骨-軟骨交互作用與骨關(guān)節(jié)炎的研究進(jìn)展

鄭　潔(綜述) ，王瑞輝，寇久社(審校)

(1.陜西中醫(yī)學(xué)院針灸推拿系,陜西 咸陽712046； 2.陜西中醫(yī)學(xué)院第二附屬醫(yī)院康復(fù)針灸科，陜西 咸陽712046)

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骨-軟骨交互作用與骨關(guān)節(jié)炎的研究進(jìn)展

鄭潔1※(綜述) ，王瑞輝1，寇久社2(審校)

(1.陜西中醫(yī)學(xué)院針灸推拿系,陜西 咸陽712046； 2.陜西中醫(yī)學(xué)院第二附屬醫(yī)院康復(fù)針灸科，陜西 咸陽712046)

摘要：骨關(guān)節(jié)炎(OA)進(jìn)程中，為適應(yīng)局部生化環(huán)境及生物信號的改變，由軟骨及軟骨下骨構(gòu)成的關(guān)節(jié)功能單位經(jīng)歷了不可控制的分解及合成代謝的重構(gòu)過程。軟骨及軟骨下骨信號分子的交互作用使兩者在病理上相互影響、相互作用。新生血管及微裂隙的形成為骨-軟骨間分子通訊提供結(jié)構(gòu)基礎(chǔ)。WNT、骨形態(tài)發(fā)生蛋白、轉(zhuǎn)化生長因子β和絲裂原活化蛋白激酶等信號通路可能是構(gòu)成OA中骨-軟骨交互作用的分子基礎(chǔ)。

關(guān)鍵詞：骨關(guān)節(jié)炎；軟骨；WNT信號；骨形態(tài)發(fā)生蛋白；絲裂原活化蛋白激酶

骨關(guān)節(jié)炎(osteoarthritis,OA)是以進(jìn)行性關(guān)節(jié)軟骨退變、骨贅形成及繼發(fā)關(guān)節(jié)間隙變窄為主要特征的退行性關(guān)節(jié)疾病[1]。OA進(jìn)程中，為適應(yīng)關(guān)節(jié)局部生化環(huán)境的變化，關(guān)節(jié)軟骨和軟骨下骨都經(jīng)歷了分解及合成代謝的重構(gòu)過程。軟骨及軟骨下骨的病理改變不只是OA的繼發(fā)表現(xiàn)，更是加快OA進(jìn)程的積極因素。OA關(guān)節(jié)骨-軟骨新生血管和微裂隙的形成提示，骨-軟骨之間可能存在信號分子的交互作用，引起骨-軟骨病理上相互影響、相互作用，進(jìn)而加速軟骨退變、軟骨下骨破壞及骨贅形成?，F(xiàn)對調(diào)控關(guān)節(jié)內(nèi)軟骨及軟骨下骨生化代謝的主要信號通路及骨-軟骨間細(xì)胞通訊在OA進(jìn)程中的作用予以綜述。

1OA關(guān)節(jié)軟骨與軟骨下骨的相互作用

正常軟骨與軟骨下骨有一層鈣化軟骨相隔，兩者很少存在功能上的相互作用。OA軟骨下骨大量新生血管及微裂隙的形成提示，OA軟骨細(xì)胞與軟骨下骨細(xì)胞分泌的介質(zhì)可能直接通過這些通道相互作用[2]。研究顯示，OA軟骨細(xì)胞可分泌調(diào)節(jié)因子介導(dǎo)破骨細(xì)胞生成，進(jìn)而導(dǎo)致軟骨下骨丟失[3]；同時，OA軟骨下骨成骨細(xì)胞來源信號可介導(dǎo)軟骨細(xì)胞出現(xiàn)肥大表型[4]；小雞肥大軟骨細(xì)胞可刺激成骨細(xì)胞分化及骨基質(zhì)沉積[5]。以上結(jié)果表明，OA進(jìn)程中軟骨下骨與軟骨之間存在著信號分子的密切交互作用。

