劉柱　張自明

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瘦素對骨關(guān)節(jié)炎軟骨細(xì)胞調(diào)控作用新進展

劉柱張自明

瘦素(LP)及其受體廣泛存在于全身各個器官，發(fā)揮著多種調(diào)節(jié)功能。近年來，研究發(fā)現(xiàn)LP在骨關(guān)節(jié)炎(OA)的病理生理改變中發(fā)揮重要的調(diào)節(jié)作用。OA患者血清及關(guān)節(jié)液LP水平均有明顯改變，LP在肥胖與OA軟骨細(xì)胞之間的樞紐作用正逐步被關(guān)注。研究表明，LP作為一種信號分子，對軟骨細(xì)胞的新陳代謝有多重調(diào)控作用，不僅可以誘導(dǎo)軟骨細(xì)胞凋亡，導(dǎo)致關(guān)節(jié)軟骨丟失和退化，還有一定的抗凋亡和促進軟骨成骨作用。該文就LP對OA軟骨細(xì)胞調(diào)控作用進展作一綜述。

瘦素；軟骨細(xì)胞；骨關(guān)節(jié)炎；肥胖

瘦素(LP)是一種由白色脂肪組織產(chǎn)生、共167個氨基酸組成的蛋白質(zhì)，于1994年被Zhang等[1]首次發(fā)現(xiàn)并報道，其主要功能是調(diào)控食物攝取和能量產(chǎn)生。近年來，LP在骨代謝、免疫、神經(jīng)內(nèi)分泌等方面的調(diào)節(jié)作用逐漸被發(fā)現(xiàn)[2-6]。骨關(guān)節(jié)炎(OA)是老年人最常見的慢性退行性關(guān)節(jié)疾病，其主要病理改變?yōu)檐浌羌?xì)胞破壞、軟骨下骨硬化以及滑膜炎，55歲以上人群中有10%為OA患者[7]。研究[8]表明，作為關(guān)節(jié)軟骨內(nèi)唯一的支持細(xì)胞，軟骨細(xì)胞的破壞和丟失是導(dǎo)致OA發(fā)生的關(guān)鍵因素。以往研究[9-11]表明，LP在OA患者血清和受累關(guān)節(jié)液中異常增加，且與其特異性受體結(jié)合后可通過Janus激酶(JAK)/信號轉(zhuǎn)導(dǎo)與轉(zhuǎn)錄激活子(STAT)信號轉(zhuǎn)導(dǎo)通路對軟骨細(xì)胞的生理功能產(chǎn)生重要的調(diào)節(jié)作用。近年來，LP對OA中軟骨細(xì)胞的調(diào)節(jié)作用不斷有新的發(fā)現(xiàn)，其促進軟骨細(xì)胞凋亡和抗軟骨細(xì)胞凋亡的雙重作用機制逐漸被學(xué)者們所認(rèn)識。

1　LP及其受體

LP在全身各個器官均有分布，不僅由白色脂肪組織產(chǎn)生，其他組織如胎盤、腦、心臟、血管、卵巢、關(guān)節(jié)和骨組織等均可產(chǎn)生[12-15]。LP的信號轉(zhuǎn)導(dǎo)主要通過特異性LP受體來完成。研究[16]表明，LP受體由糖尿病基因編碼，屬于Ⅰ類細(xì)胞因子受體超家族?，F(xiàn)已確定LP有6種拼接異構(gòu)體亞型，其中1種亞型為可溶性受體(缺乏跨膜段)，其余5種亞型都是跨膜受體，擁有相同的細(xì)胞外結(jié)構(gòu)，但根據(jù)細(xì)胞質(zhì)長度可分為長亞型受體(1個)、短亞型受體(4個)。然而，只有長亞型LP受體具有完整的細(xì)胞內(nèi)結(jié)構(gòu)，可通過其特異的細(xì)胞因子受體進行信號轉(zhuǎn)導(dǎo)，將LP信號傳遞到細(xì)胞核中。LP在血清中可以游離形式與血漿蛋白結(jié)合，也可以與可溶性LP受體亞型結(jié)合的形式存在[17-18]。

LP受體由302個氨基酸組成，可通過JAK/ STAT信號轉(zhuǎn)導(dǎo)通路來進行信號轉(zhuǎn)導(dǎo)[19]。研究[20-21]表明，LP與其受體結(jié)合后可聚集JAK2等激酶進行信號轉(zhuǎn)導(dǎo)。此外，LP受體還可通過其他替代途徑如細(xì)胞外調(diào)節(jié)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相關(guān)卷曲螺旋形成蛋白激酶(ROCK)等信號轉(zhuǎn)導(dǎo)通路進行信號轉(zhuǎn)導(dǎo)[22-25]。

