劉立杰,吳國(guó)民,胡敏
(吉林大學(xué)口腔醫(yī)院口腔正畸科1、口腔頜面外科2,吉林長(zhǎng)春130021)
軟骨下骨作為骨關(guān)節(jié)炎治療靶點(diǎn)的研究進(jìn)展
劉立杰1,吳國(guó)民2,胡敏1
(吉林大學(xué)口腔醫(yī)院口腔正畸科1、口腔頜面外科2,吉林長(zhǎng)春130021)
骨關(guān)節(jié)炎是關(guān)節(jié)疾病的主要類型之一,嚴(yán)重影響人群的生活質(zhì)量。長(zhǎng)期以來關(guān)節(jié)軟骨的修復(fù)障礙一直被認(rèn)為是關(guān)節(jié)退化的主要原因,現(xiàn)在人們逐步認(rèn)識(shí)到軟骨下骨及其分子代謝在骨關(guān)節(jié)炎的發(fā)生發(fā)展中發(fā)揮了重要作用,但關(guān)節(jié)軟骨與軟骨下骨在骨關(guān)節(jié)炎中產(chǎn)生相關(guān)分子代謝之間的聯(lián)系尚不明確,對(duì)于軟骨下骨的分子水平改變的闡述對(duì)于骨關(guān)節(jié)炎的早期診斷以及尋找有效的治療手段都會(huì)有重要意義。
關(guān)節(jié)炎;關(guān)節(jié)軟骨;軟骨下骨;骨重建
骨關(guān)節(jié)炎(Osteoarthritis,OA)是一種常見的關(guān)節(jié)疾病,是以關(guān)節(jié)軟骨的變性破壞及骨質(zhì)增生為特征的慢性關(guān)節(jié)疾病。OA的主要病理改變包括:骨關(guān)節(jié)軟骨的退行性變和繼發(fā)骨質(zhì)增生,具體表現(xiàn)為關(guān)節(jié)軟骨破壞、關(guān)節(jié)表面形成骨贅、滑膜細(xì)胞反應(yīng)性增生、滑膜炎和關(guān)節(jié)間隙變窄等[1]。反復(fù)創(chuàng)傷是OA發(fā)病的首要原因,除此之外,年齡、遺傳因素、更年期雌激素不足、肥胖以及職業(yè)因素也與其發(fā)病相關(guān)[2]。迄今為止,我們對(duì)軟骨下骨在OA疾病進(jìn)程中的作用機(jī)制還所知甚少。長(zhǎng)期以來,關(guān)節(jié)軟骨的退變和降解一直被認(rèn)為是OA發(fā)病的主要因素,現(xiàn)已逐步認(rèn)識(shí)到軟骨下骨及其分子代謝的病理變化在關(guān)節(jié)退變過程中發(fā)揮了重要的作用[3]。所以,我們?cè)诒揪C述中主要介紹國(guó)內(nèi)外學(xué)者對(duì)于軟骨下骨在OA疾病進(jìn)程和治療中的研究進(jìn)展。
目前,對(duì)軟骨下骨與關(guān)節(jié)軟骨之間的具體聯(lián)系報(bào)道甚少。1970年,Radin等[4]通過對(duì)45個(gè)生前膝關(guān)節(jié)病的膝關(guān)節(jié)標(biāo)本的尸檢發(fā)現(xiàn),關(guān)節(jié)產(chǎn)生退行性變化時(shí)軟骨下骨出現(xiàn)了不同程度的黏多糖(Mucopolysaccharides,MPS)丟失。1986年,Radin等[5]首次提出了軟骨下骨硬化可能是導(dǎo)致軟骨損傷的重要因素,Radin等認(rèn)為:軟骨下骨的主要作用是吸收應(yīng)力和緩沖震蕩,軟骨下骨剛度的增加使關(guān)節(jié)軟骨所受負(fù)荷增大,當(dāng)超過軟骨負(fù)荷限度后就會(huì)引起關(guān)節(jié)軟骨退化,高負(fù)荷引起的微骨折會(huì)促進(jìn)軟骨下骨的修復(fù)作用,使其進(jìn)一步增厚。1991年,Brandt等[6]通過對(duì)狗前交叉韌帶橫斷術(shù)后形成的膝關(guān)節(jié)OA動(dòng)物模型研究發(fā)現(xiàn),OA誘導(dǎo)第54周,既OA病程的后期,骨生成活躍,軟骨下骨骨量明顯增加。1994年,Carlson等[7]在靈長(zhǎng)類動(dòng)物的OA模型中發(fā)現(xiàn),類骨質(zhì)量的增加通常比軟骨的改變更加嚴(yán)重,在OA的進(jìn)展期出現(xiàn)大量的軟骨纖維化和軟骨丟失。2004年,Pelletier等[8]通過研究前交叉韌帶橫斷術(shù)后的狗OA模型也說明了OA早期出現(xiàn)了軟骨下骨變薄和骨小梁變小的病理改變。以上研究證明,在OA的病理過程中軟骨下骨的重建貫穿了疾病發(fā)生發(fā)展的全過程。
