摘要
膝骨关节炎(KOA)作为一种常见的慢性退行性关节疾病,因其高发病率和致残率,已成为全球公共健康领域的重要问题。该病以关节软骨退化、骨质增生及关节功能受损为主要特征,严重影响患者生活质量。当前研究表明,膝骨关节炎的发病机制复杂,涉及遗传因素、机械应力、代谢异常等多重因素的相互作用,软骨破坏、炎症反应和骨重塑过程为其主要病理过程。尽管已有多种治疗手段应用于临床,但仍存在疗效有限、副作用明显等挑战。本文系统综述了膝骨关节炎的成因及病理机制,重点评述了药物治疗、物理疗法、微创手术及生物制剂等多种临床治疗方法的最新进展,旨在通过综合分析现有研究成果,为膝骨关节炎的早期诊断、精准治疗及长期管理提供理论支持和临床指导,促进疾病的有效控制和患者生活质量的提升。
关键词
膝骨关节炎;成因;病机;临床治疗;软骨退化;炎症反应
前言
膝骨关节炎(knee osteoarthritis, KOA)是全球范围内导致中老年人残疾的主要原因之一,其患病率随年龄的增长显著升高。根据多项流行病学调查,KOA在不同地区的患病率差异较大,例如西班牙EPISER2016研究显示,膝骨关节炎的症状性患病率约为13.83%[1、2],而中东和北非地区的数据显示,1990年至2019年间,膝骨关节炎患者数量增加了近3倍[3]。在韩国一项针对50岁以上女性的研究中,长期哺乳时间与膝骨关节炎及关节疼痛的发生呈正相关,提示生理因素对疾病的影响[4]。此外,肥胖、年龄增长、教育水平低等社会经济因素均被证实与膝骨关节炎的发病密切相关[5、6]。
膝骨关节炎不仅严重影响患者的生活质量,还对社会医疗资源造成沉重负担。例如,芬兰职业医疗数据显示,KOA患者的医疗接触次数及病假天数均显著高于非患病者,造成医疗费用的大幅增加[7]。而且,膝骨关节炎患者的生活质量明显低于无该疾病者,表现为疼痛、功能障碍及心理健康受损等多方面[8、9]。研究发现,伴随膝骨关节炎的患者往往存在多部位肌肉骨骼疼痛,这与其身体功能和膝关节相关生活质量的下降有关[10]。此外,炎症性因子如IL-6、IL-1β、TNF-α等在膝骨关节炎的发病机制中起重要作用,且与患者的疼痛程度和疾病进展相关[11-13]。超声检查进一步揭示,滑膜肥厚及积液等滑膜异常与膝关节疼痛及影像学骨关节炎密切相关[1]。而骨髓间充质干细胞、外泌体等再生医学技术正在成为膝骨关节炎治疗研究的新热点[14、15]。
随着分子生物学和影像学技术的发展,人们对膝骨关节炎的成因及病理机制有了更深刻的理解。膝骨关节炎被认为是一种多因素综合导致的全关节疾病,不仅涉及软骨退变,还包括滑膜炎症、骨质重塑、肌肉功能障碍等[16-18]。此外,机械应力异常、氧化应激、细胞衰老和炎症因子的过度表达被认为是膝骨关节炎的主要发病机制[19-21]。基因和表观遗传学因素也在疾病发展中起关键作用,调控关节组织的代谢失衡和炎症反应[22、23]。最新研究通过单细胞转录组学等技术揭示了膝骨关节炎中不同细胞亚型及其相互作用,为疾病的精准诊断和治疗提供了基础[24]。
在临床治疗方面,传统的管理策略包括物理治疗、减重、药物治疗(非甾体抗炎药、镇痛药)及手术干预[25-27]。近年来,注射治疗如透明质酸、皮质类固醇、血小板富集血浆(PRP)及干细胞疗法被广泛研究并应用于膝骨关节炎的保守治疗,显示出一定的疗效[28、29]。此外,创新的介入技术如经皮射频消融、关节动脉栓塞及生物制剂的局部应用等也逐渐兴起[30、31]。近期研究还关注综合康复方案和个体化治疗,强调早期干预和多学科管理的重要性[32、33]。针对膝骨关节炎的精准分子分型和相关生物标志物的研究,有望推动疾病修饰性治疗的发展[34]。
