骨關(guān)節(jié)炎軟骨下骨的變化及其分子機制的研究進展

華秉譞(綜述) 閻作勤(審校)

(復(fù)旦大學(xué)附屬中山醫(yī)院骨科 上海 200032)

骨關(guān)節(jié)炎軟骨下骨的變化及其分子機制的研究進展

華秉譞(綜述) 閻作勤△(審校)

(復(fù)旦大學(xué)附屬中山醫(yī)院骨科 上海 200032)

骨關(guān)節(jié)炎(osteoarthritis,OA)是一種最常見的慢性骨關(guān)節(jié)疾病,可累及整個關(guān)節(jié)。軟骨下骨作為關(guān)節(jié)的重要組成部分,與OA的發(fā)生發(fā)展密切相關(guān)。OA中軟骨下骨變化的機制復(fù)雜,目前尚未完全闡明。本文通過文獻回顧對OA中軟骨下骨的病理變化,OPG/RANKL/RANK系統(tǒng)、轉(zhuǎn)化生長因子β (transforming growth factor β,TGFβ)、雌激素-雌激素受體信號通路和脂代謝等因素對軟骨下骨的影響進行綜述,探討OA中軟骨下骨變化的作用及其分子機制。

骨關(guān)節(jié)炎; 軟骨下骨; OPG/RANKL/RANK系統(tǒng); TGFβ; 雌激素; 雌激素受體; 脂代謝

骨關(guān)節(jié)炎(osteoarthritis,OA)是一種常見的慢性骨關(guān)節(jié)疾病,是造成關(guān)節(jié)疼痛和功能障礙的重要原因之一[1]。OA好發(fā)于中老年患者,女性多于男性,60歲以上的人群中患病率可達50%,75歲以上的人群中則可達到80%,該病的致殘率高達53%。OA多發(fā)于負重大、活動多的關(guān)節(jié),如膝、脊柱(頸椎和腰椎)、髖、踝、手等關(guān)節(jié)[2-3]。原發(fā)性O(shè)A的病因尚不明確,除年齡外[4-5],還與免疫、生物學(xué)等多種因素相關(guān)[6-7]。

OA主要病理變化發(fā)生在軟骨、軟骨下骨與滑膜[8]。過去研究的重點主要集中在關(guān)節(jié)軟骨,近年來軟骨下骨對于關(guān)節(jié)軟骨的重要作用逐漸被重視[9]。自Radin等[10]于1972年首次提出軟骨下骨改變是OA發(fā)病啟動因素的假說后,近年來越來越多的研究表明,軟骨下骨確實在OA病變中起到重要作用[11-14],有學(xué)者認為軟骨下骨硬化是OA軟骨病變的起始因素[15]。OA中軟骨下骨的變化及其分子機制也成為了當(dāng)前研究的熱點,本文就此作一綜述。

OA中軟骨下骨的病理及超微結(jié)構(gòu)變化 軟骨下骨是組成關(guān)節(jié)的重要部分,主要包括軟骨下皮質(zhì)終板、骨小梁結(jié)構(gòu)、血管及小梁間隙結(jié)構(gòu),主要生物學(xué)功能為吸收應(yīng)力、緩沖震蕩以及維持關(guān)節(jié)形狀等,還能為軟骨提供營養(yǎng)及清除代謝產(chǎn)物[16]。王華偉[17]通過HE、番紅O/固綠、馮庫薩、甲苯胺藍、天狼猩紅等多種染色,觀察了21例臨床診斷原發(fā)性O(shè)A的股骨髁標(biāo)本,獲得的病理學(xué)結(jié)果顯示:原發(fā)性O(shè)A的骨軟縱斷面三層結(jié)構(gòu)顯示不清,潮線斷裂、間隙增寬、鈣化軟骨層增厚。關(guān)節(jié)主要病理組織學(xué)改變包括:(1)三層結(jié)構(gòu)潮線復(fù)制、漂移; (2)鈣化層增厚,伴血管長入;(3)非鈣化軟骨及鈣化層纖維樣改變;(4)潮線間隙增寬;(5)深層軟骨及鈣化層缺損。李西海等[18]通過建立大鼠膝關(guān)節(jié)OA模型,發(fā)現(xiàn)OA膝關(guān)節(jié)的軟骨表面粗糙,完整性破壞,表層軟骨出現(xiàn)纖維化變性及軟骨缺損,甚至軟骨下骨裸露,軟骨下骨致密層變薄,骨松質(zhì)層骨小梁稀疏,硬化或囊變,邊緣有丘狀隆起的骨贅。Yan等[19]在DH豚鼠與年齡相關(guān)的OA模型中,通過掃描電鏡和透射電鏡分別觀察了1、3、6、9、12月齡的DH豚鼠,觀察到關(guān)節(jié)軟骨會隨著OA的進展逐漸出現(xiàn)微纖毛、軟骨表面潰瘍、膠原纖維退化等變化,軟骨細胞也會隨著OA進展逐漸出現(xiàn)形態(tài)的不規(guī)則以及細胞凋亡,軟骨細胞的細胞質(zhì)、細胞核會逐漸出現(xiàn)溶解和固縮。研究表明軟骨下骨與軟骨之間的緊密連接在關(guān)節(jié)活動和保護功能中起到重要的作用[20-21]。

