田紅，黃桂華，竇明金Δ

(1.山東省醫(yī)學(xué)科學(xué)院附屬醫(yī)院 藥劑科，山東 濟(jì)南 250031；2.山東大學(xué) 藥學(xué)院，山東 濟(jì)南 250012)

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透明質(zhì)酸治療骨關(guān)節(jié)炎的研究進(jìn)展

田紅1，黃桂華2，竇明金1Δ

(1.山東省醫(yī)學(xué)科學(xué)院附屬醫(yī)院 藥劑科，山東 濟(jì)南 250031；2.山東大學(xué) 藥學(xué)院，山東 濟(jì)南 250012)

骨關(guān)節(jié)炎是一種常見的慢性退行性疾病，目前其治療方式主要為藥物治療。透明質(zhì)酸是一種分布于細(xì)胞間質(zhì)中的粘多糖，具有粘彈性、潤滑性、生物相容性、可降解性以及抗炎活性，在治療骨關(guān)節(jié)炎方面具有廣泛的應(yīng)用。但是，普通的透明質(zhì)酸注射到關(guān)節(jié)腔半衰期較短，患者需要頻繁給藥，順應(yīng)性較差，因此，研究透明質(zhì)酸在制劑和臨床上的新用途是藥學(xué)工作者研究的新方向。本文綜述了透明質(zhì)酸在治療骨關(guān)節(jié)炎方面的作用、安全性、有效性及其制劑中的新用途。

透明質(zhì)酸；骨關(guān)節(jié)炎；作用機(jī)制；應(yīng)用研究

骨關(guān)節(jié)炎(osteoarthritis,OA)是一種慢性退行性疾病，常伴有關(guān)節(jié)疼痛、軟骨退化，最終喪失正常的關(guān)節(jié)功能[1]。隨著年齡的不斷增長，骨關(guān)節(jié)炎的患病率不斷增加，60歲以上的人群中約60%正遭受著軟骨異常的種種病癥[2]。當(dāng)前，骨關(guān)節(jié)炎仍然是一種不可治愈的疾病，而對于它的治療，主要集中于減輕疼痛，改善骨關(guān)節(jié)的功能[3]，包括物理治療法、矯正法、藥物治療法和手術(shù)療法[4]。其中藥物療法應(yīng)用最為廣泛，主要有止痛藥、非甾體抗炎藥、透明質(zhì)酸、硫酸軟骨素和硫酸氨基葡萄糖等[5]。

透明質(zhì)酸(hyaluronic acid，HA)是一種天然的非硫酸化粘多糖，主要分布于關(guān)節(jié)軟骨、滑液、皮膚和房水中，具有調(diào)節(jié)生物化學(xué)過程、提供支持和潤滑的功效，在維持關(guān)節(jié)的正常功能方面具有重要的作用[6]。20世紀(jì)70年代早期，透明質(zhì)酸第一次作為粘彈性補(bǔ)充療法治療人的骨關(guān)節(jié)炎[7]。透明質(zhì)酸治療骨關(guān)節(jié)炎的作用機(jī)制表現(xiàn)在：抑制組織疼痛感受器；刺激內(nèi)源性的透明質(zhì)酸生成；抑制金屬蛋白酶的活性，發(fā)揮抗炎作用[8]。

1 HA對骨關(guān)節(jié)炎的作用

1.1 HA可防止關(guān)節(jié)軟骨降解、抑制軟骨細(xì)胞凋亡 關(guān)節(jié)軟骨是一種承重的組織，為高效運(yùn)動(dòng)、有效沖擊吸收、負(fù)載損耗等提供低摩擦面，但關(guān)節(jié)軟骨易受損傷且修復(fù)能力有限[9]。骨關(guān)節(jié)的軟骨發(fā)生病理上的改變導(dǎo)致軟骨降解酶過度表達(dá)，加快了膠原纖維的分解和蛋白聚糖的降解[10]。白細(xì)胞介素1β(interleukin-1β，IL-1β)在骨關(guān)節(jié)炎的發(fā)病機(jī)理中起著重要的作用，主要是能夠減少蛋白聚糖和二型膠原的再吸收[11]，因此在OA的病變過程中通過抑制IL-1β防止軟骨降解是一種有效的方法。研究表明[12]透明質(zhì)酸能夠抑制IL-1β的分泌，防止軟骨降解。