2OA關(guān)節(jié)軟骨與軟骨下骨相互作用的信號機(jī)制

2.1WNT(wingless-type)信號機(jī)制與骨-軟骨交互作用WNT信號不僅在軟骨細(xì)胞、成骨細(xì)胞和破骨細(xì)胞生物學(xué)中發(fā)揮重要作用，而且可能是關(guān)節(jié)軟骨與軟骨下骨相互作用的關(guān)鍵信號分子。研究發(fā)現(xiàn)，WNT信號通路參與維持成熟小鼠關(guān)節(jié)軟骨表型，可抑制軟骨細(xì)胞凋亡、延長其存活時間及防止軟骨細(xì)胞向肥大表型轉(zhuǎn)化[6-8]。脂蛋白受體相關(guān)蛋白5(lipoprotein receptor-related protein 5,LRP5)(LRP5是WNTs的共受體)基因剔除OA小鼠軟骨細(xì)胞凋亡率顯著高于野生型OA小鼠[9]，表明WNT信號可促進(jìn)軟骨細(xì)胞存活、抑制其凋亡，可作為軟骨細(xì)胞存活的標(biāo)志物。然而也有研究發(fā)現(xiàn)，WNT信號的高表達(dá)可誘發(fā)關(guān)節(jié)軟骨基質(zhì)金屬蛋白酶(matrix metalloproteinases，MMPs)和聚蛋白多糖酶等軟骨分解代謝因子的表達(dá)，導(dǎo)致軟骨降解[9]。分泌性卷曲相關(guān)蛋白3(secreted frizzled-related protein 3,sFRP3,Frzb)是一種WNT信號拮抗劑，研究發(fā)現(xiàn)，sFRP3缺陷小鼠不會出現(xiàn)自發(fā)性關(guān)節(jié)炎，但藥物誘導(dǎo)的sFRP3缺陷OA小鼠模型軟骨退變程度較野生型對照組OA小鼠更加嚴(yán)重[10]。除調(diào)節(jié)軟骨細(xì)胞活動，WNT信號還參與調(diào)節(jié)骨發(fā)育及骨穩(wěn)態(tài)的維持[11]。在胚胎發(fā)育后期及生后發(fā)育過程中，關(guān)節(jié)軟骨下松質(zhì)骨形成高度依賴生長板低肥厚區(qū)軟骨細(xì)胞中β聯(lián)蛋白的表達(dá)，而肥厚軟骨細(xì)胞β聯(lián)蛋白的表達(dá)對調(diào)節(jié)核因子κB受體活化因子配體表達(dá),進(jìn)而調(diào)控軟骨下生長板破骨細(xì)胞活動十分必要[12]。研究發(fā)現(xiàn)，WNT信號高表達(dá)可誘導(dǎo)骨硬化[13]。WNT拮抗劑或受體的基因剔除可激活WNT信號通路，導(dǎo)致成骨過程活躍，骨質(zhì)變厚變硬[6，9-10]。OA進(jìn)程中，軟骨下皮質(zhì)骨和松質(zhì)骨廣泛重構(gòu)，軟骨下骨終板增厚，軟骨機(jī)械負(fù)載環(huán)境改變，退化過程加快；OA關(guān)節(jié)中多種內(nèi)源性WNT激動劑和拮抗劑的表達(dá)水平均出現(xiàn)上調(diào)。研究發(fā)現(xiàn)，OA患者關(guān)節(jié)軟骨FRP、DKK(dickkopf)1和Gremlin1等WNT信號拮抗劑的表達(dá)明顯上調(diào)[14-15]；DKK1表達(dá)下調(diào)可延緩膝OA關(guān)節(jié)軟骨細(xì)胞凋亡、軟骨降解及軟骨下骨骨量丟失[16]，提示拮抗劑介導(dǎo)的WNT信號抑制可能會誘發(fā)軟骨細(xì)胞合成分解代謝酶及軟骨下骨重構(gòu)。此外，OA患者關(guān)節(jié)軟骨中WNT1誘導(dǎo)信號通路蛋白1(WNT信號激動劑)也呈高表達(dá)；OA關(guān)節(jié)中內(nèi)源性WNT激動劑的大量分泌可直接刺激軟骨細(xì)胞分泌MMPs和聚蛋白多糖酶，加速軟骨退變[17]；與此同時，軟骨下骨重構(gòu)過程加快，導(dǎo)致關(guān)節(jié)內(nèi)骨贅形成[18]。由此可見，WNT信號通路對關(guān)節(jié)軟骨及軟骨下骨穩(wěn)態(tài)發(fā)揮著重要的調(diào)節(jié)作用，OA關(guān)節(jié)軟骨與軟骨下骨病理上的相互作用可能涉及WNT信號通路的異常活動，軟骨及軟骨下骨分泌的WNT信號激動劑和拮抗劑可能是OA骨-軟骨相互作用的效應(yīng)分子。