以顳下頜關(guān)節(jié)為例,顳下頜關(guān)節(jié)髁突是由覆蓋在表面的軟骨及軟骨下骨構(gòu)成的[9],關(guān)節(jié)表面軟骨由于不斷發(fā)生著生理改建,由上至下可分為四層:纖維層、增生層、肥大層和鈣化軟骨層。組織學(xué)染色時(shí),可發(fā)現(xiàn)增生層與肥大層間有一條嗜堿性的波浪線,被稱為潮標(biāo)(Tidemark)[10],鈣化軟骨層下為軟骨下板,與鈣化軟骨層合稱骨-軟骨交界,是高血管化的皮質(zhì)骨[11],其下為軟骨下骨。髁突軟骨下骨主要由骨小梁和骨髓腔組成,骨小梁從髁突頸部大致呈放射狀排列,垂直于關(guān)節(jié)表面,與髁突受力方向平行。軟骨下骨是髁突中剛性較大的結(jié)構(gòu)和外力的主要承擔(dān)者,對(duì)其上覆蓋的軟骨起到重要支撐作用[12]。OA時(shí)軟骨下骨的病理改變?yōu)椋很浌窍鹿潜┞丁⒐切×何⑿」钦?、骨局部溶解及被纖維粘液樣組織取代形成軟骨下囊腫。骨組織修復(fù)表現(xiàn)為軟骨下骨質(zhì)增生和硬化,表層骨小梁增厚、關(guān)節(jié)面重建和骨贅形成以及軟骨下囊腫周圍骨質(zhì)反應(yīng)性增生。
OA病程中的骨重建包括骨形成與骨吸收。現(xiàn)普遍認(rèn)為[13],軟骨下骨在OA早期表現(xiàn)為骨吸收,在OA的晚期則表現(xiàn)為骨硬化,骨硬化則是骨關(guān)節(jié)炎病理改變的標(biāo)志之一。2002年,Bettica等[14]的一項(xiàng)人群縱向研究顯示,通過仔細(xì)評(píng)估一些膝關(guān)節(jié)OA患者不同時(shí)期內(nèi)的骨吸收標(biāo)志物NTXs(Serum amino terminal telopeptides)與CTXs(Serum carboxy terminal telopeptides),發(fā)現(xiàn)在OA早期并處于進(jìn)展期的膝關(guān)節(jié)出現(xiàn)了軟骨下骨的吸收,在非進(jìn)展期的病例中未出現(xiàn)骨吸收。2004年,Hayami等[15]通過大鼠OA模型發(fā)現(xiàn)OA早期骨吸收增強(qiáng)并出現(xiàn)骨小梁變小和破骨細(xì)胞數(shù)量增加的變化。2011年Jiao等[16]也發(fā)現(xiàn)大鼠OA病程中出現(xiàn)了以BMD(Bone mineral density)、BV/TV (Bone volume/tissue volume)和Tb.Th(trabecular thickness)下降以及Tb.Sp(Trabecular separation)上升為特征的軟骨下骨丟失,這些骨密度變化伴隨著新骨形成的減少,同時(shí)血清CTXs與破骨細(xì)胞數(shù)目在軟骨下骨表面區(qū)域的增加,反映出骨吸收水平升高。1999年,Pastoureau等[17]通過X線對(duì)月板切除術(shù)后的豬OA模型的骨密度檢測(cè),發(fā)現(xiàn)軟骨下骨吸收后出現(xiàn)了明顯的骨密度增加。2004年,Lajeunesse[18]在其一篇綜述中提出在OA的進(jìn)程中軟骨下骨在高頻改建時(shí)會(huì)有多種多樣的細(xì)胞因子與生長(zhǎng)因子參與,這些細(xì)胞因子和生長(zhǎng)因子能夠進(jìn)入軟骨下骨表面覆蓋的軟骨來調(diào)節(jié)軟骨細(xì)胞生物學(xué)行為,從而形成一個(gè)軟骨與軟骨下骨間的正反饋環(huán)路。2008年,Kadri等[19]通過對(duì)右側(cè)膝關(guān)節(jié)進(jìn)行半月板切除小鼠模型注射骨保護(hù)素,發(fā)現(xiàn)接受OPG治療的OA關(guān)節(jié)的BV/TV相比對(duì)照組有顯著提升,而Tb.Sp值減少,與此同時(shí),OA關(guān)節(jié)的OA指數(shù)與聚蛋白多糖酶(A disintegrin and metalloproteinase with thrombospondin motifs,ADAMTS)卻顯著下降,表明OPG在作用于軟骨下骨的同時(shí)抑制了軟骨退化,間接證明了Lajeunesse[18]的假設(shè)。
