骨关节炎软骨下骨的变化及其分子机制的研究进展

华秉譞(综述) 阎作勤(审校)

(复旦大学附属中山医院骨科 上海 200032)

骨关节炎软骨下骨的变化及其分子机制的研究进展

华秉譞(综述) 阎作勤△(审校)

(复旦大学附属中山医院骨科 上海 200032)

骨关节炎(osteoarthritis,OA)是一种最常见的慢性骨关节疾病,可累及整个关节。软骨下骨作为关节的重要组成部分,与OA的发生发展密切相关。OA中软骨下骨变化的机制复杂,目前尚未完全阐明。本文通过文献回顾对OA中软骨下骨的病理变化,OPG/RANKL/RANK系统、转化生长因子β (transforming growth factor β,TGFβ)、雌激素-雌激素受体信号通路和脂代谢等因素对软骨下骨的影响进行综述,探讨OA中软骨下骨变化的作用及其分子机制。

骨关节炎; 软骨下骨; OPG/RANKL/RANK系统; TGFβ; 雌激素; 雌激素受体; 脂代谢

骨关节炎(osteoarthritis,OA)是一种常见的慢性骨关节疾病,是造成关节疼痛和功能障碍的重要原因之一[1]。OA好发于中老年患者,女性多于男性,60岁以上的人群中患病率可达50%,75岁以上的人群中则可达到80%,该病的致残率高达53%。OA多发于负重大、活动多的关节,如膝、脊柱(颈椎和腰椎)、髋、踝、手等关节[2-3]。原发性OA的病因尚不明确,除年龄外[4-5],还与免疫、生物学等多种因素相关[6-7]。

OA主要病理变化发生在软骨、软骨下骨与滑膜[8]。过去研究的重点主要集中在关节软骨,近年来软骨下骨对于关节软骨的重要作用逐渐被重视[9]。自Radin等[10]于1972年首次提出软骨下骨改变是OA发病启动因素的假说后,近年来越来越多的研究表明,软骨下骨确实在OA病变中起到重要作用[11-14],有学者认为软骨下骨硬化是OA软骨病变的起始因素[15]。OA中软骨下骨的变化及其分子机制也成为了当前研究的热点,本文就此作一综述。

OA中软骨下骨的病理及超微结构变化 软骨下骨是组成关节的重要部分,主要包括软骨下皮质终板、骨小梁结构、血管及小梁间隙结构,主要生物学功能为吸收应力、缓冲震荡以及维持关节形状等,还能为软骨提供营养及清除代谢产物[16]。王华伟[17]通过HE、番红O/固绿、冯库萨、甲苯胺蓝、天狼猩红等多种染色,观察了21例临床诊断原发性OA的股骨髁标本,获得的病理学结果显示:原发性OA的骨软纵断面三层结构显示不清,潮线断裂、间隙增宽、钙化软骨层增厚。关节主要病理组织学改变包括:(1)三层结构潮线复制、漂移; (2)钙化层增厚,伴血管长入;(3)非钙化软骨及钙化层纤维样改变;(4)潮线间隙增宽;(5)深层软骨及钙化层缺损。李西海等[18]通过建立大鼠膝关节OA模型,发现OA膝关节的软骨表面粗糙,完整性破坏,表层软骨出现纤维化变性及软骨缺损,甚至软骨下骨裸露,软骨下骨致密层变薄,骨松质层骨小梁稀疏,硬化或囊变,边缘有丘状隆起的骨赘。Yan等[19]在DH豚鼠与年龄相关的OA模型中,通过扫描电镜和透射电镜分别观察了1、3、6、9、12月龄的DH豚鼠,观察到关节软骨会随着OA的进展逐渐出现微纤毛、软骨表面溃疡、胶原纤维退化等变化,软骨细胞也会随着OA进展逐渐出现形态的不规则以及细胞凋亡,软骨细胞的细胞质、细胞核会逐渐出现溶解和固缩。研究表明软骨下骨与软骨之间的紧密连接在关节活动和保护功能中起到重要的作用[20-21]。

OA软骨下骨重建及硬化 OA骨端发生的病理变化主要包括骨重建及骨质硬化,包含软骨下骨密度增高、骨量增加。骨重建是指骨组织的形态和密度随着生物力学环境的改变而改变的生理行为,载荷高的地方骨的质量和密度增高,反之骨的质量和密度发生下降。正常生理情况下,骨重建是通过成骨细胞和破骨细胞来调节的,成骨细胞负责骨基质的合成、分泌和矿化,破骨细胞具有骨吸收功能,两者作用互相拮抗、互相平衡,它们的活化和凋亡在骨骼的生长发育中起重要作用。

