜黄素概述姜黄素是姜黄主要的化学成分，约占姜黄素类化合物的70%。其他主要的姜黄素类化合物是脱甲氧基姜黄素及双脱甲氧基姜黄素^[4]，姜黄素化学结构式见图1。

姜黄素的生物利用度很低，当口服摄入姜黄素后，其吸收和代谢的分子在胃肠道内迅速被转化，仅一小部分会到达血液循环。临床试验证明：口服姜黄素的生物利用度相对较低^[5]。姜黄素能迅速转变为姜黄素葡糖苷酸和姜黄素硫酸盐或者在小肠和肝内降解为六氢姜黄素^[6]。姜黄素的代谢衍生品不具备与原来相同的生物活性，在某研究中，姜黄素的代谢产物比姜黄素对人结肠癌细胞产生前列腺素E2的抑制作用弱^[7]。

它易溶于甲醇、乙醇、丙酮、醋酸乙酯和碱液中，不溶于水，是一种光敏性很强的物质^[8]。因此为了得到姜黄素溶液，它必须溶解在如乙醇、二甲亚砜、丙酮等有机溶剂中^[9-10]。许多学者的体外实验都证实了姜黄素能溶解在二甲基亚砜中。

2.2 姜黄素在保护关节软骨及抑制骨关节炎的作用及相关机制

2.2.1 姜黄素能抗氧化骨关节炎软骨细胞的退化是由于一系列的机械因素、炎性介质、生化因素，尤其是基质金属蛋白酶和活性氧等共同作用导致的^[11]。姜黄素在体外已被证明是一种有效地活性氧清除剂和活性氮提供剂^[12-13]。Benqmark^[14]认为姜黄素抗氧化效应强于常规维生素。

姜黄素的很多功能基团都具有抗氧化作用。Priyadarsini等^[15]指出酚基团对于姜黄素清除氧自由基是必要的，甲氧基的存在进一步的增加其抗氧化活性。有人认为，姜黄素在体内外可以清除自由基，其原因是通过抑制炎症相关的酶比如基质金属蛋白酶9的活性^[16]，或者增强谷胱甘肽的合成实现抗氧化作用的^[17]。在骨关节炎的病理和进展中，主要的活性氧物质为一氧化氮、过氧硝酸盐、超氧化物阴离子^[18]。这些因素不仅是参与软骨细胞凋亡的有毒物质，而且是细胞代谢重要的信号分子^[19]。通过抑制氧化作用的酶，清除自由基，螯合金属离子，完成抗氧化作用^[20]。此外姜黄素的抗氧化活性还与其能够抑制脂质过氧化反应，增加超氧化物歧化酶、过氧化氢酶、谷胱甘肽过氧化酶等的活性有关。Yang等^[21]实验证实了这一点，姜黄素通过增加超氧化物歧化酶和过氧化氢酶的活性，并同时降低丙二醛的含量来完成抗氧化作用，见图2。

2.2.2 姜黄素可抗分解代谢研究表明，白细胞介素1β下调软骨细胞Ⅱ型胶原的表达，这一过程能够被姜黄素逆转。除了对Ⅱ型胶原的作用外，姜黄素还能逆转白细胞介素1β诱导的整合素β1的下调^[22]。来自风湿性关节炎患者滑膜成纤维细胞培养研究表明巨噬细胞迁移抑制因子(MIF)上调了编码基质金属蛋白酶的信使RNA，这一过程可以被姜黄素抑制^[23]。细胞因子白细胞介素 6超家族成员抑瘤素M(OSM)在骨关节炎患者中升高，与白细胞介素1β一起通过基质金属蛋白酶促进软骨退变^[24]。姜黄素能通过抑制转录因子核因子kB的激活和核易位来抑制白细胞介素1β和抑瘤素M诱导的人软骨细胞基质金属蛋白酶1、基质金属蛋白酶3、基质金属蛋白酶9、基质金属蛋白酶13等基因的表达^[25]。Mathy-Hartert等^[26]揭示了高生物利用度的姜黄素通过抑制基质金属蛋白酶3从而对抗软骨细胞的分解，但却不能改变蛋白多糖的产生。新研究表明，姜黄素能抑

制聚蛋白多糖酶5(ADAMTS-5)对蛋白多糖的降解，从而保护体外软骨细胞^[27]。以上研究均说明了姜黄素通过其抗分解代谢的功能，完成了对软骨细胞或者骨关节炎组织的保护作用。

2.2.3 姜黄素可抑制炎症异常的花生四烯酸代谢发生在炎症反应过程中，姜黄素能从几个角度来调节花生四烯酸的代谢。它抑制细胞产生胞浆磷脂酶A2(cPLA2)、环氧合酶2、脂氧合酶(5-LOX)^[28]，是因为可以直接抑制脂氧合酶的催化活性，阻止胞浆磷脂酶A2的磷酸化和抑制环氧合酶2的表达和催化活性(虽然很微弱)。转录因子核因子kB增强了环氧合酶2基因和其他促炎基因如诱导型一氧化氮合酶的转录，在软骨细胞中姜黄素能抑制依赖核因子kB转录因子的环氧合酶2基因和其他促炎基因的转录^[29-30]。另外，动物和细胞实验也证实姜黄素能抑