3.1 Wnt/β-catenin信號(hào)通路Wnt/β-catenin信號(hào)通路又稱經(jīng)典Wnt通路,是調(diào)節(jié)軟骨生長(zhǎng)及其內(nèi)穩(wěn)態(tài)的關(guān)鍵通路之一,根據(jù)現(xiàn)有研究,其作用機(jī)制為[20]:Wnt配體蛋白與靶細(xì)胞膜上的7次穿膜蛋白(Fz,F(xiàn)rizzled)及其共同受體LRP-5/6(Low-density lipoprotein receptor related protein-5/6)結(jié)合形成復(fù)合物,激活細(xì)胞內(nèi)散亂蛋白(Dvl,Dishevelled)磷酸化,繼而釋放信號(hào)抑制糖原合成激酶3(GSK-3)的激活,從而抑制下游酪蛋白激-結(jié)直腸腺瘤性息肉蛋白-糖原合成酶激酶3β-軸蛋白(CK-APC-GSK3β-Axin)復(fù)合物的聚合,這意味著胞質(zhì)蛋白(β-catenin)降解的減少,使β-catenin在細(xì)胞內(nèi)積累并有機(jī)會(huì)進(jìn)入細(xì)胞核與核內(nèi)轉(zhuǎn)錄因子/淋巴樣增強(qiáng)因子(TCF/LEF)形成復(fù)合體,特異性啟動(dòng)下游靶基因轉(zhuǎn)錄(見圖1a)。Wnt信號(hào)通路與成骨細(xì)胞的分化和成熟密切相關(guān)。Wnt信號(hào)通路不僅能激活間充質(zhì)干細(xì)胞的成骨方向分化,并且在激活骨性關(guān)節(jié)炎患者關(guān)節(jié)軟骨下骨骨化過程中發(fā)揮重要作用,因此Wnt信號(hào)通路對(duì)骨組織的調(diào)節(jié)作用主要表現(xiàn)在胚胎時(shí)期的骨發(fā)育、骨量調(diào)節(jié)以及骨的再生過程,在骨折修復(fù)中也起重要作用[20]。對(duì)于軟骨,Wnt通路已被研究證實(shí)[21]可以在間充質(zhì)干細(xì)胞分化初期調(diào)控軟骨分化及軟骨細(xì)胞表型的生成。Wnt信號(hào)通路與體內(nèi)多種細(xì)胞因子互有協(xié)同、拮抗作用。Dkk1 (Dickkopf1)是一種Wnt信號(hào)通路的可溶性細(xì)胞外抑制劑,通過直接或間接競(jìng)爭(zhēng)性結(jié)合Wnt蛋白的共同受體-LRP-5/6,阻斷Wnt信號(hào)通路[20]。Wnt與OPG/ RANK/RANKL通路也相互影響,由于Wnt信號(hào)通路可促進(jìn)間充質(zhì)干細(xì)胞向成骨細(xì)胞分化,上調(diào)其OPG的表達(dá),進(jìn)一步抑制了RANK發(fā)揮誘導(dǎo)破骨細(xì)胞分化的生物學(xué)效應(yīng)。而Dkk1通過阻斷Wnt信號(hào)通路而減少OPG的表達(dá),從而增強(qiáng)RANK發(fā)揮誘導(dǎo)破骨細(xì)胞分化的生物學(xué)效應(yīng),因此,Dkk1具有間接誘導(dǎo)破骨細(xì)胞分化成熟的作用[22]。另一個(gè)可以抑制Wnt信號(hào)通路的物質(zhì)是骨硬化蛋白(Sclerostin,SOST),其可以與LRP-5/6結(jié)合從而破壞Frizzled-LRP-5/6復(fù)合體,達(dá)到抑制Wnt信號(hào)通路的效果[23](見圖1b)。
圖1 Wnt/β-catenin信號(hào)通路受Dkk1及SOST的調(diào)控機(jī)制