2.2轉(zhuǎn)化生長因子β(transforming growth factor-β，TGF-β)/骨形態(tài)發(fā)生蛋白(bone morphogenetic protein，BMP)信號機(jī)制與骨-軟骨交互作用TGF-β和BMP在胚胎發(fā)育、組織穩(wěn)態(tài)和多種疾病的發(fā)病機(jī)制中起著關(guān)鍵作用。BMP是具有調(diào)節(jié)骨骼系統(tǒng)細(xì)胞外基質(zhì)合成和骨重構(gòu)等多種功能的高度保守的蛋白。BMP通過經(jīng)典Smad信號通路介導(dǎo)骨誘導(dǎo)，促進(jìn)軟骨內(nèi)成骨及軟骨特異性Smad1、5基因缺失小鼠出現(xiàn)嚴(yán)重的軟骨發(fā)育異常[19]。BMP-2、BMP-4、BMP-5、BMP-6、BMP-11和生長分化因子5(growth differentiation factor 5,GDF5)在正常及OA患者軟骨均有表達(dá)[20]。局部分泌的BMPs在軟骨生物學(xué)中的具體作用還不明確，但有研究發(fā)現(xiàn)，BMPs參與調(diào)節(jié)蛋白多糖和蛋白聚糖的合成，在軟骨保護(hù)及修復(fù)中發(fā)揮作用[21-22]。BMPs信號通路除促進(jìn)軟骨基質(zhì)合成外，還可促進(jìn)軟骨細(xì)胞終末分化，導(dǎo)致MMP-13大量分泌，軟骨降解[23]。同時，BMPs也是強(qiáng)有力的成骨刺激因子，可調(diào)節(jié)體內(nèi)外成骨細(xì)胞和破骨細(xì)胞活動[24]。GDF5(BMP信號通路激活因子)單缺陷小鼠可出現(xiàn)軟骨下骨密度下降及骨組織膠原纖維排列紊亂[25]，證明BMP信號通路在軟骨下骨重構(gòu)中具有重要的調(diào)節(jié)作用。伴隨BMPs，TGF-β在維持關(guān)節(jié)完整及代謝平衡中也發(fā)揮著不可或缺的作用。TGF-β是細(xì)胞外基質(zhì)合成的強(qiáng)誘導(dǎo)劑，TGF-β 的缺失可導(dǎo)致蛋白多糖丟失和軟骨降解[26]。內(nèi)源性TGF-β1活性抑制可阻抑OA大鼠關(guān)節(jié)內(nèi)骨贅形成，但同時也可加快軟骨降解過程[27]。除調(diào)節(jié)軟骨穩(wěn)態(tài)外，TGF-β1還參與骨吸收過程，并誘導(dǎo)骨髓間充質(zhì)干細(xì)胞向骨吸收區(qū)遷移形成新骨[28]。OA損傷軟骨大量分泌TGF-β[29]，軟骨下骨TGF-β 活性顯著提高[30]，提示TGF-β可能是OA骨-軟骨相互影響的信號機(jī)制之一。此外，骨-軟骨之間可能存在WNT信號通路與TGF-β信號通路的交聯(lián)。OA患者軟骨中經(jīng)典WNT信號激活后可誘導(dǎo)軟骨分泌WNT誘導(dǎo)信號蛋白1[17]，WNT誘導(dǎo)信號蛋白1 可通過增強(qiáng)成骨細(xì)胞分化促進(jìn)成骨過程[31]，提示OA中WNT誘導(dǎo)信號蛋白1 可能通過誘導(dǎo)軟骨下骨成骨過程加速軟骨下骨OA樣變化。