關(guān)節(jié)腔內(nèi)注射透明質(zhì)酸可抑制前交叉韌帶術(shù)后的軟骨細(xì)胞凋亡[13]，Barreto等[14]研究骨關(guān)節(jié)炎中軟骨細(xì)胞凋亡百分?jǐn)?shù)以及注射透明質(zhì)酸后是否可抑制軟骨細(xì)胞凋亡，將20只(40個(gè)膝關(guān)節(jié))平均年齡8周，體質(zhì)量4～6 kg的新西蘭兔進(jìn)行挫傷造模，隨后在一膝關(guān)節(jié)注射2 mL透明質(zhì)酸，另一膝關(guān)節(jié)注射2 mL 0.9%NaCl作為對照，1周2次，持續(xù)30 d后處死兔子，樣本處理后進(jìn)行顯微鏡和TUNEL檢測。結(jié)果顯示，對照組軟骨細(xì)胞凋亡為(68.01±19.73)%高于預(yù)期結(jié)果，透明質(zhì)酸組軟骨細(xì)胞凋亡率為(53.52±18.09)%，差異有統(tǒng)計(jì)學(xué)意義(P<0.001)，說明透明質(zhì)酸可抑制軟骨細(xì)胞凋亡。

1.2 HA可刺激內(nèi)源性透明質(zhì)酸合成 在骨關(guān)節(jié)炎中，內(nèi)源性透明質(zhì)酸的濃度和分子量都明顯降低[15]，大量證據(jù)已經(jīng)表明骨關(guān)節(jié)炎軟骨降解包括機(jī)械因素和生物因素[16]，Ⅳ型膠原酶(明膠酶)是基質(zhì)金屬蛋白酶的一部分，可分為明膠酶-A(gelatinase A，MMP-2)和明膠酶-B(gelatinase，MMP-9),它們作為一種前體酶被分泌，能夠被特定的蛋白水解作用激活導(dǎo)致?lián)p失大約10kDa的HA[17], 另外有研究證明，骨關(guān)節(jié)炎患者顳下頜關(guān)節(jié)中的HA分子量減少，可能是因?yàn)镠A鏈的自由基解鏈或者滑膜的異常生物合成[18]。關(guān)節(jié)腔注射外源性的透明質(zhì)酸意在彌補(bǔ)這種逆差，刺激產(chǎn)生內(nèi)源性的透明質(zhì)酸從而減輕骨關(guān)節(jié)炎的癥狀[19]。

1.3 HA的抗炎作用 不同分子量的HA能夠提高細(xì)胞外基質(zhì)的滲透率，促進(jìn)特定受體的識別，如CD44細(xì)胞決定簇[20]，高分子的HA能夠識別特定細(xì)胞表面的受體，CD44受體在多種細(xì)胞中表達(dá)，為多功能的跨膜糖蛋白[21]，依賴于分子量的結(jié)合性能到達(dá)特定的細(xì)胞受體，允許透明質(zhì)酸直接修改細(xì)胞功能[22]。有報(bào)道證明正常和OA患者中都存在CD44細(xì)胞決定簇[23]，但是HA和CD44在軟骨細(xì)胞中的相互作用是通過下調(diào)分子量為38KD的絲裂原蛋白激酶(mitogen-actived protein kinase,p38 MAPK)抑制膠原酶和基質(zhì)金屬蛋白酶13抗體(matrix metalloproteinase-13,MMP13)的表達(dá)[24]，CD44單克隆抗體顯著的抑制了高分子量HA對IL-1β誘導(dǎo)的整合素樣金屬蛋白酶與凝血酶4型抗體(a disintegrins and metalloproteinases with thrombospondin motifs 4，ADAMTS4)的表達(dá)。這些發(fā)現(xiàn)證明通過修正IL-1β的調(diào)解信號途徑，使外源性高分量的HA發(fā)揮保護(hù)作用，抑制基質(zhì)降解[21],發(fā)揮抗炎作用。