3.2 OPG/RANKL/RANK通路OPG/RANKL/ RANK通路是成骨細(xì)胞與破骨細(xì)胞之間相互作用的重要信號(hào)通道。成骨細(xì)胞分泌RANKL(Receptor activator of nuclear factor-κB ligand)與破骨細(xì)胞前體(Os-teoclast precursors,OCPs)上的RANK(Receptor activator of nuclear factor-κB)結(jié)合后促進(jìn)破骨細(xì)胞的分化成熟及其活性增強(qiáng),并影響相關(guān)基因表達(dá)。而包括成骨細(xì)胞在內(nèi)的間質(zhì)細(xì)胞也可以分泌骨保護(hù)素(Osteoprotegerin,OPG)與RANK競(jìng)爭(zhēng)性結(jié)合RANKL,從而降低破骨細(xì)胞活性,促進(jìn)骨形成[24-25]。因此,OPG/RANKL的比率對(duì)于骨量與骨質(zhì)的變化具有決定性的影響[26]。2008年,Kwan Tat等[27]的研究在OA患者身上驗(yàn)證了這點(diǎn),他們依據(jù)OPG/RANKL比率將軟骨下骨中的成骨細(xì)胞分為兩種,高比率組與低比率組,不同比率的成骨細(xì)胞可以誘導(dǎo)分化的破骨細(xì)胞數(shù)量不同,在OA患者體內(nèi),低比率的OPG/RANKL對(duì)應(yīng)軟骨下骨有大量破骨細(xì)胞,而高比率正好相反,OPG/RANKL的比率決定了破骨細(xì)胞介導(dǎo)的骨吸收的水平。2008年,Zhang等[28]發(fā)現(xiàn)RANKL可刺激破骨細(xì)胞及其前體細(xì)胞釋放VEGF-C,說明VEGF-C基因也是RANKL的靶基因之一,通過自分泌作用調(diào)節(jié)破骨細(xì)胞活性2014年,Kukiat等[29]在凝血酶受體(Thrombin recptor,TR)基因敲除小鼠發(fā)現(xiàn),由于缺乏凝血酶受體,小鼠體內(nèi)成骨細(xì)胞分泌的RANKL減少,而OPG的特征性升高,使正常的破骨細(xì)胞生成速率減緩,最終導(dǎo)致骨量增加。基于OPG/RANKL/RANK通路在OA過程中的重要作用,一些旨在通過調(diào)節(jié)該通路活性阻止OA進(jìn)展的相關(guān)研究已在進(jìn)行[25]。
3.3 IGF與TGF-β1IGF是調(diào)節(jié)骨形成的重要的生長(zhǎng)因子之一。2005年,Koch等[30]發(fā)現(xiàn)IGF可以上調(diào)人骨髓間充質(zhì)干細(xì)胞(hMSCs)早期成骨基因的表達(dá),包括I型膠原、堿性磷酸酶、轉(zhuǎn)錄因子Runx2基因,骨髓間充質(zhì)干細(xì)胞能進(jìn)一步分化為成骨細(xì)胞。在骨關(guān)節(jié)炎時(shí),軟骨下骨的成骨細(xì)胞可以產(chǎn)生大量的不同類型的IGF-1,同時(shí)其生成的IGF-1結(jié)合蛋白相比正常軟骨下骨減少[31],因此大量的游離IGF-1促進(jìn)骨重建,導(dǎo)致骨硬化的發(fā)生,這同時(shí)加劇了軟骨基質(zhì)的退化。TGF-β信號(hào)通路可以維持健康軟骨的新陳代謝穩(wěn)態(tài)及其結(jié)構(gòu)的完整性。而在OA過程中,退化軟骨引起的TGF-β增加可能同時(shí)對(duì)軟骨及軟骨下骨中穩(wěn)態(tài)產(chǎn)生作用,表明TGF-β可能對(duì)于軟骨及軟骨下骨起到媒介作用[32]。2009年,Couchourel等[33]發(fā)現(xiàn)OA軟骨下骨的成骨細(xì)胞無法正常礦化,而通過持續(xù)性的抑制TGF-β1水平可以增加其礦化程度。2013年,Zhen等[34]對(duì)行前交叉韌帶切斷術(shù)的大鼠OA模型的研究發(fā)現(xiàn),軟骨下骨中的TGF-β對(duì)于改變的機(jī)械負(fù)荷反應(yīng)性激活,軟骨下骨中增長(zhǎng)的TGF-β使得間質(zhì)干細(xì)胞、骨祖細(xì)胞以及成骨細(xì)胞的數(shù)目增加,導(dǎo)致了異常的骨重建以及血管形成。
3.4 Sox9轉(zhuǎn)錄因子與Ⅱ型膠原Sox蛋白家族對(duì)很多生發(fā)過程都起重要作用,Sox9轉(zhuǎn)錄因子是其中一員。它在間質(zhì)細(xì)胞分化為軟骨細(xì)胞的過程中起到關(guān)鍵作用[35],在軟骨生成的地方可以發(fā)現(xiàn)大量Sox9,間質(zhì)細(xì)胞在分化為軟骨細(xì)胞之前濃縮時(shí)也能找到豐富的Sox9。在髁突軟骨中,Sox9可以調(diào)節(jié)軟骨細(xì)胞合成Ⅱ型膠原[36]。Ⅱ型膠原只存在于軟骨中,間質(zhì)細(xì)胞在分化為軟骨細(xì)胞并成熟后開始表達(dá)Ⅱ型膠原,它是髁突中軟骨生成的標(biāo)志[35]。Sox9可以受到甲狀旁腺相關(guān)肽的作用而上調(diào)[37]。2014年,Juhasz等[38]通過對(duì)體外培養(yǎng)的軟骨祖細(xì)胞進(jìn)行生物機(jī)械刺激發(fā)現(xiàn),軟骨祖細(xì)胞向軟骨細(xì)胞的分化以及細(xì)胞外基質(zhì)出現(xiàn)了明顯增長(zhǎng),而Sox9基因再其過程中發(fā)揮了關(guān)鍵的作用,表明Sox9基因在壓力的傳導(dǎo)和應(yīng)答中可能發(fā)揮重要作用。