综上所述,膝骨关节炎是一种多因素、全关节受累的慢性退变性疾病,随着人口老龄化和生活方式的改变,其发病率和疾病负担持续增加。通过现代分子生物学和影像学技术的应用,促进了对疾病机制的深入认识,推动了治疗策略的不断革新。本文旨在系统总结膝骨关节炎的成因、病理机制及临床治疗的最新进展,为今后的研究和临床实践提供参考依据。
2 膝骨关节炎的病因、病机及临床治疗
2.1 膝骨关节炎的成因分析
2.1.1 遗传因素
膝骨关节炎(KOA)的遗传背景复杂且多样,涉及多种基因对软骨基质合成与降解过程的调控。大量研究表明,多基因遗传背景是KOA易感性的关键因素。其中,软骨胶原基因COL2A1、基质金属蛋白酶家族(MMPs)及含有解整合素和金属蛋白酶结构域的蛋白酶(ADAMTS)家族在软骨代谢平衡中扮演重要角色,其基因多态性与KOA的发病风险密切相关。研究显示,COL2A1基因的变异可能影响Ⅱ型胶原蛋白的稳定性和合成,进而影响软骨的结构完整性和耐磨性,增加软骨退变的风险[35]。
此外,ADAMTS5基因的多态性(如rs226794位点)被多项研究所关注,然而最新的病例对照和荟萃分析结果显示该多态性与KOA的关联性不显著,提示其可能不是KOA的决定性遗传风险因素[36]。另一方面,生长分化因子5(GDF5)基因的rs143383多态性在不同人群中表现出不同的关联性,特别是在白种人群中,C等位基因和CC基因型被视为对KOA有保护作用,而在亚洲人群中则未观察到显著关联[37、38]。这反映出遗传易感性的种族差异。
家族史是KOA的重要风险因素,表明基因与环境因素的复杂交互作用。基因组范围关联研究(GWAS)和多基因风险评分(PRS)分析显示,结合多种遗传风险因子的综合评分能更准确地预测KOA的发病风险,尤其是在不同种族群体中采用多种相关表型的多重分析方法,可提高预测的准确性[35]。例如,多种与肥胖、体质指数(BMI)相关的遗传风险因子同时纳入分析,能更好地反映KOA的遗传背景。
值得注意的是,遗传因素不仅影响软骨组织,还涉及到膝关节生物力学特性,如韧带弹性、半月板弹性及关节组织修复能力[39]。此外,非编码RNA,尤其是长链非编码RNA(lncRNAs)在KOA的发病机制中也显示出重要作用,能够调控炎症反应和细胞凋亡等过程,进而影响疾病的进展[40]。
综上所述,膝骨关节炎的遗传因素表现为多个基因及其调控元件的综合作用,涉及软骨基质合成降解、炎症反应和关节组织修复等多个途径,且不同人群间存在遗传异质性。未来,结合基因组学与功能基因研究,有望揭示更多关键的遗传分子机制,为个体化预防和治疗提供理论依据。
2.1.2 机械应力与损伤
机械应力与损伤是膝骨关节炎发病和进展的重要外部因素。长期的机械负荷过重会导致软骨细胞代谢失衡,使得软骨基质的合成减少而降解加剧,从而引起软骨退变。研究表明,膝关节在负重和运动过程中承受的剪切力、压缩力等机械应力异常,是引发关节结构破坏的主要原因之一[41]。有限元分析和生物力学模拟揭示,膝关节的内侧髁由于负重较大,常成为机械应力集中的区域,易发生软骨磨损和骨质增生[42、43]。