OA的早期病理变化主要表现为骨吸收增强,破骨细胞溶骨作用增强,软骨下骨骨质疏松,骨量减少,骨小梁变薄。Intema等[22]利用狗前交叉韧带切断和内侧半月板切除的方法复制OA模型,通过观察组织学以及影像学超微结构发现,早期OA关节软骨蛋白聚糖丢失增多,软骨下骨厚度降低,骨小梁厚度及体积均下降。晚期软骨下骨骨形成增加,发生硬化。Ham等[23]通过卵巢切除的成年母猴复制OA模型,发现雌激素替代治疗(estrogen replacement therapy,ERT)的实验组发生OA的概率显著低于无雌激素治疗的对照组,对比骨形态组织计量发现OA晚期骨小梁厚度增加,新生骨组织矿化升高,骨形成率增加,软骨下骨骨密度增高,发生硬化。软骨下骨的硬化可导致其吸收应力、缓冲震荡的作用减少,从而加剧了关节的损害及退变[24]。软骨下骨的损害还可加重软骨的病变[12,25]。同时,OA晚期关节微血管形成增加,并且浸润到软骨下骨,也可通过表达基质金属蛋白酶(matrix metalloproteinase,MMP)加剧软骨的退化,从而加重OA病情[26-27]。随着OA病情的加重,则会出现上述典型的病理及超微结构的变化及相关的临床表现。

调控OA中软骨下骨变化的分子机制

OPG/RANKL/RANK系统的作用 2000年,美国骨与矿物质协会最早提出骨保护素(osteoprotegerin,OPG)、核因子κB受体活化因子(receptor activator for nuclear factor-κB,RANK)、RANK配体(receptor activator for nuclear factor-κB ligand,RANKL)是紧密联系的整体,命名为OPG/RANKL/RANK系统[28]。RANK是唯一已知的RANKL发挥作用的受体,两者结合后激活信号通路,使破骨细胞前体分化,促使破骨细胞成熟,发挥骨吸收作用;OPG是抑制骨吸收的细胞因子,其功能是阻断RANK与RANKL的结合,抑制破骨细胞的成熟,从而抑制其骨吸收作用[29-30]。

OA中OPG/RANKL/RANK系统对于软骨下骨起到重要作用。Kwan Tat等[31]证实,OA软骨下骨中OPG水平降低,RANKL在早期OA中表达增加,在晚期OA中表达减少。软骨下骨破骨细胞的激活在OA的起始病变中起到重要的作用[32],而OPG/RANKL比值可以作为反映破骨细胞活动水平的一个指标,调控骨代谢[33]。OPG/RANKL比值与软骨下骨厚度成正比,在早期OA中OPG/RANKL比值降低,破骨细胞活性增强,致使骨吸收增加,软骨下骨发生异常重建;而在晚期OA中该比值上升,破骨细胞活性降低,此时骨形成增加,导致骨质硬化、形成骨赘等。Martinez-Calatrava等[34]和Moreno-Rubio等[35]研究发现,OA中不仅软骨细胞高表达RANKL,细胞外基质中也可以发现RANKL,并作用于软骨下骨,造成骨丢失。Funck-Brentano等[32]在半月板切除诱导OA小鼠模型中,将小鼠软骨下骨上清液加入到软骨组织中,发现软骨代谢中的蛋白多糖和蛋白聚糖释放减少,提示骨分泌的可溶性因子参与调节软骨代谢[36],这种细胞因子和信号传导通路可能通过软骨下骨新生血管以及局部骨裂隙及钙化软骨中的微管进行传导。由此说明OPG和RANKL参与关节软骨和骨之间的双向调节,包括软骨代谢和软骨下骨吸收,表明OPG/RANKL/RANK系统在OA中的重要性。