3.5 PTH甲狀旁腺激素(Parathyroid hormone,PTH)是人體鈣磷代謝最重要的調(diào)節(jié)因子,血清鈣水平降低時(shí)其會(huì)反應(yīng)性的表達(dá)增加,其分泌過多會(huì)導(dǎo)致骨吸收的發(fā)生,而低劑量的、間歇性的作用卻可以促進(jìn)骨量增加[39]。近年來的動(dòng)物實(shí)驗(yàn)表明,一種人工合成的甲狀旁腺激素PTH(1-34)可以改善OA中軟骨表面的結(jié)構(gòu),并有助于軟骨下骨重建[40]。2014年,Yan等[41]通過對(duì)豚鼠自然OA模型的研究發(fā)現(xiàn),相比對(duì)照組,PTH(1-34)治療組軟骨中Ⅱ型膠原表達(dá)增高,SOST表達(dá)降低,OPG/RANKL的比率升高,同時(shí)軟骨下小梁骨的數(shù)量增加。表明PTH(1-34)具有阻止OA軟骨破壞及延遲軟骨下小梁骨退化的作用。
3.6 M-CSF巨噬細(xì)胞集落刺激因子(Macrophage colony-stimulating factor,M-CSF)與RANKL是破骨細(xì)胞分化成熟的兩個(gè)必須因子[26]。M-CSF是由包括成骨細(xì)胞在內(nèi)的間質(zhì)細(xì)胞分泌的一種糖蛋白生長(zhǎng)因子。M-CSF可以通過與細(xì)胞表面的選擇性表達(dá)受體c-Fms結(jié)合而特異性調(diào)節(jié)單核巨噬細(xì)胞系統(tǒng)的增殖、分化并且維持其活性。2007年,Jason等[42]通過骨誘裂的體外研究不僅驗(yàn)證了M-CSF可以調(diào)節(jié)破骨細(xì)胞的增生分化以及其細(xì)胞前體融合等多個(gè)步驟,并發(fā)現(xiàn)M-CSF還可以調(diào)節(jié)成熟破骨細(xì)胞的吸收活性,其在細(xì)胞質(zhì)中的傳播同時(shí)抑制成熟破骨細(xì)胞的凋亡,Jason認(rèn)為M-CSF對(duì)于破骨細(xì)胞的存活不是必須的。
目前尚無可以有效阻止OA進(jìn)一步破壞關(guān)節(jié)、或者可恢復(fù)關(guān)節(jié)功能的治療手段。全關(guān)節(jié)置換(Total joint replacement,TJR)雖然可有效改善生活質(zhì)量,但作為一種花費(fèi)高昂且需不可逆移除大量原有組織的外科手段,只能作為老年OA患者的最終選擇[43]。隨著分子生物學(xué)的發(fā)展,生物標(biāo)記技術(shù)、組織工程技術(shù)、分子靶向治療以及基因治療等技術(shù)對(duì)于治療OA均呈現(xiàn)出巨大潛力[44]。與此同時(shí),軟骨下骨在OA發(fā)病過程中的重要作用已經(jīng)被越來越多的研究得以證明,其分子代謝的過程以及其與關(guān)節(jié)軟骨在OA進(jìn)展中相互作用得到的研究與認(rèn)識(shí),為OA的早期診斷及治療提供了新的策略與研究方向。
[1]Bonnet CS,Walsh DA.Osteoarthritis,angiogenesis and inflammation[J].Rheumatology,2005,44(1)∶7-16.
[2]Herrero-Beaumont G,Roman-Blas JA,Casta?eda S,et al.Primary osteoarthritis no longer primary∶three subsets with distinct etiological,clinical,and therapeutic characteristics[C]//Seminars in arthritis and rheumatism.WB Saunders,2009,39(2)∶71-80.