1.4 HA可緩解關(guān)節(jié)疼痛、提高肌動(dòng)活度 在骨關(guān)節(jié)炎中，關(guān)節(jié)的穩(wěn)定性減少引起關(guān)節(jié)疼痛、四頭肌力量受損、關(guān)節(jié)結(jié)構(gòu)改變[25]。骨關(guān)節(jié)炎患者肌肉強(qiáng)度平衡的喪失將損傷關(guān)節(jié)軟骨，很明顯，在較高的激動(dòng)劑/抑制劑共活化水平時(shí)，肌肉可損害運(yùn)動(dòng)調(diào)節(jié)，減少韌帶保護(hù)活動(dòng)[19]，為了保持關(guān)節(jié)功能，減少不穩(wěn)定性，需要在關(guān)節(jié)中補(bǔ)充肌動(dòng)活性度[26]。Tang等[25]的研究證明了關(guān)節(jié)腔內(nèi)注射透明質(zhì)酸有效地減少了下肢肌肉的同步收縮，提高了肌動(dòng)活動(dòng)，效果持續(xù)長達(dá)6個(gè)月。

Gencer等[27]的研究指出透明質(zhì)酸通過減少炎性介質(zhì)從而緩解關(guān)節(jié)疼痛，相比于其他非甾體抗炎藥(替諾昔康、倍他米松)能夠更好地改善疼痛分?jǐn)?shù)(P<0.05)且其緩解疼痛的效果自第1天到第6周沒有顯著地減少(P<0.05)。另有文獻(xiàn)報(bào)道，關(guān)節(jié)腔內(nèi)注射透明質(zhì)酸相對于注射皮質(zhì)類固醇能夠更持久地緩解疼痛[28]。

2 HA治療骨關(guān)節(jié)炎的安全性與有效性

最近的一項(xiàng)綜合分析指出在骨關(guān)節(jié)炎患者的治療中，粘彈性補(bǔ)充療法與臨床的療效具有很小的相關(guān)性并且增加了嚴(yán)重不良反應(yīng)的危險(xiǎn)[29]。透明質(zhì)酸的不良反應(yīng)主要為局部反應(yīng)，如短暫性疼痛、注射部位腫脹等，研究發(fā)現(xiàn)透明質(zhì)酸的局部不良反應(yīng)發(fā)生率和0.9%NaCl相當(dāng)[30]。另有研究表明注射透明質(zhì)酸3～6月后，關(guān)節(jié)疼痛和關(guān)節(jié)功能都明顯改善，無明顯的不良反應(yīng)[31]。 Zhang等[10]通過臨床隨機(jī)試驗(yàn)比較了關(guān)節(jié)腔注射2種不同形式透明質(zhì)酸的療效。通過OMERACT-OARSI標(biāo)準(zhǔn)得知90%以上的患者在18～26周具有較好的治療效果，92%的患者在走路時(shí)感覺疼痛明顯減少，由西部安大略與麥克馬斯特大學(xué)骨關(guān)節(jié)炎指數(shù)(The Western Ontario and McMaster Universities，WOMAC)疼痛量化表得知多于77%的患者癥狀減輕，2組不良反應(yīng)率為1.7%(3/175)和3.4% (6/174)，不良反應(yīng)與實(shí)驗(yàn)藥物無關(guān)。這些都說明了對于骨關(guān)節(jié)炎患者來說透明質(zhì)酸是安全、有效且耐受良好的治療方法。Altman等[32]通過回顧性分析，評估一次或多次注射透明質(zhì)酸與不注射透明質(zhì)酸對骨關(guān)節(jié)患者進(jìn)行手術(shù)治療的影響，結(jié)果顯示接受了透明質(zhì)酸治療的患者進(jìn)行手術(shù)治療的間隔時(shí)間明顯延長，表明透明質(zhì)酸在治療骨關(guān)節(jié)炎中具有重大的臨床和經(jīng)濟(jì)意義。