2　LP與OA

2.1關(guān)節(jié)液和血清LP水平

多研究[26-28]表明，LP在受累關(guān)節(jié)液中的水平與OA密切相關(guān)。Fowler-Brown等[26]研究發(fā)現(xiàn)，OA患者關(guān)節(jié)液LP水平與其體重指數(shù)(BMI)呈正相關(guān)。不同關(guān)節(jié)的OA與LP的相關(guān)性不同，以膝關(guān)節(jié)OA最為顯著。Bas等[27]研究發(fā)現(xiàn)，OA膝關(guān)節(jié)的關(guān)節(jié)液中LP水平高于OA髖關(guān)節(jié)。Gandhi等[28]研究發(fā)現(xiàn)，LP與膝關(guān)節(jié)OA相關(guān)性高于肩關(guān)節(jié)OA。

LP不僅在關(guān)節(jié)液中分布，在血清中也有分布，LP血清水平與OA有關(guān)。de Boer 等[29]研究認(rèn)為，血清中包括LP在內(nèi)的脂肪因子含量增加與OA發(fā)生密切相關(guān)，且認(rèn)為血清中脂肪因子與局部滑膜組織炎癥發(fā)生有關(guān)。Kim等[30]研究報道，血清LP水平與膝關(guān)節(jié)OA患者的超聲檢查結(jié)果及膝關(guān)節(jié)功能狀況密切相關(guān)。Massengale等[31]研究發(fā)現(xiàn)，血清LP水平與慢性手OA的疼痛程度有關(guān)。以上研究表明，血清LP水平不僅與OA發(fā)生有關(guān)，還能對OA受累關(guān)節(jié)的功能狀態(tài)進行評價。

此外，OA患者血清和關(guān)節(jié)液中LP水平不同。有研究[32-33]認(rèn)為，OA關(guān)節(jié)液LP水平等于甚至超過血清LP水平。此外，OA不同階段關(guān)節(jié)液和血清LP水平不同，在膝關(guān)節(jié)OA發(fā)生期關(guān)節(jié)液LP、血清脂聯(lián)素、可溶性LP受體和游離LP水平并無明顯改變，但在OA進展期關(guān)節(jié)液LP與血清LP的比值明顯低于早期階段[32]。

2.2LP或為肥胖導(dǎo)致OA的前提

長久以來，肥胖所產(chǎn)生的生物機械作用被認(rèn)為是OA發(fā)生的重要危險因素之一，肥胖通過增加關(guān)節(jié)面壓力而促進OA發(fā)生[34-35]。但也有學(xué)者[36-37]研究發(fā)現(xiàn)，肥胖患者非負(fù)重關(guān)節(jié)如手關(guān)節(jié)也會發(fā)生OA。有研究[27,38]表明，白色脂肪組織的代謝產(chǎn)物與肥胖患者中較高的OA發(fā)生率密切相關(guān)。也有研究[39]認(rèn)為，在分析LP對OA的作用時，需要考慮患者身體特征(如年齡、性別、BMI等)的作用。LP作為脂肪因子的一員，與肥胖的關(guān)系非常密切。研究[37]表明，LP或為肥胖導(dǎo)致OA的前提。Griffin等[40]研究發(fā)現(xiàn)，肥胖并不一定是關(guān)節(jié)退變的原因，雖然缺乏LP的極度肥胖可誘導(dǎo)軟骨下骨形態(tài)改變，但并不增加膝關(guān)節(jié)OA發(fā)生率，肥胖在無LP信號作用時不足以誘發(fā)全身性炎癥和膝關(guān)節(jié)OA。LP對OA患者的體重也有一定影響。Nicholson等[41]分析20例膝關(guān)節(jié)OA肥胖患者的性別、BMI及LP、內(nèi)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，發(fā)現(xiàn)LP可通過調(diào)節(jié)下丘腦內(nèi)的內(nèi)源性大麻水平控制攝食行為，進而影響患者的肥胖程度。Pallu等[42]研究認(rèn)為，不同BMI的OA患者軟骨細(xì)胞對LP的反應(yīng)不同。綜上所述，肥胖在LP與OA關(guān)系中具有重要作用。研究[43]表明，體育鍛煉(增加力量的訓(xùn)練模式)對OA中軟骨細(xì)胞結(jié)構(gòu)改變具有保護作用，且能緩解相關(guān)臨床癥狀，而這一作用的實現(xiàn)可能是因為體育鍛煉可降低LP水平。