OA軟骨下骨重建及硬化 OA骨端發(fā)生的病理變化主要包括骨重建及骨質(zhì)硬化,包含軟骨下骨密度增高、骨量增加。骨重建是指骨組織的形態(tài)和密度隨著生物力學(xué)環(huán)境的改變而改變的生理行為,載荷高的地方骨的質(zhì)量和密度增高,反之骨的質(zhì)量和密度發(fā)生下降。正常生理情況下,骨重建是通過成骨細胞和破骨細胞來調(diào)節(jié)的,成骨細胞負責(zé)骨基質(zhì)的合成、分泌和礦化,破骨細胞具有骨吸收功能,兩者作用互相拮抗、互相平衡,它們的活化和凋亡在骨骼的生長發(fā)育中起重要作用。

OA的早期病理變化主要表現(xiàn)為骨吸收增強,破骨細胞溶骨作用增強,軟骨下骨骨質(zhì)疏松,骨量減少,骨小梁變薄。Intema等[22]利用狗前交叉韌帶切斷和內(nèi)側(cè)半月板切除的方法復(fù)制OA模型,通過觀察組織學(xué)以及影像學(xué)超微結(jié)構(gòu)發(fā)現(xiàn),早期OA關(guān)節(jié)軟骨蛋白聚糖丟失增多,軟骨下骨厚度降低,骨小梁厚度及體積均下降。晚期軟骨下骨骨形成增加,發(fā)生硬化。Ham等[23]通過卵巢切除的成年母猴復(fù)制OA模型,發(fā)現(xiàn)雌激素替代治療(estrogen replacement therapy,ERT)的實驗組發(fā)生OA的概率顯著低于無雌激素治療的對照組,對比骨形態(tài)組織計量發(fā)現(xiàn)OA晚期骨小梁厚度增加,新生骨組織礦化升高,骨形成率增加,軟骨下骨骨密度增高,發(fā)生硬化。軟骨下骨的硬化可導(dǎo)致其吸收應(yīng)力、緩沖震蕩的作用減少,從而加劇了關(guān)節(jié)的損害及退變[24]。軟骨下骨的損害還可加重軟骨的病變[12,25]。同時,OA晚期關(guān)節(jié)微血管形成增加,并且浸潤到軟骨下骨,也可通過表達基質(zhì)金屬蛋白酶(matrix metalloproteinase,MMP)加劇軟骨的退化,從而加重OA病情[26-27]。隨著OA病情的加重,則會出現(xiàn)上述典型的病理及超微結(jié)構(gòu)的變化及相關(guān)的臨床表現(xiàn)。