3 HA在治療骨關(guān)節(jié)炎中的新型應(yīng)用

有研究指出普通的透明質(zhì)酸注射到關(guān)節(jié)腔半衰期僅為10～13 h[33]，患者需要頻繁給藥，順應(yīng)性差，研究透明質(zhì)酸在制劑和臨床上的新用途是藥學(xué)工作者研究的新方向。

3.1 透明質(zhì)酸的經(jīng)皮給藥系統(tǒng) 注射透明質(zhì)酸可恢復(fù)骨關(guān)節(jié)的流變性，緩解骨關(guān)節(jié)炎的癥狀[6]，經(jīng)皮給藥方式可以避免關(guān)節(jié)腔注射中不必要的副反應(yīng)。研究發(fā)現(xiàn)[34]HA透過大鼠皮膚的滲透率很低，單獨(dú)的HA不能完全滲透皮膚，從而阻礙了其在骨科中的有效利用，因此需要一個(gè)載體有效提高皮膚滲透率,Chen等[35]利用縮氨酸和磷脂共軛以提高HA的經(jīng)皮給藥，結(jié)果發(fā)現(xiàn)提高了HA的滲透率，但是藥物僅局限在角質(zhì)層和表皮?；谕该髻|(zhì)酸對關(guān)節(jié)組織的止痛作用，EI-Refaie等[36]成功制備了一種新型的自組裝納米微凝膠，將透明質(zhì)酸以經(jīng)皮給藥方式遞送到關(guān)節(jié)組織，在緩解骨關(guān)節(jié)癥狀的同時(shí)避免了注射引起的疼痛。近期的研究發(fā)現(xiàn)，透明質(zhì)酸在提高皮膚遞送增加藥物局部含量方面有巨大的作用[37]，透明質(zhì)酸可增加角質(zhì)層的水合作用，建立一種親水通道，增加了新型納米微凝膠的粘彈性和穩(wěn)定性，提高皮膚滲透率，透明質(zhì)酸凝膠基質(zhì)中的囊泡可以作為一種藥物儲庫，增加藥物在皮膚中的局部含量，研究發(fā)現(xiàn)在4 ℃的條件下，新型納米微凝膠的自組裝性和物理穩(wěn)定性長達(dá)6個(gè)月，活體外的滲透性比傳統(tǒng)的脂質(zhì)體和單獨(dú)的HA凝膠高，活體內(nèi)的經(jīng)皮滲透性呈6倍增加[36]。因此，新型納米微凝膠在局部治療關(guān)節(jié)炎方面具有較好的應(yīng)用前景。

3.2 透明質(zhì)酸作為藥物載體材料 HA是一種新型的生物相容性好、可降解的高分子聚合物材料[39]，同時(shí)HA也是一種黏附調(diào)節(jié)分子，能夠調(diào)整軟骨早期的細(xì)胞基質(zhì)反應(yīng)[38]，應(yīng)用HA 作為藥物的載體能夠增強(qiáng)其與OA軟骨細(xì)胞的相互作用。Ma等[39]以透明質(zhì)酸和殼聚糖(chitosan，CS)為載體材料，制備了載細(xì)胞因子反應(yīng)調(diào)節(jié)因子A(cytokine response modifier A，CrmA)的微球用于抑制關(guān)節(jié)軟骨的降解。在HA-CS-CrmA微球中，透明質(zhì)酸和殼聚糖以靜電作用結(jié)合[40]，又因透明質(zhì)酸具有較高的負(fù)電性和凝膠彈性，所以通過松散殼聚糖蛋白結(jié)合CS-CrmA來控制藥物的釋放。CrmA在HA-CS-CrmA組的釋放速度比CS-CrmA組慢，2組CrmA的最終釋放率分別為75%和85%，差異具有統(tǒng)計(jì)學(xué)意義(P<0.05)。因此，透明質(zhì)酸作為藥物的載體材料不僅可發(fā)揮抗炎作用還可延緩藥物的釋放，在骨關(guān)節(jié)炎的治療中具有較大的應(yīng)用價(jià)值。