[3]Goldring S,Goldring M.Bone and cartilage in osteoarthritis∶is what's best for one good or bad for the other?[J].Arthritis Research and Therapy,2010,12(5)∶143.
[4]Radin EL,Paul IL,Tolkoff MJ.Subchondral bone changes in patients with early degenerative joint disease[J].Arthritis&Rheumatism,1970,13(4)∶400-405.
[5]Radin EL,Rose RM.Role of subchondral bone in the initiation and progression of cartilage damage[J].Clinical Orthopaedics and Related Research,1986,213∶34-40.
[6]Brandt KD,Myers SL,Burr D,et al.Osteoarthritic changes in canine articular cartilage,subchondral bone,and synovium fifty-four months after transection of the anterior cruciate ligament[J].Arthritis&Rheumatism,1991,34(12)∶1560-1570.
[7]Carlson CS,Loeser RF,Jayo MJ,et al.Osteoarthritis in cynomolgus macaques∶a primate model of naturally occurring disease[J].Journal of Orthopaedic Research,1994,12(3)∶331-339.
[8]Pelletier JP,Boileau C,Brunet J,et al.The inhibition of subchondral bone resorption in the early phase of experimental dog osteoarthritis by licofelone is associated with a reduction in the synthesis of MMP-13 and cathepsin K[J].Bone,2004,34(3)∶527-538.
[9]Rabie ABM,Tsai MJM,H?gg U,et al.The correlation of replicating cells and osteogenesis in the condyle during stepwise advancement [J].TheAngle Orthodontist,2003,73(4)∶457-465.
[10]Chen R,Chen S,Chen XM,et al.Study of the tidemark in human mandibular condylar cartilage[J].Archives of Oral Biology,2011, 56(11)∶1390-1397.
[11]Pesesse L,Sanchez C,Henrotin Y.Osteochondral plate angiogenesis∶a new treatment target in osteoarthritis[J].Joint Bone Spine, 2011,78(2)∶144-149.
[12]Hongo T,Orihara K,Onoda Y,et al.Quantitative and morphological studies of the trabecular bones in the condyloid processes of the Japanese mandibles;changes due to aging[J].The Bulletin of Tokyo Dental College,1989,30(3)∶165.