2.3絲裂原活化蛋白激酶(mitogen-activated protein kinases，MAPKs)信號機(jī)制與骨-軟骨交互作用MAPKs包括三大類激酶，即細(xì)胞外信號調(diào)節(jié)激酶(the extracelluar signal-regulated kinases，ERKs)、c-Jun氨基末端激酶(c-Jun N-terminal kinases，JNKs)和p38激酶。這三類激酶不僅在骨、軟骨生物學(xué)中具有重要調(diào)節(jié)作用，而且也涉及OA病理過程。ERK和p38的激活是關(guān)節(jié)軟骨退變的上游關(guān)鍵信號，ERK和p38信號的激活是MMPs表達(dá)和活化的必要條件，而ERK激活是聚蛋白多糖酶介導(dǎo)的軟骨退變的必須條件[32]。機(jī)械應(yīng)變可誘導(dǎo)成骨細(xì)胞內(nèi)ERK信號的激活，導(dǎo)致成骨細(xì)胞合成MMP-13[33]，提示OA進(jìn)程中機(jī)械應(yīng)變可誘導(dǎo)軟骨下骨中的成骨細(xì)胞合成MMP-13，促進(jìn)軟骨退變。體外研究發(fā)現(xiàn)，正常軟骨細(xì)胞可抑制軟骨下成骨細(xì)胞分化，而OA軟骨細(xì)胞可促進(jìn)軟骨下成骨細(xì)胞分化，后者與ERK的激活密不可分[34]。ERK-1/2磷酸化和p38去磷酸化可介導(dǎo)OA軟骨細(xì)胞與軟骨下骨細(xì)胞的病理性相互作用，導(dǎo)致軟骨細(xì)胞呈現(xiàn)肥大表型[35]。還有研究發(fā)現(xiàn)，OA軟骨或軟骨下骨可釋放一些未知可溶性因子，這些因子通過激活正?；騉A軟骨或軟骨下骨ERK信號通路介導(dǎo)蛋白聚糖酶和MMPs的釋放[36]。以上研究結(jié)果表明，OA軟骨與軟骨下骨存在異常細(xì)胞間通訊并借此相互影響，MAPKs信號通路很可能是其物質(zhì)基礎(chǔ)。

3小結(jié)

滑膜關(guān)節(jié)內(nèi)，結(jié)構(gòu)上的緊密聯(lián)系使關(guān)節(jié)軟骨與軟骨下骨得以通過分子間相互作用并借此在組織結(jié)構(gòu)和功能上相互影響。OA軟骨下骨新生血管向軟骨層的入侵以及軟骨和軟骨下骨微裂隙的形成為骨-軟骨間分子交互作用提供了結(jié)構(gòu)基礎(chǔ)。由軟骨及軟骨下骨分泌的多種生物因子在OA病理生理中發(fā)揮重要的調(diào)控作用，其中尤以WNT、BMP、TGF-β和MAPK等關(guān)節(jié)穩(wěn)態(tài)相關(guān)信號分子較為突出，可能是OA骨-軟骨交互作用的分子基礎(chǔ)。

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Research Progress of Cross Talk between Cartilage and Subchondral Bone in OsteoarthritisZHENGJie1,WANGRui-hui1,KOUJiu-she2.(1.DepartmentofAcupunctureandMoxibustion,ShaanxiUniversityofChineseMedicine,Xianyang712046，China； 2.DepartmentofAcupuncture&Rehabilitation,theSecondAffiliatedHospitalofShaanxiUniversityofChineseMedicine,Xianyang712046,China)

Abstract:During osteoarthritis(OA),functional units of joints comprising cartilage and subchondral bone undergo uncontrolled catabolic and anabolic remodeling processes to adapt to local biochemical and biological signals.There is interplay between articular cartilage and subchondral bone in OA pathology.Formation of vascularization and microcracks in joints contribute to molecular crosstalk between cartilage and subchondral bone during the process of OA.Wingless-type,bone morphogenic protein,transforming growth factor-β and mitogen-activated protein kinases signals may be the molecular basis for interaction of cartilage and subchondral bone in OA pathology.

Key words:Osteoarthritis； Cartilage； Wingless-type; Bone morphogenic protein； Mitogen-activated protein kinases

收稿日期：2014-10-10修回日期：2014-12-03編輯：鄭雪

基金項(xiàng)目：陜西省中醫(yī)康復(fù)學(xué)重點(diǎn)學(xué)科建設(shè)項(xiàng)目(陜中醫(yī)藥發(fā)〔2011〕46號)；陜西省教育廳科學(xué)研究項(xiàng)目(14JK1209)；陜西中醫(yī)學(xué)院創(chuàng)新基金培育項(xiàng)目(14XJZR27)

doi：10.3969/j.issn.1006-2084.2015.14.005

中圖分類號：R683

文獻(xiàn)標(biāo)識碼：A

文章編號：1006-2084(2015)14-2507-03