骨關節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)

(復旦大學附屬中山醫院骨科 上海 200032)

骨關節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)

(復旦大學附屬中山醫院骨科 上海 200032)

骨關節炎(osteoarthritis,OA)是一種最常見的慢性骨關節疾病,可累及整個關節。軟骨下骨作為關節的重要組成部分,與OA的發生發展密切相關。OA中軟骨下骨變化的機制復雜,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、轉化生長因子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。

骨關節炎; 軟骨下骨; OPG/RANKL/RANK系統; TGFβ; 雌激素; 雌激素受體; 脂代謝

骨關節炎(osteoarthritis,OA)是一種常見的慢性骨關節疾病,是造成關節疼痛和功能障礙的重要原因之一[1]。OA好發于中老年患者,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多發于負重大、活動多的關節,如膝、脊柱(頸椎和腰椎)、髖、踝、手等關節[2-3]。原發性OA的病因尚不明確,除年齡外[4-5],還與免疫、生物學等多種因素相關[6-7]。

OA主要病理變化發生在軟骨、軟骨下骨與滑膜[8]。過去研究的重點主要集中在關節軟骨,近年來軟骨下骨對于關節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構變化 軟骨下骨是組成關節的重要部分,主要包括軟骨下皮質終板、骨小梁結構、血管及小梁間隙結構,主要生物學功能為吸收應力、緩沖震蕩以及維持關節形狀等,還能為軟骨提供營養及清除代謝產物[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例臨床診斷原發性OA的股骨髁標本,獲得的病理學結果顯示:原發性OA的骨軟縱斷面三層結構顯示不清,潮線斷裂、間隙增寬、鈣化軟骨層增厚。關節主要病理組織學改變包括:(1)三層結構潮線復制、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]通過建立大鼠膝關節OA模型,發現OA膝關節的軟骨表面粗糙,完整性破壞,表層軟骨出現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,觀察到關節軟骨會隨著OA的進展逐漸出現微纖毛、軟骨表面潰瘍、膠原纖維退化等變化,軟骨細胞也會隨著OA進展逐漸出現形態的不規則以及細胞凋亡,軟骨細胞的細胞質、細胞核會逐漸出現溶解和固縮。研究表明軟骨下骨與軟骨之間的緊密連接在關節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骨端發生的病理變化主要包括骨重建及骨質硬化,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和密度隨著生物力學環境的改變而改變的生理行為,載荷高的地方骨的質量和密度增高,反之骨的質量和密度發生下降。正常生理情況下,骨重建是通過成骨細胞和破骨細胞來調節的,成骨細胞負責骨基質的合成、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育中起重要作用。

OA的早期病理變化主要表現為骨吸收增強,破骨細胞溶骨作用增強,軟骨下骨骨質疏松,骨量減少,骨小梁變薄。Intema等[22]利用狗前交叉韌帶切斷和內側半月板切除的方法復制OA模型,通過觀察組織學以及影像學超微結構發現,早期OA關節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,發生硬化。Ham等[23]通過卵巢切除的成年母猴復制OA模型,發現雌激素替代治療(estrogen replacement therapy,ERT)的實驗組發生OA的概率顯著低于無雌激素治療的對照組,對比骨形態組織計量發現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,發生硬化。軟骨下骨的硬化可導致其吸收應力、緩沖震蕩的作用減少,從而加劇了關節的損害及退變[24]。軟骨下骨的損害還可加重軟骨的病變[12,25]。同時,OA晚期關節微血管形成增加,并且浸潤到軟骨下骨,也可通過表達基質金屬蛋白酶(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,則會出現上述典型的病理及超微結構的變化及相關的臨床表現。

調控OA中軟骨下骨變化的分子機制

OPG/RANKL/RANK系統的作用 2000年,美國骨與礦物質協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)是緊密聯系的整體,命名為OPG/RANKL/RANK系統[28]。RANK是唯一已知的RANKL發揮作用的受體,兩者結合后激活信號通路,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,調控骨代謝[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,導致骨質硬化、形成骨贅等。Martinez-Calatrava等[34]和Moreno-Rubio等[35]研究發現,OA中不僅軟骨細胞高表達RANKL,細胞外基質中也可以發現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,發現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節軟骨代謝[36],這種細胞因子和信號傳導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。由此說明OPG和RANKL參與關節軟骨和骨之間的雙向調節,包括軟骨代謝和軟骨下骨吸收,表明OPG/RANKL/RANK系統在OA中的重要性。

TGF-β信號通路的作用 轉化生長因子β(transforming growth factor β,TGFβ)屬于一類促進細胞生長和轉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],是維持關節軟骨代謝平衡與結構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,發現機械應力改變軟骨下骨形態并導致軟骨下骨TGFβ濃度升高,同樣在膝關節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)可以穩定軟骨下骨結構(劑量過大會導致關節軟骨蛋白多糖丟失),防止OA中關節軟骨的退化。此外,TGFβ可以誘導骨髓間充質干細胞(bone marrow stem cell,BMSC)的遷移聚集,從而導致異常骨重塑[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可以通過影響內皮祖細胞以及促進間充質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相關異常骨形成。Yusup等[44]通過對40例晚期膝關節OA患者行磁共振、血清細胞因子及組織學檢查,發現滑膜血管組織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。Jiao等[45]使用TGFβ1轉基因CED小鼠模型,使TGFβ1在骨髓中高表達,導致下頜髁軟骨下骨異常骨重建,進而出現軟骨的異常,表明TGFβ在顳下頜關節骨關節炎的發展中起到重要作用。