[13]Al-kalaly AA,Leung FYC,Wong RWK,et al.The molecular markers for condylar growth∶Experimental and clinical implications[J]. Orthodontic Waves,2009,68(2)∶51-56.
[14]Bettica P,Cline G,Hart D J,et al.Evidence for increased bone resorption in patients with progressive knee osteoarthritis∶longitudinal results from the Chingford study[J].Arthritis&Rheumatism, 2002,46(12)∶3178-3184.
[15]Hayami T,Pickarski M,Wesolowski GA,et al.The role of subchondral bone remodeling in osteoarthritis∶reduction of cartilage degeneration and prevention of osteophyte formation by alendronate in the rat anterior cruciate ligament transection model[J].Arthritis& Rheumatism,2004,50(4)∶1193-1206.
[16]Jiao K,Niu LN,Wang MQ,et al.Subchondral bone loss following orthodontically induced cartilage degradation in the mandibular condyles of rats[J].Bone,2011,48(2)∶362-371.
[17]Pastoureau PC,Chomel AC,Bonnet J.Evidence of early subchondral bone changes in the meniscectomized guinea pig.A densitometric study using dual-energy X-ray absorptiometry subregional analysis[J].Osteoarthritis and Cartilage,1999,7(5)∶466-473.
[18]Lajeunesse D.The role of bone in the treatment of osteoarthritis[J]. Osteoarthritis and Cartilage,2004,12∶34-38.
[19]Kadri A,Ea HK,Bazille C,et al.Osteoprotegerin inhibits cartilage degradation through an effect on trabecular bone in murine experimental osteoarthritis[J].Arthritis&Rheumatism,2008,58(8)∶2379-2386.
[20]Chen Y,Alman BA.Wnt pathway,an essential role in bone regeneration[J].Journal of Cellular Biochemistry,2009,106(3)∶353-362.
[21]Velasco J,Zarrabeitia MT,Prieto JR,et al.Wnt pathway genes in osteoporosis and osteoarthritis∶differential expression and genetic association study[J].Osteoporosis International,2010,21(1)∶109-118.
[22]Heath DJ,Chantry AD,Buckle CH,et al.Inhibiting Dickkopf-1 (Dkk1)removes suppression of bone formation and prevents the development of osteolytic bone disease in multiple myeloma[J].Journal of Bone and Mineral Research,2009,24(3)∶425-436.
[23]Poole KES,van Bezooijen RL,Loveridge N,et al.Sclerostin is a delayed secreted product of osteocytes that inhibits bone formation [J].The FASEB Journal,2005,19(13)∶1842-1844.
[24]Tanaka S.Signaling axis in osteoclast biology and therapeutic targeting in the RANKL/RANK/OPG system[J].American Journal of Nephrology,2007,27(5)∶466-478.
[25]Rigoglou S,Papavassiliou AG,The NF-κB signalling pathway in osteoarthritis[J].The International Journal of Biochemistry&Cell Biology,2013,45(11)∶2580-2584.
[26]Boyce BF,Xing L.Biology of RANK,RANKL,and osteoprotegerin[J].Arthritis Research and Therapy,2007,9(1)∶S1.
[27]Kwan Tat S,Pelletier JP,Lajeunesse D,et al.The differential expression of osteoprotegerin(OPG)and receptor activator of nuclear factor kappa B ligand(RANKL)in human osteoarthritic subchondral bone osteoblasts is an indicator of the metabolic state of these disease cells[J].Clinical and Experimental Rheumatology,2008,26 (2)∶295-304.
[28]Zhang Q,Guo R,Lu Y,et al.VEGF-C,a lymphatic growth factor,is a RANKL target gene in osteoclasts that enhances osteoclastic bone resorption through an autocrine mechanism[J].Journal of Biological Chemistry,2008,283(19)∶13491-13499.
[29]Tudpor K,vander Eerden BC,Jongwattanapisan P,et al.Thrombin receptor deficiency leads to a high bone mass phenotype by decreasing the RANKL/OPG ratio[J].Bone,2014,18,72C∶14-22.
[30]Koch H,Jadlowiec JA,Campbell PG.Insulin-like growth factor-I induces early osteoblast gene expression in human mesenchymal stem cells[J].Stem Cells and Development,2005,14(6)∶621-631.