3.3 透明質(zhì)酸與其他藥物聯(lián)合應(yīng)用 HA和其他藥物的聯(lián)合作用尚不明確，有研究[41]將透明質(zhì)酸和多西環(huán)素聯(lián)合制備成凝膠，透明質(zhì)酸覆蓋在軟骨表面起緩解作用，多西環(huán)素起抗炎作用，2者聯(lián)合制備成的凝膠相對于單獨(dú)的透明質(zhì)酸具有更高的粘彈性，軟骨保護(hù)作用更強(qiáng)且凝膠對骨關(guān)節(jié)炎的保護(hù)作用時(shí)間比單獨(dú)應(yīng)用透明質(zhì)酸和阿霉素要長。Chen等[42]研究證明HA和PRP聯(lián)合應(yīng)用能夠協(xié)同促進(jìn)軟骨再生，抑制骨關(guān)節(jié)的炎癥反應(yīng)。但是，Rezende等[43]評估關(guān)節(jié)腔注射HA和口服雙醋瑞因的療效，結(jié)果顯示雙醋瑞因降低了膝關(guān)節(jié)的退行性病變，HA保護(hù)關(guān)節(jié)軟骨，但2者聯(lián)用并沒有提高藥效。

4 展望

透明質(zhì)酸是一種分布于細(xì)胞間質(zhì)中的粘多糖，作為一種粘彈性補(bǔ)充療法，關(guān)節(jié)腔注射治療骨關(guān)節(jié)炎已被廣泛應(yīng)用，不僅如此，透明質(zhì)酸還可與CD44受體相互作用抑制炎癥介質(zhì)，產(chǎn)生抗炎活性。但是關(guān)節(jié)腔注射透明質(zhì)酸藥效持續(xù)時(shí)間較短，需多次注射，降低了患者的順應(yīng)性，但由于透明質(zhì)酸具有粘彈性、生物相容性和可降解性，在治療骨關(guān)節(jié)炎方面具有較好的應(yīng)用前景，因此，研究透明質(zhì)酸在治療骨關(guān)節(jié)中的新型應(yīng)用，在保持藥效的同時(shí)降低患者的痛苦，仍將是本課題組長期的奮斗目標(biāo)。

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(編校：王儼儼)

Progress on hyaluronic acid in treatment of osteoarthritis

TIAN Hong1, HUANG Gui-hua2, DOU Ming-jin1Δ

(1.Department of Pharmacy, Affiliated Hospital of Shandong Academy of Medical Sciences, Ji’nan 250031, China; 2. School of Pharmaceutical Sciences, Shandong University, Ji’nan 250012, China)

Osteoarthritis is a common chronic degenerative disease, which is currently the main drug therapy. Hyaluronic acid (HA) is a kind of glycosaminoglycan in the interstitial cells, which has the character of viscoelasticity, lubricity, biocompatibility,biodegradability and anti-inflammatory. It is wide applicated in the treatment of osteoarthritis. However, the half-life of the common hyaluronic acid injected into the joint cavity is shorter, patients need frequent dosing and the compliance is poor, research on new uses of hyaluronic acid formulations and clinical pharmacy workers is the new direction of research. In this paper, the recent advance of HA on function, safety, effectivity and novel application in osteoarthritis therapy are summarized.

hyaluronic acid; osterarthritis; mechanism; application

山東省科技發(fā)展計(jì)劃項(xiàng)目(2014GSF121012)

田紅，女，碩士在讀，研究方向：新劑型對骨關(guān)節(jié)炎的治療，E-mail：18363885175@163.com；竇明金，通信作者，男，碩士，主任藥師，研究方向：醫(yī)院藥事管理、臨床藥學(xué)的研究，E-mail：mingjindou1965@126.com。

R684.3

A

1005-1678(2015)10-0168-04