瘦素对骨关节炎软骨细胞调控作用新进展

刘柱　张自明



瘦素对骨关节炎软骨细胞调控作用新进展

刘柱张自明

瘦素(LP)及其受体广泛存在于全身各个器官，发挥着多种调节功能。近年来，研究发现LP在骨关节炎(OA)的病理生理改变中发挥重要的调节作用。OA患者血清及关节液LP水平均有明显改变，LP在肥胖与OA软骨细胞之间的枢纽作用正逐步被关注。研究表明，LP作为一种信号分子，对软骨细胞的新陈代谢有多重调控作用，不仅可以诱导软骨细胞凋亡，导致关节软骨丢失和退化，还有一定的抗凋亡和促进软骨成骨作用。该文就LP对OA软骨细胞调控作用进展作一综述。

瘦素；软骨细胞；骨关节炎；肥胖

瘦素(LP)是一种由白色脂肪组织产生、共167个氨基酸组成的蛋白质，于1994年被Zhang等[1]首次发现并报道，其主要功能是调控食物摄取和能量产生。近年来，LP在骨代谢、免疫、神经内分泌等方面的调节作用逐渐被发现[2-6]。骨关节炎(OA)是老年人最常见的慢性退行性关节疾病，其主要病理改变为软骨细胞破坏、软骨下骨硬化以及滑膜炎，55岁以上人群中有10%为OA患者[7]。研究[8]表明，作为关节软骨内唯一的支持细胞，软骨细胞的破坏和丢失是导致OA发生的关键因素。以往研究[9-11]表明，LP在OA患者血清和受累关节液中异常增加，且与其特异性受体结合后可通过Janus激酶(JAK)/信号转导与转录激活子(STAT)信号转导通路对软骨细胞的生理功能产生重要的调节作用。近年来，LP对OA中软骨细胞的调节作用不断有新的发现，其促进软骨细胞凋亡和抗软骨细胞凋亡的双重作用机制逐渐被学者们所认识。

1　LP及其受体

LP在全身各个器官均有分布，不仅由白色脂肪组织产生，其他组织如胎盘、脑、心脏、血管、卵巢、关节和骨组织等均可产生[12-15]。LP的信号转导主要通过特异性LP受体来完成。研究[16]表明，LP受体由糖尿病基因编码，属于Ⅰ类细胞因子受体超家族。现已确定LP有6种拼接异构体亚型，其中1种亚型为可溶性受体(缺乏跨膜段)，其余5种亚型都是跨膜受体，拥有相同的细胞外结构，但根据细胞质长度可分为长亚型受体(1个)、短亚型受体(4个)。然而，只有长亚型LP受体具有完整的细胞内结构，可通过其特异的细胞因子受体进行信号转导，将LP信号传递到细胞核中。LP在血清中可以游离形式与血浆蛋白结合，也可以与可溶性LP受体亚型结合的形式存在[17-18]。

LP受体由302个氨基酸组成，可通过JAK/ STAT信号转导通路来进行信号转导[19]。研究[20-21]表明，LP与其受体结合后可聚集JAK2等激酶进行信号转导。此外，LP受体还可通过其他替代途径如细胞外调节蛋白激酶(ERK)1/2、p38促分裂素原活化蛋白激酶(MAPK)、c-Jun氨基末端激酶(JNK)、磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(AKT)、核因子(NF)-κB、RhoA/Rho相关卷曲螺旋形成蛋白激酶(ROCK)等信号转导通路进行信号转导[22-25]。

2　LP与OA

2.1关节液和血清LP水平

多研究[26-28]表明，LP在受累关节液中的水平与OA密切相关。Fowler-Brown等[26]研究发现，OA患者关节液LP水平与其体重指数(BMI)呈正相关。不同关节的OA与LP的相关性不同，以膝关节OA最为显著。Bas等[27]研究发现，OA膝关节的关节液中LP水平高于OA髋关节。Gandhi等[28]研究发现，LP与膝关节OA相关性高于肩关节OA。

LP不仅在关节液中分布，在血清中也有分布，LP血清水平与OA有关。de Boer 等[29]研究认为，血清中包括LP在内的脂肪因子含量增加与OA发生密切相关，且认为血清中脂肪因子与局部滑膜组织炎症发生有关。Kim等[30]研究报道，血清LP水平与膝关节OA患者的超声检查结果及膝关节功能状况密切相关。Massengale等[31]研究发现，血清LP水平与慢性手OA的疼痛程度有关。以上研究表明，血清LP水平不仅与OA发生有关，还能对OA受累关节的功能状态进行评价。