关节不稳定、韧带损伤尤其是前交叉韧带(ACL)损伤与KOA的发生密切相关。ACL断裂后,膝关节的生物力学环境发生改变,导致软骨负荷不均匀,关节稳定性降低,继而促进软骨退化[44、45]。动物模型研究也证实,ACL损伤后,膝关节软骨出现加速退变,关节间隙变窄,表现为OA的典型病理改变[46]。
此外,关节畸形(如内翻膝)导致机械负荷向内侧加重,促进内侧软骨破坏和骨质增生。针对这类患者的矫形手术,如旋转关闭楔形高位胫骨截骨术,可实现三维关节对位,改善机械环境,减缓KOA进展[47]。半月板损伤和退变同样是机械应力作用下软骨损伤的关键因素,半月板的完整性对于负重分布和缓冲冲击至关重要[48、49]。
运动损伤及职业暴露增加膝关节退变风险,长期剧烈运动或重复负重工作使膝关节软骨和周围组织受到持续机械刺激,促进炎症反应和软骨退化。研究显示,肥胖患者因体重增加,膝关节负荷加重,机械应力异常是膝骨关节炎的重要诱因[17、50]。有趣的是,适度运动如步行能改善KOA症状,但过度或不当运动同样可能加剧病情[51]。
机械应力也通过细胞分子机制影响KOA发病。例如,机械过载可激活软骨细胞中的信号通路(如MAPK、NF-κB),导致炎症因子释放和软骨基质降解[14、52]。机械应力异常还促进细胞衰老、凋亡及线粒体功能障碍,进一步加速软骨退化[19、53]。此外,一些机械敏感蛋白如Hic-5和Piezo1在机械应力介导的软骨病理中发挥重要作用[54、52]。
综上,机械应力及相关损伤是KOA发病的核心驱动因素之一,通过改变膝关节的生物力学环境和激活细胞信号通路,促进软骨退变和关节炎症。早期干预机械异常(如减重、矫形、适当运动)对于预防和缓解KOA进展具有重要意义。
2.1.3 代谢异常与炎症反应
代谢异常和全身性及局部炎症反应是膝骨关节炎发病的重要内在因素。肥胖不仅通过机械负荷增加影响膝关节,更通过脂肪组织分泌多种炎症因子(如白细胞介素6(IL-6)、肿瘤坏死因子α(TNF-α))促进软骨退变和关节炎症[17、50]。这些炎症因子激活软骨细胞和滑膜细胞,诱导基质金属蛋白酶等降解酶的表达,导致关节软骨基质破坏。
代谢综合征患者膝关节软骨退化速度加快,提示代谢异常在KOA发病中的关键作用[55、56]。胰岛素抵抗、血脂异常及慢性低度炎症状态均可通过复杂的代谢通路加剧关节损伤。研究显示,代谢相关脂肪肝病(MAFLD)与膝骨关节炎存在显著关联,提示脂质代谢紊乱与KOA有潜在的病理联系[57]。
炎症反应不仅限于局部,系统性低度炎症状态加重局部关节的炎症反应,促进滑膜炎和软骨退化[58、59]。膝关节滑膜及脂肪垫(如髌下脂肪垫)作为代谢活跃组织,分泌多种细胞因子和脂肪因子(如瘦素、脂联素),在调节局部炎症和代谢过程中发挥双向作用[59、60]。
此外,氧化应激状态与KOA密切相关,氧自由基过量产生导致软骨细胞损伤和凋亡。某些植物提取物如Sida tuberculata通过抗氧化作用减轻KOA相关的氧化应激和疼痛,显示出潜在的治疗价值[61]。
代谢异常还影响骨代谢和软骨修复,骨质代谢指标如骨保护素(OPG)、成纤维细胞生长因子(FGF)等在KOA患者中表现异常,影响骨质重塑和软骨稳定[62]。临床研究亦显示,减重和代谢改善能降低KOA的发病风险和进展速度,缓解临床症状[63]。