[31]Massicotte F,Fernandes JC,Martel-Pelletier J,et al.Modulation of insulin-like growth factor 1 levels in human osteoarthritic subchondral bone osteoblasts[J].Bone,2006,38(3)∶333-341.
[32]Yuan XL,Meng HY,Wang YC,et al.Bone-cartilage interface crosstalk in osteoarthritis∶potential pathways and future therapeutic strategies[J].Osteoarthritis and Cartilage,2014,22(8)∶1077-1089.
[33]Couchourel D,Aubry I,Delalandre A,et al.Altered mineralization of human osteoarthritic osteoblasts is attributable to abnormal type I collagen production[J].Arthritis&Rheumatism,2009,60 (5)∶1438-1450.
[34]Zhen GC.Wen XJ,Li Y,et al.Inhibition of TGF-beta signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis[J].Nat Med,2013,19∶704-712.
[35]Rabie ABM,She TT,H?gg U.Functional appliance therapy accelerates and enhances condylar growth[J].American Journal of Orthodontics and Dentofacial Orthopedics,2003,123(1)∶40-48.
[36]Suda N,Shibata S,Yamazaki K,et al.Parathyroid Hormone-Related Protein Regulates Proliferation of Condylar Hypertrophic Chondrocytes[J].Journal of Bone and Mineral Research,1999,14(11)∶1838-1847.
[37]Huang W,Chung U,Kronenberg HM,et al.The chondrogenic transcription factor Sox9 is a target of signaling by the parathyroid hormone-related peptide in the growth plate of endochondral bones[J]. Proceedings of the National Academy of Sciences,2001,98(1)∶160-165.
[38]Juhasz T,Matta C,Somogyi C,et al.Mechanical loading stimulates chondrogenesis via the PKA/CREB-Sox9 and PP2A pathways in chicken micromass cultures[J].Cell Signal,2014,26(3)∶468-482.
[39]Lombardi G,Di Somma C,Rubino M,et al.The roles of parathyroid hormone in bone remodeling∶prospects for novel therapeutics [J],J Endocrinol Invest,2011,34(7)∶18-22.
[40]Orth P,Cucchiarini M,Zurakowski D,et al.Madry,Parathyroid hormone[1-34]improves articular cartilage surface architecture and integration and subchondral bone reconstitution in osteochondral defects in vivo[J].Osteoarthritis and Cartilage,2013,21(4)∶614-624.
[41]Yan JY,Tian FM,Wang WY,et al.Parathyroid hormone(1-34)prevents cartilage degradation and preserves subchondral bone micro-architecture in guinea pigs with spontaneous osteoarthritis[J]. Osteoarthritis and Cartilage,2014,22(11)∶1869-1877.
[42]Hodge JM,Kirkland MA,Nicholson GC.Multiple roles of M-CSF in human osteoclastogenesis[J].Journal of Cellular Biochemistry, 2007,102(3)∶759-768.
[43]Kirksey M,Chiu YL,Ma Y,et al.Trends in in-hospital major morbidity and mortality after total joint arthroplasty∶United States 1998-2008[J].AnesthAnalg,2012,115(2)∶321-7.
[44]Labusca L,Mashayekhi K.The role of progenitor cells in osteoarthritis development and progression[J].Current Stem Cell Research& Therapy,2014,9∶1-9.
Progress in subchondral bone as a key target for the treatment of osteoarthritis.
LIU Li-jie1,WU Guo-min2,HU Min1.Department of Orthodontics Dentistry1,Department of Oral and Cranio-Maxillofacial Science2,Hospital of Stomatology,Jilin University,Changchun 130021,Jilin,CHINA
Osteoarthritis(OA),one of the most common form of arthritis,has become a major cause of disability and impaired quality of life.The incapability of cartilage to heal has been long time regarded as the major cause of progressive joint degeneration.Recent study indicated that subchondral bone play significant roles in the development or progression of OA pathology.The interplay between articular cartilage and subchondral bone are not yet fully understood.Elucidation of these complex correlations at molecular level could lead to progress for early detection, finding targets for the causal treatment of OA.
Osteoarthritis;Articular cartilage;Subchondral bone;Bone remodeling
R684.3
A
1003—6350(2015)12—1800—05
2014-11-04)
胡敏。E-mail:ydhhm@sohu.com。
doi∶10.3969/j.issn.1003-6350.2015.12.0644