制环氧合酶2和诱导型一氧化氮合酶的产生^[31-32]。有实验结果证实姜黄素能够通过抑制炎症反应来阻止兔软骨细胞糖基化终末产物(AGEs）)的激活并且能通过抑制软骨细胞活性氧和核因子KB的激活来阻止肿瘤坏死因子α和基质金属蛋白酶13的糖基化终末产物的上调。

姜黄素能抑制中性粒细胞和基质金属蛋白酶的激活^[33]，这被认为是它治疗关节炎的机制。许多人都证实了姜黄素治疗骨关节炎的潜力，Arora等^[34]认为固体脂质纳米微粒搭载的姜黄素能通过减少炎症反应有效缓解关节炎大鼠的症状。Moon等^[35]的数据也显示，姜黄素能够显著减弱CIA小鼠的肿瘤坏死因子α和白细胞介素1β的产生，并通过增加环氧合酶2的表达来阻断前列腺素E2的产生。Buhrmann^[36]的实验阐明了姜黄素作为转录因子核因子kB的抑制剂，能保护间充质干细胞免受促炎症因子的损害，从而为间充质干细胞的软骨形成创造了稳定的微环境，见图3。这项研究结果将有助于在体外刺激软骨再生，为下一步治疗骨关节炎奠定实验基础。

2.2.4 姜黄素的抗凋亡现象有学者验证了姜黄素保护白细胞介素1β诱导的凋亡软骨细胞，透射电子显微镜观察到白细胞介素1β作用软骨细胞后，软骨细胞出现了早期退行性的变化，而姜黄素试验组逆转了该现象。Csaki等^[37]证实了姜黄素能够抵消掉白细胞介素1β对软骨细胞的毒性，它改变了由于白细胞介素1β导致的线粒体肿胀和凋亡，减少了白细胞介素1β诱导软骨细胞凋亡的特征。与此同时，它增强了抗凋亡因子(Bcl-2，Bcl-xL，TRAF1)的作用，并抑制了促凋亡因子半胱天冬酶3(caspase-3)的作用，见图4。Shakibaei等^[38]证实白细胞介素1β和MAPK信号通路的阻断会导致软骨细胞的凋亡，下调β1整合素受体和细胞外调节蛋白激酶(Erk1/2)的表达，姜黄素能够抑制这种现象。这些研究说明了姜黄素对白细胞介素1β刺激的软骨细胞有明显抑制凋亡作用。

2.3 姜黄素修复骨关节炎的临床研究关于姜黄素的临床相关试验一直较偏少，最早的临床试验来自于Kulkarni^[39]，结果显示与安慰剂对照组相比，姜黄素组能改善患者的疼痛和关节活动度。最近有两项临床随机双盲安慰剂对照试验揭示了姜黄素的功效，Yasuaki Nakagawa等^[40]披露在治疗8周后，姜黄素组的膝关节疼痛目测类比评分明显低于安慰剂组，见图5；姜黄素组明显比安慰剂组降低了患者对塞来昔布的依赖，而且在治疗过程中没有发现姜黄素的明显不良反应。Panahi等^[41]的数据显示姜黄素组在骨关节炎指数、目测类比评分、理奎森氏指数等方面较安慰剂对照组明显降低，在疼痛、膝关节功能方面较安慰剂对照组明显改善。

近年来，又发现众多姜黄素衍生物或混合物对治疗骨关节炎有效。Appelboom等^[42]研究Flexofytol(姜黄素的提取物)在前6周能够缓解疼痛，改善关节灵活性并提高生活质量。其中超过一半的人数不需要持续使用镇痛和抗炎药，提示Flexofytol(姜黄素提取物)能够作为一种潜在的类营养品提供给关节炎患者。另外，Belcaro等^[43]报道Meriva(一种姜黄素和大豆卵磷脂的混合物)对治疗膝关节炎有效。Kuptinatsaikul等^[44]研究表明姜黄素在治疗骨关节炎患者和布洛芬一样有效，比布洛芬的胃肠道副作用少。

2.4 姜黄素的毒副作用很多学者关于姜黄素在体外的毒性和有效性存在矛盾^[45-46]，Clutterbuck等^[47]的结果显示，用浓度大于25 μmol/L的姜黄素处理单层软骨细胞48 h或5 d，会导致软骨细胞死亡，见图6。之前他的结果也说明高浓度姜黄素能抑制体外培养的组织块释放糖胺聚糖，从而抑制软骨细胞的增殖^[48]。其实，姜黄素的细胞毒性作用早在癌症的有关研究中就被观察到了，这可能是与细胞色素C的释放和半胱天冬酶(caspase)的激活有关^[49]。Toegel^[50]的实验支持了这一点，浓度为 50 μmol/L姜黄素被证实降低了永生化软骨细胞系的生存能力。但在软骨组织培养中，用浓度为100 μmol/L的姜黄素培养组织块5 d才会观察到其毒性作用。这可能是因为没有细胞外基质的保护，单层软骨细胞直接被暴露，从而易受环境干扰和影响。Kim等^[51]和同事们证实当 20 μmol/L的姜黄素加入到骨髓间充质干细胞里会导致细胞凋亡，并阻止骨髓间充质干细胞向软骨细胞分化。这充分说明了间充质干细胞在体外仅仅能忍受超低浓度的姜黄素。当姜黄素浓度达到10 μmol/L的时候，它会对滑膜细胞起到凋亡和抑制增殖的作用。MTT实验证实，姜黄素浓度在10-50 μmol/L时，普通滑膜细胞会随着姜黄素剂量增加，生存能力逐渐减弱^[52]。

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