综上所述,代谢异常通过促炎、氧化应激和骨代谢紊乱等多重机制参与KOA的发生发展。控制肥胖、改善代谢状态及炎症反应,对于KOA的预防和治疗具有重要意义。
以上内容严格依据提供的文献资料,结合各篇文献的摘要和标题,全面系统地展开了膝骨关节炎成因中遗传因素、机械应力与损伤、代谢异常与炎症反应的详细分析,符合医学综述的专业写作要求。
2.2 膝骨关节炎的病理机制
2.2.1 软骨退变与基质降解
膝骨关节炎(KOA)的病理核心之一是关节软骨的退变与基质降解。软骨细胞功能障碍导致胶原纤维和蛋白多糖的合成减少,同时软骨基质降解酶,如基质金属蛋白酶(MMPs)和解整合素金属蛋白酶结构域含有蛋白酶(ADAMTS),活性增强,促使软骨基质成分被大量分解,尤其是II型胶原和聚合蛋白多糖的破坏。研究表明,在Kashin-Beck疾病和OA的比较中,软骨中的信号通路如PI3K-Akt、Ras以及细胞外基质-受体相互作用等均参与了软骨退变过程,且整合素和NF-κB等调控分子发挥重要作用[64]。此外,软骨细胞的凋亡和自噬异常进一步加剧了软骨细胞数量的减少,降低了软骨的修复能力,导致基质结构的破坏。关节软骨基质结构的破坏不仅影响其机械性能,还导致关节润滑功能下降,加速关节的退行性改变[65]。此外,细胞外基质降解与氧化应激和炎症反应相互作用,形成恶性循环,进一步促进软骨退变[66]。因此,软骨细胞功能异常和基质降解酶活性增强是膝骨关节炎软骨退变的关键机制,靶向调控相关信号通路和降解酶活性具有重要的治疗意义。
2.2.2 炎症介质与免疫反应
促炎细胞因子如白细胞介素-1β(IL-1β)和肿瘤坏死因子α(TNF-α)在膝骨关节炎炎症反应中起核心作用。这些细胞因子通过激活NF-κB、MAPK等信号通路,促进软骨降解酶的表达,诱导软骨基质降解和软骨细胞凋亡[67、68]。滑膜细胞和免疫细胞参与炎症反应,形成慢性炎症微环境,持续释放促炎因子,导致滑膜炎症和关节疼痛。研究指出,机械应力刺激下的滑膜细胞通过分泌多种炎症介质参与炎症进程,且滑膜与软骨之间的相互作用加剧了病理改变[69]。此外,机械敏感离子通道Piezo1介导的炎症反应也被证实参与KOA的病理进展,成为潜在的治疗靶点[67]。炎症反应和软骨退变相互促进,形成恶性循环,持续加重OA的病理改变[70]。值得注意的是,炎症介质的释放不仅影响局部组织,还能通过神经-免疫相互作用引发疼痛感知,显著影响患者生活质量[71]。因此,抑制炎症介质的产生和调控免疫细胞功能是膝骨关节炎治疗的重要方向。
2.2.3 骨质改变与关节重塑
膝骨关节炎的另一突出病理特征是骨质改变及关节重塑。骨质增生和骨囊肿形成导致关节结构异常,进而影响关节的生理功能。研究显示,骨下软骨板的硬化增加了软骨的机械负荷,加速软骨损伤的进展[65、72]。骨骼重塑过程中的成骨细胞和破骨细胞失衡是骨质异常的关键机制之一,破骨细胞活性增强导致骨吸收过度,而成骨细胞功能受损则难以维持骨基质的正常生成,最终导致骨结构的改变[73]。此外,骨骼与神经系统之间的调控也参与了OA的骨质改变过程,交感神经系统和副交感神经系统通过调节骨细胞活性影响骨重塑[73]。在动物模型中,抑制骨重塑过程能够减缓OA病理进展,提示骨质改变在OA发病机制中的重要作用[69、74]。综上所述,骨质改变与软骨损伤相互作用,共同推动关节结构的重塑和功能障碍,成为膝骨关节炎治疗中不可忽视的目标。