TGFβ對于軟骨下骨微環境的調控也影響著OA的進展,TGFβ通過調節BMSC的分化募集,形成骨樣小島,導致異常骨重塑[41,46];可以介導上皮間質轉化(epithelial-mesenchymal transition,EMT)及內皮間質轉化(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現,它不但保護軟骨對于應力的變化,還可以保護軟骨下骨對于應力的變化,在切斷兔前交叉韌帶復制的OA模型中,阿侖膦酸鈉可以防止關節區域骨丟失,抑制破骨細胞向軟骨下骨區域募集[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 雌激素是人體內分泌的重要激素之一。流行病學調查顯示,雌激素減退有增加OA患病的可能[53],女性OA發病率高于男性,特別是在絕經以后[54],一項研究表明64%的女性膝關節OA或出現相關OA癥狀者在5年內絕經或者接受子宮切除術[55]。絕經后女性比同齡男性更易出現髖、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,說明關節組織是雌激素的作用目標之一[57-60]。雌激素對于關節穩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性能,隨之會導致軟骨的損傷[55,61-62]。Sniekers等[63]敲除雌性小鼠的雌激素受體基因,導致小鼠脛骨骨贅增加、軟骨下骨板變薄,發生了OA早期的病變。通過切除母猴卵巢可復制OA模型,ERT的實驗組發生OA的概率顯著低于對照組,表明雌激素對于維持關節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患者關節置換術后翻修的概率,提示HRT對于OA關節置換的積極效果[65]。選擇性雌激素受體調節劑(selective estrogen receptor modulators,SERMs)被多次報道對于OA治療有益,并且已經在歐美市場上使用[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]。也有學者認為,過高水平的雌激素不利于關節穩態,會誘發關節損傷,因為高劑量的雌激素增加IL-1β誘導的蛋白聚糖降解和MMP的生成而損害關節軟骨[54,67]。

雌激素及其受體在分子水平上可調節一系列細胞因子。雌激素可上調OPG表達[68],體外實驗證實雌激素可以誘導OPG產生[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的疾病[73-74],長期以來肥胖被認為是導致OA的高危因素之一[75],與肥胖密切相關的脂代謝被認為在OA發病中起重要作用[76-77]。Chaput等[78]通過對OA患者和健康者股骨標本的蛋白組學研究發現,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側半月板切除復制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基因的表達情況,發現多種脂蛋白相關基因在術后1個月內發生變化。瘦素、脂聯素、內脂素和抵抗素作為脂肪組織釋放的脂肪因子被認為在OA軟骨和骨的動態平衡中發揮重要作用[77]。Mutabaruka等[80]通過臨床研究和尸體解剖發現,在OA患者膝關節軟骨下骨中瘦素顯著增加,并通過調節堿性磷酸酶、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,從而導致OA晚期異常骨贅的產生。Berry等[81]通過一項為期2年的隨訪發現,OA患者瘦素水平的增加與骨形成標志物骨鈣素和I型前膠原N末端前肽呈正相關。體外研究表明,脂聯素通過增加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素的水平較低,提示其與早期骨贅生成的相關性[77]。Choe等[83]發現血清抵抗素水平與手OA影像學軟骨下侵蝕程度呈正相關。Wang等[84]通過OA患者和正常人的特殊磁共振序列掃描發現,OA患者脛骨軟骨下骨脂質的影像學變化,可能與OA軟骨下骨髓水腫相關。脂代謝相關疾病如動脈粥樣硬化的發生也與OA的發生有一定的聯系,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性炎性反應,從而導致OA病理生理作用[85-87]。當前,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,主要是通過增加關節軟骨細胞和滑膜成纖維細胞促炎介質的產生,炎性介質和細胞因子誘導了關節局部炎性因子及軟骨基質裂解酶的產生,在OA炎癥產生、軟骨破壞過程中發揮著重要作用[88-89]。瘦素通過轉錄因子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NO和MMP引起炎性反應[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導致軟骨下骨內環境的變化。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OA的病變,但其機制及通路仍有待進一步研究。脂代謝導致軟骨下骨內環境的變化,進而影響自身和軟骨代謝,在OA的發生發展中起到一定的作用。

結語 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節軟骨的病變還是軟骨病變影響軟骨下骨這一問題至今學界仍無定論。可以明確的是,軟骨下骨在OA的發生發展中扮演重要的角色,OPG/RANKL/RANK系統、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,引起軟骨下骨內環境改變和病理變化,也會對軟骨代謝和軟骨細胞起到影響,從而導致OA的發生發展。OA診斷主要依靠X線攝片,并被認為是金標準。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、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節軟骨的作用,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