以上研究皆表明，LP與肥胖者OA的發(fā)生密切相關(guān)。此外，LP不僅對肥胖者OA的發(fā)生有影響，還會反過來影響OA患者的體重。因此，LP是連接肥胖與OA的紐帶，在肥胖OA發(fā)生發(fā)展中具有重要作用。

2.3性別對LP與OA關(guān)系的影響

LP與OA的關(guān)系也受性別影響。Iwamoto等[44]研究發(fā)現(xiàn)，日本女性絕經(jīng)后膝關(guān)節(jié)OA患者血清LP水平與體重呈正比。Karvonen-Gutierrez等[45]研究發(fā)現(xiàn)，中年婦女血清LP水平與軟骨缺損和滑膜炎有關(guān)，且對OA導(dǎo)致的關(guān)節(jié)退變有重要作用。有研究[46]發(fā)現(xiàn)，女性膝關(guān)節(jié)和髖關(guān)節(jié)OA患者血清LP水平與疼痛程度呈正相關(guān)，男性則不相關(guān)。Hooshmand等[47]也發(fā)現(xiàn)，僅女性O(shè)A患者總關(guān)節(jié)液LP水平增高，男性則無此現(xiàn)象。以上研究表明，女性O(shè)A患者LP與OA關(guān)系更加密切。

綜上所述，無論是血清LP水平還是關(guān)節(jié)液LP水平，均與OA發(fā)生密切相關(guān)。LP或為肥胖導(dǎo)致OA的前提。此外，LP與OA的相關(guān)性還受性別影響，肥胖女性O(shè)A發(fā)生與LP相關(guān)性更高。

3　LP對軟骨細(xì)胞的影響

軟骨細(xì)胞為關(guān)節(jié)軟骨內(nèi)唯一的支持細(xì)胞，其生理功能受LP廣泛調(diào)節(jié)。但LP對軟骨細(xì)胞是發(fā)揮破壞作用還是保護作用，目前仍有爭議。

3.1促凋亡作用

3.1.1宏觀調(diào)控

LP促軟骨細(xì)胞凋亡的宏觀調(diào)控表現(xiàn)為軟骨細(xì)胞數(shù)目及增殖的減少。Martel-Pelletier等[48]對138例膝關(guān)節(jié)OA患者進行研究，發(fā)現(xiàn)LP可增加全膝關(guān)節(jié)和股骨內(nèi)側(cè)軟骨體積的丟失，且LP水平與膝關(guān)節(jié)置換率呈正相關(guān)。Stannus等[49]研究發(fā)現(xiàn)，老年人群血清LP水平與關(guān)節(jié)軟骨變薄密切相關(guān)。Zhao等[50]研究發(fā)現(xiàn)，OA患者LP受體高表達(dá)與軟骨退變、組織衰老明顯相關(guān)，LP介導(dǎo)的軟骨祖細(xì)胞衰老可加快OA進展。

3.1.2微觀調(diào)控

LP可通過對一氧化氮(NO)、基質(zhì)金屬蛋白酶(MMP)等促炎因子的調(diào)控促進軟骨細(xì)胞凋亡。Otero等[51]研究發(fā)現(xiàn)，LP通過JAK2途徑與干擾素(IFN)-γ協(xié)同作用，促進軟骨細(xì)胞NO及一氧化氮合酶(iNOS)產(chǎn)生。此外，LP可通過直接調(diào)控MMP-1、MMP-3、MMP-9和MMP-13的產(chǎn)生促進軟骨細(xì)胞凋亡[30,51-53]。Yaykasli等[25]研究報道，LP通過絲裂原活化蛋白激酶(MAPK)和NF-κB信號轉(zhuǎn)導(dǎo)通路上調(diào)ADAMTS-4、ADAMTS-5和ADAMTS-9基因表達(dá)，從而促進軟骨細(xì)胞凋亡。Huang 等[54]研究認(rèn)為，在OA大鼠模型中，LP一方面通過賴氨酸氧化酶樣蛋白(LOXL)3/雷帕霉素靶蛋白(mTORC)1信號轉(zhuǎn)導(dǎo)通路抑制軟骨細(xì)胞自噬,另一方面通過LOXL3途經(jīng)直接促進軟骨細(xì)胞凋亡。Zhang等[21]研究報道，LP可通過JAK2/STAT3信號轉(zhuǎn)導(dǎo)通路誘導(dǎo)軟骨細(xì)胞凋亡。以上研究表明，LP可通過多種途徑發(fā)揮對軟骨細(xì)胞的破壞作用。