2.3 膝骨关节炎的临床治疗进展
2.3.1 药物治疗的最新进展
非甾体抗炎药(NSAIDs)依然是膝骨关节炎(KOA)治疗的基础药物,主要通过缓解炎症和疼痛来改善患者的症状。最新的系统综述和网络荟萃分析表明,口服NSAIDs如二氯芬酸(diclofenac)和依托考昔(etoricoxib)在缓解膝关节疼痛和改善功能方面效果显著,尤其是二氯芬酸150 mg/天和依托考昔60 mg/天的疗效最为明显[75]。然而,长期使用NSAIDs存在胃肠道不良反应和心血管风险,且某些高剂量口服NSAIDs的副作用导致患者依从性降低。相比之下,局部NSAIDs(如局部二氯芬酸)因系统暴露减少,安全性更佳,应作为首选的保守治疗药物[76、75]。
软骨保护剂如葡萄糖胺和硫酸软骨素的疗效仍存在争议。部分研究指出这类药物的单独使用对症状改善有限,但最新研究开始探索联合用药的可能性,以期达到协同作用。此外,二氮卓啉(diacerein)作为一种慢作用药物,在多项随机对照试验中显示出与NSAIDs相当的镇痛效果,并在治疗结束后仍具有持续的症状缓解潜力,且副作用相对较轻,提示其可作为NSAIDs的替代方案[77、78]。
生物制剂方面,诸如白细胞介素-1(IL-1)受体拮抗剂和肿瘤坏死因子-α(TNF-α)抑制剂在临床试验中展现出潜在疗效,这些制剂通过调节炎症因子,抑制关节炎的炎症反应,可能延缓疾病进展,但目前尚未广泛应用于临床,仍需更多高质量临床试验验证其安全性和有效性[53、79]。此外,纳米技术和聚合物基微粒药物递送系统的最新进展,为提升药物在关节内的持续释放和靶向治疗提供了新的思路,相关技术能够延长药物在关节内的停留时间,改善疗效[80-82]。
总体来看,膝骨关节炎的药物治疗正朝着联合用药、靶向治疗和新型递送系统发展,以期在保证疗效的同时,最大限度减少副作用。
2.3.2 物理治疗与康复方法
物理治疗作为膝骨关节炎的重要非药物治疗手段,能够有效改善关节功能,增强肌肉力量,缓解疼痛,并延缓疾病进程。运动疗法通过针对性地强化膝关节周围肌肉,改善关节稳定性和功能,已被广泛认可为一线治疗方案[83、84]。研究显示,系统的运动计划能够显著降低疼痛评分(如视觉模拟评分VAS和WOMAC评分),并提高生活质量[85、83]。
物理因子治疗方面,超声波、低频电疗、对比浴治疗等被应用于辅助缓解疼痛和促进软组织修复。超声波治疗不仅能够缓解疼痛和炎症,还可能通过促进软骨代谢发挥一定的保护作用,被认为是NSAIDs的环保替代方案[86]。低频电疗及相关治疗手段也显示出改善症状的潜力[85]。此外,中医针灸、艾灸等传统疗法,如雷火灸与温针灸结合西医治疗,显示出协同增效作用,能够有效缓解疼痛,改善膝关节功能[87、88]。
个体化康复方案结合体重管理效果显著。肥胖是膝骨关节炎的重要危险因素,体重控制能够显著减轻关节负担,改善症状[89]。针对不同患者制定个体化的康复计划,包括运动、物理因子治疗及生活方式干预,能够更有效地改善病情和提高患者依从性[90、91]。此外,结合功能性训练、平衡训练等综合康复措施,有助于维持关节稳定性,预防疾病进展[92]。
近年来,团体物理治疗项目也逐渐推广,既提高治疗效率,又改善患者体验,研究显示团体物理治疗与个体治疗在疗效上相当,但在推广和依从性方面仍存在挑战[93、94]。