此外，OA患者血清和关节液中LP水平不同。有研究[32-33]认为，OA关节液LP水平等于甚至超过血清LP水平。此外，OA不同阶段关节液和血清LP水平不同，在膝关节OA发生期关节液LP、血清脂联素、可溶性LP受体和游离LP水平并无明显改变，但在OA进展期关节液LP与血清LP的比值明显低于早期阶段[32]。

2.2LP或为肥胖导致OA的前提

长久以来，肥胖所产生的生物机械作用被认为是OA发生的重要危险因素之一，肥胖通过增加关节面压力而促进OA发生[34-35]。但也有学者[36-37]研究发现，肥胖患者非负重关节如手关节也会发生OA。有研究[27,38]表明，白色脂肪组织的代谢产物与肥胖患者中较高的OA发生率密切相关。也有研究[39]认为，在分析LP对OA的作用时，需要考虑患者身体特征(如年龄、性别、BMI等)的作用。LP作为脂肪因子的一员，与肥胖的关系非常密切。研究[37]表明，LP或为肥胖导致OA的前提。Griffin等[40]研究发现，肥胖并不一定是关节退变的原因，虽然缺乏LP的极度肥胖可诱导软骨下骨形态改变，但并不增加膝关节OA发生率，肥胖在无LP信号作用时不足以诱发全身性炎症和膝关节OA。LP对OA患者的体重也有一定影响。Nicholson等[41]分析20例膝关节OA肥胖患者的性别、BMI及LP、内源性大麻素花生四稀乙醇胺(AEA)、2-花生四烯酸甘油酯(AG)水平，发现LP可通过调节下丘脑内的内源性大麻水平控制摄食行为，进而影响患者的肥胖程度。Pallu等[42]研究认为，不同BMI的OA患者软骨细胞对LP的反应不同。综上所述，肥胖在LP与OA关系中具有重要作用。研究[43]表明，体育锻炼(增加力量的训练模式)对OA中软骨细胞结构改变具有保护作用，且能缓解相关临床症状，而这一作用的实现可能是因为体育锻炼可降低LP水平。

以上研究皆表明，LP与肥胖者OA的发生密切相关。此外，LP不仅对肥胖者OA的发生有影响，还会反过来影响OA患者的体重。因此，LP是连接肥胖与OA的纽带，在肥胖OA发生发展中具有重要作用。

2.3性别对LP与OA关系的影响

LP与OA的关系也受性别影响。Iwamoto等[44]研究发现，日本女性绝经后膝关节OA患者血清LP水平与体重呈正比。Karvonen-Gutierrez等[45]研究发现，中年妇女血清LP水平与软骨缺损和滑膜炎有关，且对OA导致的关节退变有重要作用。有研究[46]发现，女性膝关节和髋关节OA患者血清LP水平与疼痛程度呈正相关，男性则不相关。Hooshmand等[47]也发现，仅女性OA患者总关节液LP水平增高，男性则无此现象。以上研究表明，女性OA患者LP与OA关系更加密切。

综上所述，无论是血清LP水平还是关节液LP水平，均与OA发生密切相关。LP或为肥胖导致OA的前提。此外，LP与OA的相关性还受性别影响，肥胖女性OA发生与LP相关性更高。

3　LP对软骨细胞的影响

软骨细胞为关节软骨内唯一的支持细胞，其生理功能受LP广泛调节。但LP对软骨细胞是发挥破坏作用还是保护作用，目前仍有争议。

3.1促凋亡作用

3.1.1宏观调控

LP促软骨细胞凋亡的宏观调控表现为软骨细胞数目及增殖的减少。Martel-Pelletier等[48]对138例膝关节OA患者进行研究，发现LP可增加全膝关节和股骨内侧软骨体积的丢失，且LP水平与膝关节置换率呈正相关。Stannus等[49]研究发现，老年人群血清LP水平与关节软骨变薄密切相关。Zhao等[50]研究发现，OA患者LP受体高表达与软骨退变、组织衰老明显相关，LP介导的软骨祖细胞衰老可加快OA进展。