調(diào)控OA中軟骨下骨變化的分子機制

OPG/RANKL/RANK系統(tǒng)的作用 2000年,美國骨與礦物質(zhì)協(xié)會最早提出骨保護素(osteoprotegerin,OPG)、核因子κB受體活化因子(receptor activator for nuclear factor-κB,RANK)、RANK配體(receptor activator for nuclear factor-κB ligand,RANKL)是緊密聯(lián)系的整體,命名為OPG/RANKL/RANK系統(tǒng)[28]。RANK是唯一已知的RANKL發(fā)揮作用的受體,兩者結(jié)合后激活信號通路,使破骨細胞前體分化,促使破骨細胞成熟,發(fā)揮骨吸收作用;OPG是抑制骨吸收的細胞因子,其功能是阻斷RANK與RANKL的結(jié)合,抑制破骨細胞的成熟,從而抑制其骨吸收作用[29-30]。

OA中OPG/RANKL/RANK系統(tǒng)對于軟骨下骨起到重要作用。Kwan Tat等[31]證實,OA軟骨下骨中OPG水平降低,RANKL在早期OA中表達增加,在晚期OA中表達減少。軟骨下骨破骨細胞的激活在OA的起始病變中起到重要的作用[32],而OPG/RANKL比值可以作為反映破骨細胞活動水平的一個指標(biāo),調(diào)控骨代謝[33]。OPG/RANKL比值與軟骨下骨厚度成正比,在早期OA中OPG/RANKL比值降低,破骨細胞活性增強,致使骨吸收增加,軟骨下骨發(fā)生異常重建;而在晚期OA中該比值上升,破骨細胞活性降低,此時骨形成增加,導(dǎo)致骨質(zhì)硬化、形成骨贅等。Martinez-Calatrava等[34]和Moreno-Rubio等[35]研究發(fā)現(xiàn),OA中不僅軟骨細胞高表達RANKL,細胞外基質(zhì)中也可以發(fā)現(xiàn)RANKL,并作用于軟骨下骨,造成骨丟失。Funck-Brentano等[32]在半月板切除誘導(dǎo)OA小鼠模型中,將小鼠軟骨下骨上清液加入到軟骨組織中,發(fā)現(xiàn)軟骨代謝中的蛋白多糖和蛋白聚糖釋放減少,提示骨分泌的可溶性因子參與調(diào)節(jié)軟骨代謝[36],這種細胞因子和信號傳導(dǎo)通路可能通過軟骨下骨新生血管以及局部骨裂隙及鈣化軟骨中的微管進行傳導(dǎo)。由此說明OPG和RANKL參與關(guān)節(jié)軟骨和骨之間的雙向調(diào)節(jié),包括軟骨代謝和軟骨下骨吸收,表明OPG/RANKL/RANK系統(tǒng)在OA中的重要性。

TGF-β信號通路的作用 轉(zhuǎn)化生長因子β(transforming growth factor β,TGFβ)屬于一類促進細胞生長和轉(zhuǎn)化的細胞因子超家族,有6種不同亞型,其中TGFβ1、TGFβ2和TGFβ3亞型表達于哺乳動物[37-38],是維持關(guān)節(jié)軟骨代謝平衡與結(jié)構(gòu)完整性的重要因素之一[39]。Zhen等[40]通過切斷大鼠前交叉韌帶制作OA模型,發(fā)現(xiàn)機械應(yīng)力改變軟骨下骨形態(tài)并導(dǎo)致軟骨下骨TGFβ濃度升高,同樣在膝關(guān)節(jié)OA患者軟骨下骨TGFβ濃度也明顯升高;而在動物模型中,在軟骨下骨加入適量的TGFβI型受體抑制劑(TβRI)可以穩(wěn)定軟骨下骨結(jié)構(gòu)(劑量過大會導(dǎo)致關(guān)節(jié)軟骨蛋白多糖丟失),防止OA中關(guān)節(jié)軟骨的退化。此外,TGFβ可以誘導(dǎo)骨髓間充質(zhì)干細胞(bone marrow stem cell,BMSC)的遷移聚集,從而導(dǎo)致異常骨重塑[41],促進OA的病理進展。使用TβRI可以減少骨重塑,為OA治療提供新的思路[40]。骨形成總是伴隨著血管生成,TGFβ可以通過影響內(nèi)皮祖細胞以及促進間充質(zhì)干細胞的旁分泌機制來促進血管生成[42-43],抑制 TGFβ 的活性,減少血管生成可以減少TGFβ相關(guān)異常骨形成。Yusup等[44]通過對40例晚期膝關(guān)節(jié)OA患者行磁共振、血清細胞因子及組織學(xué)檢查,發(fā)現(xiàn)滑膜血管組織TGFβ水平與軟骨下骨髓病變、軟骨下骨囊腫、軟骨下骨磨損程度呈正相關(guān)。Jiao等[45]使用TGFβ1轉(zhuǎn)基因CED小鼠模型,使TGFβ1在骨髓中高表達,導(dǎo)致下頜髁軟骨下骨異常骨重建,進而出現(xiàn)軟骨的異常,表明TGFβ在顳下頜關(guān)節(jié)骨關(guān)節(jié)炎的發(fā)展中起到重要作用。