TGF-β信号通路的作用 转化生长因子β(transforming growth factor β,TGFβ)属于一类促进细胞生长和转化的细胞因子超家族,有6种不同亚型,其中TGFβ1、TGFβ2和TGFβ3亚型表达于哺乳动物[37-38],是维持关节软骨代谢平衡与结构完整性的重要因素之一[39]。Zhen等[40]通过切断大鼠前交叉韧带制作OA模型,发现机械应力改变软骨下骨形态并导致软骨下骨TGFβ浓度升高,同样在膝关节OA患者软骨下骨TGFβ浓度也明显升高;而在动物模型中,在软骨下骨加入适量的TGFβI型受体抑制剂(TβRI)可以稳定软骨下骨结构(剂量过大会导致关节软骨蛋白多糖丢失),防止OA中关节软骨的退化。此外,TGFβ可以诱导骨髓间充质干细胞(bone marrow stem cell,BMSC)的迁移聚集,从而导致异常骨重塑[41],促进OA的病理进展。使用TβRI可以减少骨重塑,为OA治疗提供新的思路[40]。骨形成总是伴随着血管生成,TGFβ可以通过影响内皮祖细胞以及促进间充质干细胞的旁分泌机制来促进血管生成[42-43],抑制 TGFβ 的活性,减少血管生成可以减少TGFβ相关异常骨形成。Yusup等[44]通过对40例晚期膝关节OA患者行磁共振、血清细胞因子及组织学检查,发现滑膜血管组织TGFβ水平与软骨下骨髓病变、软骨下骨囊肿、软骨下骨磨损程度呈正相关。Jiao等[45]使用TGFβ1转基因CED小鼠模型,使TGFβ1在骨髓中高表达,导致下颌髁软骨下骨异常骨重建,进而出现软骨的异常,表明TGFβ在颞下颌关节骨关节炎的发展中起到重要作用。

TGFβ对于软骨下骨微环境的调控也影响着OA的进展,TGFβ通过调节BMSC的分化募集,形成骨样小岛,导致异常骨重塑[41,46];可以介导上皮间质转化(epithelial-mesenchymal transition,EMT)及内皮间质转化(endothelial-mesenchymal transition,EndoMT)通路,为OA软骨下骨血管生成增加提供上皮细胞和内皮细胞的资源[47-49]。二膦酸盐类治疗OA的研究已有很长一段时间[50],其中阿仑膦酸钠对于OA的治疗被认为是一项重要的发现,它不但保护软骨对于应力的变化,还可以保护软骨下骨对于应力的变化,在切断兔前交叉韧带复制的OA模型中,阿仑膦酸钠可以防止关节区域骨丢失,抑制破骨细胞向软骨下骨区域募集[51]。阿仑膦酸钠可以抑制早期软骨下骨吸收和防止异常骨赘形成,这一效果可以用减少局部TGFβ的活化来解释[52]。鉴于TGFβ在OA的病理过程中起到重要作用,特异性抑制软骨下骨TGFβ活性也给OA的治疗提供了新的临床思路。

雌激素-雌激素受体信号通路的作用 雌激素是人体内分泌的重要激素之一。流行病学调查显示,雌激素减退有增加OA患病的可能[53],女性OA发病率高于男性,特别是在绝经以后[54],一项研究表明64%的女性膝关节OA或出现相关OA症状者在5年内绝经或者接受子宫切除术[55]。绝经后女性比同龄男性更易出现髋、膝OA症状,且病程进展更快[56]。雌激素受体(estrogen receptor,ER)分为ER-α和ER-β两种亚型,此两型受体在软骨细胞、软骨下骨细胞、滑膜细胞和韧带成纤维细胞中均有表达,说明关节组织是雌激素的作用目标之一[57-60]。雌激素对于关节稳定起到重要的保护作用。在动物模型中,卵巢切除会引起强烈的软骨下骨丢失和重建,削弱软骨下骨小梁生物力学性能,随之会导致软骨的损伤[55,61-62]。Sniekers等[63]敲除雌性小鼠的雌激素受体基因,导致小鼠胫骨骨赘增加、软骨下骨板变薄,发生了OA早期的病变。通过切除母猴卵巢可复制OA模型,ERT的实验组发生OA的概率显著低于对照组,表明雌激素对于维持关节骨量和功能的重要作用[23],ERT对于OA有一定治疗作用,可延缓OA发展[64]。一项大样本量临床分析表明,激素替代治疗(hormone replacement therapy,HRT)可以显著减少OA患者关节置换术后翻修的概率,提示HRT对于OA关节置换的积极效果[65]。选择性雌激素受体调节剂(selective estrogen receptor modulators,SERMs)被多次报道对于OA治疗有益,并且已经在欧美市场上使用[66],相较于对于软骨的短期作用,SERMs对于软骨下骨的作用是长期的[64]。也有学者认为,过高水平的雌激素不利于关节稳态,会诱发关节损伤,因为高剂量的雌激素增加IL-1β诱导的蛋白聚糖降解和MMP的生成而损害关节软骨[54,67]。