3.1.2微观调控

LP可通过对一氧化氮(NO)、基质金属蛋白酶(MMP)等促炎因子的调控促进软骨细胞凋亡。Otero等[51]研究发现，LP通过JAK2途径与干扰素(IFN)-γ协同作用，促进软骨细胞NO及一氧化氮合酶(iNOS)产生。此外，LP可通过直接调控MMP-1、MMP-3、MMP-9和MMP-13的产生促进软骨细胞凋亡[30,51-53]。Yaykasli等[25]研究报道，LP通过丝裂原活化蛋白激酶(MAPK)和NF-κB信号转导通路上调ADAMTS-4、ADAMTS-5和ADAMTS-9基因表达，从而促进软骨细胞凋亡。Huang 等[54]研究认为，在OA大鼠模型中，LP一方面通过赖氨酸氧化酶样蛋白(LOXL)3/雷帕霉素靶蛋白(mTORC)1信号转导通路抑制软骨细胞自噬,另一方面通过LOXL3途经直接促进软骨细胞凋亡。Zhang等[21]研究报道，LP可通过JAK2/STAT3信号转导通路诱导软骨细胞凋亡。以上研究表明，LP可通过多种途径发挥对软骨细胞的破坏作用。

3.2抗凋亡作用

3.2.1宏观调控

研究[23,55-56]认为，LP对OA中软骨细胞有抗凋亡和促进软骨成骨的作用。Lee等[23]研究发现，LP可通过JNK途径抑制肿瘤坏死因子(TNF)-α诱导的软骨细胞凋亡。刘柱等[55]也发现，LP对TNF-α诱导的软骨细胞凋亡具有保护作用。Zheng等[56]分析了影像学阳性的OA患者血清LP、脂联素和抵抗素水平与膝关节软骨体积的关系，结果发现只有血清LP水平与膝关节软骨体积增加有关，表明血清LP有助于促进关节软骨增殖。

3.2.2微观调控

Mutabaruka等[57]研究认为，OA中异常的成骨现象与LP有关，LP可促进细胞增殖，并促进ERK1/2和p38 MAPK信号转导。有研究[58]发现，在低氧环境下通过低氧诱导因子(HIF)-2(尤其是在维生素D3的作用下)诱导产生的LP与OA软骨下成骨过程有关。Wang等[59]研究认为，OA中LP下游因子双特异性蛋白磷酸酶(DUSP)19可通过JNK途径抑制软骨细胞凋亡。Conde等[60]研究发现，在人和鼠ATDC5软骨细胞中，LP可通过JAK2、PI3K和腺苷酸活化蛋白激酶(AMPK)途径上调血管细胞黏附因子(VCAM)-1的表达，从而延缓软骨降解。Kang等[61]研究报道，在肥胖大鼠的软骨细胞中，血清LP水平增加可促进VCAM-1产生。Chang等[20]研究发现，人软骨细胞中LP可与骨形态发生蛋白(BMP)-2协同作用增加Ⅱ型胶原蛋白生成，对OA发生发展有一定调控作用。Liang等[62]研究报道，LP可通过RhoA/ROCK/LIMK/Cofilin信号转导通路介导软骨细胞骨架重塑。以上研究表明，在OA肥胖患者中，LP不仅对软骨细胞发挥抗凋亡作用，还有促进软骨成骨的功能。

4　结语

尽管肥胖等力学因素在OA关节软骨破坏中具有重要作用，但非力学因素如LP也对OA病理生理的发生和发展有重要作用。LP在肥胖与OA软骨细胞之间的枢纽作用正逐渐被学者们关注。目前的研究表明，LP及其受体在OA发病机制中发挥的作用主要通过对关节软骨细胞的调控来实现。LP对OA中软骨细胞影响的作用机制尚存较多争议。在OA中，LP作为一种信号分子，对软骨细胞的新陈代谢有多重调控作用，不仅可诱导软骨细胞凋亡，导致关节软骨丢失和退化，还具有一定的抗凋亡和促进软骨成骨作用。以上研究均表明，LP在OA病理生理中有着不可或缺的作用。LP对软骨细胞新陈代谢的作用研究可为未来治疗OA靶向药物的研究提供新方向。然而，LP在OA中对软骨细胞发挥具体调控作用机制有待进一步研究。

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(收稿：2016-06-06；修回：2016-07-03)

(本文编辑：李昱霏)

200092，上海交通大学医学院附属新华医院小儿骨科

张自明E-mail： zmzhang23@163.com

10.3969/j.issn.1673-7083.2016.05.011