TGFβ對于軟骨下骨微環(huán)境的調(diào)控也影響著OA的進展,TGFβ通過調(diào)節(jié)BMSC的分化募集,形成骨樣小島,導(dǎo)致異常骨重塑[41,46];可以介導(dǎo)上皮間質(zhì)轉(zhuǎn)化(epithelial-mesenchymal transition,EMT)及內(nèi)皮間質(zhì)轉(zhuǎn)化(endothelial-mesenchymal transition,EndoMT)通路,為OA軟骨下骨血管生成增加提供上皮細胞和內(nèi)皮細胞的資源[47-49]。二膦酸鹽類治療OA的研究已有很長一段時間[50],其中阿侖膦酸鈉對于OA的治療被認為是一項重要的發(fā)現(xiàn),它不但保護軟骨對于應(yīng)力的變化,還可以保護軟骨下骨對于應(yīng)力的變化,在切斷兔前交叉韌帶復(fù)制的OA模型中,阿侖膦酸鈉可以防止關(guān)節(jié)區(qū)域骨丟失,抑制破骨細胞向軟骨下骨區(qū)域募集[51]。阿侖膦酸鈉可以抑制早期軟骨下骨吸收和防止異常骨贅形成,這一效果可以用減少局部TGFβ的活化來解釋[52]。鑒于TGFβ在OA的病理過程中起到重要作用,特異性抑制軟骨下骨TGFβ活性也給OA的治療提供了新的臨床思路。

雌激素-雌激素受體信號通路的作用 雌激素是人體內(nèi)分泌的重要激素之一。流行病學(xué)調(diào)查顯示,雌激素減退有增加OA患病的可能[53],女性O(shè)A發(fā)病率高于男性,特別是在絕經(jīng)以后[54],一項研究表明64%的女性膝關(guān)節(jié)OA或出現(xiàn)相關(guān)OA癥狀者在5年內(nèi)絕經(jīng)或者接受子宮切除術(shù)[55]。絕經(jīng)后女性比同齡男性更易出現(xiàn)髖、膝OA癥狀,且病程進展更快[56]。雌激素受體(estrogen receptor,ER)分為ER-α和ER-β兩種亞型,此兩型受體在軟骨細胞、軟骨下骨細胞、滑膜細胞和韌帶成纖維細胞中均有表達,說明關(guān)節(jié)組織是雌激素的作用目標(biāo)之一[57-60]。雌激素對于關(guān)節(jié)穩(wěn)定起到重要的保護作用。在動物模型中,卵巢切除會引起強烈的軟骨下骨丟失和重建,削弱軟骨下骨小梁生物力學(xué)性能,隨之會導(dǎo)致軟骨的損傷[55,61-62]。Sniekers等[63]敲除雌性小鼠的雌激素受體基因,導(dǎo)致小鼠脛骨骨贅增加、軟骨下骨板變薄,發(fā)生了OA早期的病變。通過切除母猴卵巢可復(fù)制OA模型,ERT的實驗組發(fā)生OA的概率顯著低于對照組,表明雌激素對于維持關(guān)節(jié)骨量和功能的重要作用[23],ERT對于OA有一定治療作用,可延緩OA發(fā)展[64]。一項大樣本量臨床分析表明,激素替代治療(hormone replacement therapy,HRT)可以顯著減少OA患者關(guān)節(jié)置換術(shù)后翻修的概率,提示HRT對于OA關(guān)節(jié)置換的積極效果[65]。選擇性雌激素受體調(diào)節(jié)劑(selective estrogen receptor modulators,SERMs)被多次報道對于OA治療有益,并且已經(jīng)在歐美市場上使用[66],相較于對于軟骨的短期作用,SERMs對于軟骨下骨的作用是長期的[64]。也有學(xué)者認為,過高水平的雌激素不利于關(guān)節(jié)穩(wěn)態(tài),會誘發(fā)關(guān)節(jié)損傷,因為高劑量的雌激素增加IL-1β誘導(dǎo)的蛋白聚糖降解和MMP的生成而損害關(guān)節(jié)軟骨[54,67]。