雌激素及其受体在分子水平上可调节一系列细胞因子。雌激素可上调OPG表达[68],体外实验证实雌激素可以诱导OPG产生[69]。同时,雌激素可以抑制RANKL的作用,通过抑制破骨细胞的作用而影响骨代谢[70-71]。另外,在卵巢切除小鼠中TGFβ表达下降,说明内源性雌激素缺乏可能直接抑制成骨活性[72]。

脂代谢的作用 OA被认为是一项和年龄及代谢相关的疾病[73-74],长期以来肥胖被认为是导致OA的高危因素之一[75],与肥胖密切相关的脂代谢被认为在OA发病中起重要作用[76-77]。Chaput等[78]通过对OA患者和健康者股骨标本的蛋白组学研究发现,在OA患者中载脂蛋白A-I显著下降。张荣凯等[79]以大鼠前交叉韧带切断和内侧半月板切除复制OA模型,通过基因芯片筛查研究早期OA软骨下骨脂蛋白相关基因的表达情况,发现多种脂蛋白相关基因在术后1个月内发生变化。瘦素、脂联素、内脂素和抵抗素作为脂肪组织释放的脂肪因子被认为在OA软骨和骨的动态平衡中发挥重要作用[77]。Mutabaruka等[80]通过临床研究和尸体解剖发现,在OA患者膝关节软骨下骨中瘦素显著增加,并通过调节碱性磷酸酶、骨钙素、Ⅰ型胶原蛋白和TGF-β1水平完成促进异常成骨细胞的分化,从而导致OA晚期异常骨赘的产生。Berry等[81]通过一项为期2年的随访发现,OA患者瘦素水平的增加与骨形成标志物骨钙素和I型前胶原N末端前肽呈正相关。体外研究表明,脂联素通过增加RANKL表达和抑制OPG表达增加破骨细胞的形成[82],而在骨赘生成中脂联素的水平较低,提示其与早期骨赘生成的相关性[77]。Choe等[83]发现血清抵抗素水平与手OA影像学软骨下侵蚀程度呈正相关。Wang等[84]通过OA患者和正常人的特殊磁共振序列扫描发现,OA患者胫骨软骨下骨脂质的影像学变化,可能与OA软骨下骨髓水肿相关。脂代谢相关疾病如动脉粥样硬化的发生也与OA的发生有一定的联系,可能的机制是代谢性疾病造成的软骨下骨代谢障碍以及由脂肪因子引起的系统性炎性反应,从而导致OA病理生理作用[85-87]。当前,更多的研究表明,脂代谢及脂肪因子对于OA软骨细胞具有重要的作用,主要是通过增加关节软骨细胞和滑膜成纤维细胞促炎介质的产生,炎性介质和细胞因子诱导了关节局部炎性因子及软骨基质裂解酶的产生,在OA炎症产生、软骨破坏过程中发挥着重要作用[88-89]。瘦素通过转录因子NF-κB、蛋白激酶(protein kinase C,PKC)和丝裂原活化蛋白A激酶(mitogen-activated protein kinase,MAPK)信号通路[90-91],而脂联素是通过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)信号通路分别诱导NO和MMP引起炎性反应[88,92]。瘦素等脂肪因子对于软骨下骨的作用机制目前仍未完全明确,可能是通过引起局部的炎性反应导致软骨下骨内环境的变化。软骨是一种无血管组织,软骨下骨的代谢不仅作用于其本身,还通过分子扩散直接影响软骨[93],继而引发OA的病变,但其机制及通路仍有待进一步研究。脂代谢导致软骨下骨内环境的变化,进而影响自身和软骨代谢,在OA的发生发展中起到一定的作用。

结语 OA中软骨下骨的变化被日渐重视,但究竟是软骨下骨的变化引起关节软骨的病变还是软骨病变影响软骨下骨这一问题至今学界仍无定论。可以明确的是,软骨下骨在OA的发生发展中扮演重要的角色,OPG/RANKL/RANK系统、TGFβ、雌激素-雌激素受体信号通路和脂代谢等因素均对OA软骨下骨起到重要的作用,引起软骨下骨内环境改变和病理变化,也会对软骨代谢和软骨细胞起到影响,从而导致OA的发生发展。OA诊断主要依靠X线摄片,并被认为是金标准。目前对于OA尚无可以治愈疾病的药物,只能从症状上缓解病情。明确OPG/RANKL/RANK系统、TGFβ、雌激素-雌激素受体信号通路和脂代谢等因素在OA中对于软骨下骨及整个关节软骨的作用,可以为OA的早期诊断和治疗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;编辑:段佳)

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