3.2抗凋亡作用

3.2.1宏觀調(diào)控

研究[23,55-56]認(rèn)為，LP對OA中軟骨細(xì)胞有抗凋亡和促進軟骨成骨的作用。Lee等[23]研究發(fā)現(xiàn)，LP可通過JNK途徑抑制腫瘤壞死因子(TNF)-α誘導(dǎo)的軟骨細(xì)胞凋亡。劉柱等[55]也發(fā)現(xiàn)，LP對TNF-α誘導(dǎo)的軟骨細(xì)胞凋亡具有保護作用。Zheng等[56]分析了影像學(xué)陽性的OA患者血清LP、脂聯(lián)素和抵抗素水平與膝關(guān)節(jié)軟骨體積的關(guān)系，結(jié)果發(fā)現(xiàn)只有血清LP水平與膝關(guān)節(jié)軟骨體積增加有關(guān)，表明血清LP有助于促進關(guān)節(jié)軟骨增殖。

3.2.2微觀調(diào)控

Mutabaruka等[57]研究認(rèn)為，OA中異常的成骨現(xiàn)象與LP有關(guān)，LP可促進細(xì)胞增殖，并促進ERK1/2和p38 MAPK信號轉(zhuǎn)導(dǎo)。有研究[58]發(fā)現(xiàn)，在低氧環(huán)境下通過低氧誘導(dǎo)因子(HIF)-2(尤其是在維生素D3的作用下)誘導(dǎo)產(chǎn)生的LP與OA軟骨下成骨過程有關(guān)。Wang等[59]研究認(rèn)為，OA中LP下游因子雙特異性蛋白磷酸酶(DUSP)19可通過JNK途徑抑制軟骨細(xì)胞凋亡。Conde等[60]研究發(fā)現(xiàn)，在人和鼠ATDC5軟骨細(xì)胞中，LP可通過JAK2、PI3K和腺苷酸活化蛋白激酶(AMPK)途徑上調(diào)血管細(xì)胞黏附因子(VCAM)-1的表達(dá)，從而延緩軟骨降解。Kang等[61]研究報道，在肥胖大鼠的軟骨細(xì)胞中，血清LP水平增加可促進VCAM-1產(chǎn)生。Chang等[20]研究發(fā)現(xiàn)，人軟骨細(xì)胞中LP可與骨形態(tài)發(fā)生蛋白(BMP)-2協(xié)同作用增加Ⅱ型膠原蛋白生成，對OA發(fā)生發(fā)展有一定調(diào)控作用。Liang等[62]研究報道，LP可通過RhoA/ROCK/LIMK/Cofilin信號轉(zhuǎn)導(dǎo)通路介導(dǎo)軟骨細(xì)胞骨架重塑。以上研究表明，在OA肥胖患者中，LP不僅對軟骨細(xì)胞發(fā)揮抗凋亡作用，還有促進軟骨成骨的功能。

4　結(jié)語

盡管肥胖等力學(xué)因素在OA關(guān)節(jié)軟骨破壞中具有重要作用，但非力學(xué)因素如LP也對OA病理生理的發(fā)生和發(fā)展有重要作用。LP在肥胖與OA軟骨細(xì)胞之間的樞紐作用正逐漸被學(xué)者們關(guān)注。目前的研究表明，LP及其受體在OA發(fā)病機制中發(fā)揮的作用主要通過對關(guān)節(jié)軟骨細(xì)胞的調(diào)控來實現(xiàn)。LP對OA中軟骨細(xì)胞影響的作用機制尚存較多爭議。在OA中，LP作為一種信號分子，對軟骨細(xì)胞的新陳代謝有多重調(diào)控作用，不僅可誘導(dǎo)軟骨細(xì)胞凋亡，導(dǎo)致關(guān)節(jié)軟骨丟失和退化，還具有一定的抗凋亡和促進軟骨成骨作用。以上研究均表明，LP在OA病理生理中有著不可或缺的作用。LP對軟骨細(xì)胞新陳代謝的作用研究可為未來治療OA靶向藥物的研究提供新方向。然而，LP在OA中對軟骨細(xì)胞發(fā)揮具體調(diào)控作用機制有待進一步研究。

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(收稿：2016-06-06；修回：2016-07-03)

(本文編輯：李昱霏)

200092，上海交通大學(xué)醫(yī)學(xué)院附屬新華醫(yī)院小兒骨科

張自明E-mail： zmzhang23@163.com

10.3969/j.issn.1673-7083.2016.05.011