雌激素及其受體在分子水平上可調(diào)節(jié)一系列細胞因子。雌激素可上調(diào)OPG表達[68],體外實驗證實雌激素可以誘導(dǎo)OPG產(chǎn)生[69]。同時,雌激素可以抑制RANKL的作用,通過抑制破骨細胞的作用而影響骨代謝[70-71]。另外,在卵巢切除小鼠中TGFβ表達下降,說明內(nèi)源性雌激素缺乏可能直接抑制成骨活性[72]。

脂代謝的作用 OA被認為是一項和年齡及代謝相關(guān)的疾病[73-74],長期以來肥胖被認為是導(dǎo)致OA的高危因素之一[75],與肥胖密切相關(guān)的脂代謝被認為在OA發(fā)病中起重要作用[76-77]。Chaput等[78]通過對OA患者和健康者股骨標(biāo)本的蛋白組學(xué)研究發(fā)現(xiàn),在OA患者中載脂蛋白A-I顯著下降。張榮凱等[79]以大鼠前交叉韌帶切斷和內(nèi)側(cè)半月板切除復(fù)制OA模型,通過基因芯片篩查研究早期OA軟骨下骨脂蛋白相關(guān)基因的表達情況,發(fā)現(xiàn)多種脂蛋白相關(guān)基因在術(shù)后1個月內(nèi)發(fā)生變化。瘦素、脂聯(lián)素、內(nèi)脂素和抵抗素作為脂肪組織釋放的脂肪因子被認為在OA軟骨和骨的動態(tài)平衡中發(fā)揮重要作用[77]。Mutabaruka等[80]通過臨床研究和尸體解剖發(fā)現(xiàn),在OA患者膝關(guān)節(jié)軟骨下骨中瘦素顯著增加,并通過調(diào)節(jié)堿性磷酸酶、骨鈣素、Ⅰ型膠原蛋白和TGF-β1水平完成促進異常成骨細胞的分化,從而導(dǎo)致OA晚期異常骨贅的產(chǎn)生。Berry等[81]通過一項為期2年的隨訪發(fā)現(xiàn),OA患者瘦素水平的增加與骨形成標(biāo)志物骨鈣素和I型前膠原N末端前肽呈正相關(guān)。體外研究表明,脂聯(lián)素通過增加RANKL表達和抑制OPG表達增加破骨細胞的形成[82],而在骨贅生成中脂聯(lián)素的水平較低,提示其與早期骨贅生成的相關(guān)性[77]。Choe等[83]發(fā)現(xiàn)血清抵抗素水平與手OA影像學(xué)軟骨下侵蝕程度呈正相關(guān)。Wang等[84]通過OA患者和正常人的特殊磁共振序列掃描發(fā)現(xiàn),OA患者脛骨軟骨下骨脂質(zhì)的影像學(xué)變化,可能與OA軟骨下骨髓水腫相關(guān)。脂代謝相關(guān)疾病如動脈粥樣硬化的發(fā)生也與OA的發(fā)生有一定的聯(lián)系,可能的機制是代謝性疾病造成的軟骨下骨代謝障礙以及由脂肪因子引起的系統(tǒng)性炎性反應(yīng),從而導(dǎo)致OA病理生理作用[85-87]。當(dāng)前,更多的研究表明,脂代謝及脂肪因子對于OA軟骨細胞具有重要的作用,主要是通過增加關(guān)節(jié)軟骨細胞和滑膜成纖維細胞促炎介質(zhì)的產(chǎn)生,炎性介質(zhì)和細胞因子誘導(dǎo)了關(guān)節(jié)局部炎性因子及軟骨基質(zhì)裂解酶的產(chǎn)生,在OA炎癥產(chǎn)生、軟骨破壞過程中發(fā)揮著重要作用[88-89]。瘦素通過轉(zhuǎn)錄因子NF-κB、蛋白激酶(protein kinase C,PKC)和絲裂原活化蛋白A激酶(mitogen-activated protein kinase,MAPK)信號通路[90-91],而脂聯(lián)素是通過腺苷酸活化蛋白激酶(adenosine 5′-monophosphate-activated protein kinase,AMPK)及c-Jun氨基末端激酶(c-Jun N-terminal kinase,JNK)信號通路分別誘導(dǎo)NO和MMP引起炎性反應(yīng)[88,92]。瘦素等脂肪因子對于軟骨下骨的作用機制目前仍未完全明確,可能是通過引起局部的炎性反應(yīng)導(dǎo)致軟骨下骨內(nèi)環(huán)境的變化。軟骨是一種無血管組織,軟骨下骨的代謝不僅作用于其本身,還通過分子擴散直接影響軟骨[93],繼而引發(fā)OA的病變,但其機制及通路仍有待進一步研究。脂代謝導(dǎo)致軟骨下骨內(nèi)環(huán)境的變化,進而影響自身和軟骨代謝,在OA的發(fā)生發(fā)展中起到一定的作用。

結(jié)語 OA中軟骨下骨的變化被日漸重視,但究竟是軟骨下骨的變化引起關(guān)節(jié)軟骨的病變還是軟骨病變影響軟骨下骨這一問題至今學(xué)界仍無定論?？梢悦鞔_的是,軟骨下骨在OA的發(fā)生發(fā)展中扮演重要的角色,OPG/RANKL/RANK系統(tǒng)、TGFβ、雌激素-雌激素受體信號通路和脂代謝等因素均對OA軟骨下骨起到重要的作用,引起軟骨下骨內(nèi)環(huán)境改變和病理變化,也會對軟骨代謝和軟骨細胞起到影響,從而導(dǎo)致OA的發(fā)生發(fā)展。OA診斷主要依靠X線攝片,并被認為是金標(biāo)準(zhǔn)。目前對于OA尚無可以治愈疾病的藥物,只能從癥狀上緩解病情。明確OPG/RANKL/RANK系統(tǒng)、TGFβ、雌激素-雌激素受體信號通路和脂代謝等因素在OA中對于軟骨下骨及整個關(guān)節(jié)軟骨的作用,可以為OA的早期診斷和治療提供新的思路和方法。

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Research progress on the changes of subchondral bone in osteoarthritis and its molecular mechanisms

HUA Bing-xuan, YAN Zuo-qin△

(DepartmentofOrthopaedics,ZhongshanHospital,FudanUniversity,Shanghai200032,China)

Osteoarthritis (OA) is one of the most common chronic osteoarthritic diseases,which can involve the whole joint.Subchondral bone is an important part of the joint and has a close relationship to the development of OA.The changes and mechanisms of subchondral bone in OA are complex and remain disputes.In this review,we will discuss the advances of the molecular mechanisms of subchondral bone in OA,which include the pathological changes and the roles of the OPG/RANKL/RANK system,transforming growth factor β (TGFβ),estrogen-estrogen receptors and lipid metabolism in OA.

osteoarthritis; subchondral bone; OPG/RANKL/RANK system; TGFβ; estrogen; estrogen receptors; lipid metabolism

R684.3

B

10.3969/j.issn.1672-8467.2017.02.018

2016-05-06;編輯:段佳)

△Corresponding author E-mail:yan1002@hotmail.com