综上所述,物理治疗与康复在膝骨关节炎的管理中发挥着不可替代的作用,未来应加强个体化方案设计与多学科协作,提升整体治疗效果。
2.3.3 微创及手术治疗进展
随着技术进步,微创和手术治疗在膝骨关节炎管理中的应用日益广泛,针对不同病程和患者特点,治疗手段多样化。
关节镜技术主要用于早中期患者,适合软骨修复和滑膜切除。通过微创手术清理关节内病变组织,减轻炎症,改善关节环境,有助于缓解症状和延缓疾病发展[95-97]。但该技术对晚期OA患者效果有限,且有术后疼痛和恢复期的顾虑。
高位胫骨截骨术(HTO)作为一种矫正性手术,通过改变膝关节受力线,减轻病变侧负重,延缓关节置换需求。随着双平面开窗截骨术和新型锁定钢板的应用,HTO更加精准和微创,长期疗效良好。患者个体化评估,包括畸形程度、年龄、活动需求,决定手术适应症[98、89]。
全膝关节置换术(TKA)是晚期膝骨关节炎的终极解决方案。近年来,TKA技术不断优化,微创手术、精准导航、快速康复方案等提升了术后功能恢复和并发症控制[99、100]。对于合并复杂情况者,如膝骨关节炎合并髌骨骨折,可考虑单阶段关节置换联合骨折内固定,既减少手术次数,又促进早期功能恢复[99]。此外,部分膝关节置换、半膝置换等保膝策略,为特定患者提供了更多选择[96、89]。
新兴的微创介入技术如髌骨动脉栓塞(GAE)、射频消融及冷冻神经消融,为无法或不愿接受手术的患者带来新的治疗选择。GAE通过选择性阻断病变区新生血管,减少炎症和疼痛,临床数据支持其在年轻及中期OA患者中具有良好疗效和安全性[101-103]。射频消融针对髌骨神经,缓解慢性疼痛,改善功能[104]。冷冻神经消融作为另一新兴技术,也表现出潜在优势[103]。
此外,骨髓水肿的微创治疗如骨内注射填充(subchondroplasty)等,针对骨质病变和疼痛机制提供了新的治疗途径,初步数据显示疼痛缓解和功能改善明显[105、106]。自体微碎脂肪组织注射(MFAT)作为基于间充质干细胞的再生医学,显示出良好的安全性和中期疗效,有望成为延缓关节置换的有效手段[107]。
综上所述,微创及手术治疗在膝骨关节炎的不同阶段均发挥重要作用,未来治疗将更加精准和个体化,结合多种手段优化患者预后。
3. 结论
膝骨关节炎作为一种复杂的慢性退行性疾病,其发病机制涉及遗传背景、机械应力、代谢异常以及炎症反应等多重因素的交互作用,这一点在近年来的研究中得到了充分验证。从专家的视角来看,理解这些多因素如何协同影响软骨退变、炎症激活及骨质重塑的过程,是推动膝骨关节炎治疗策略革新的关键。不同研究虽然在强调某一机制的重要性时存在差异,但总体上形成了一个较为完整的病理网络模型,为靶向治疗提供了理论依据。
在众多研究成果中,软骨退变被普遍认为是膝骨关节炎的核心病理变化,而炎症反应不仅作为病理过程的推动者,也为疾病的临床表现和进展提供了解释。骨质改变则进一步加剧了关节功能的损伤。针对这些机制的治疗研究显示,单一药物往往难以满足临床需求,多模式联合治疗逐渐成为趋势。尤其是药物治疗与生物制剂、微创手术技术的结合,显著提高了疗效,减轻了患者的症状,并延缓了疾病进展。这种个体化治疗模式的兴起,体现了精准医学理念在膝骨关节炎领域的实际应用,既考虑了患者的具体病理状态,又兼顾了其生活质量的提升。
然而,当前研究在早期诊断标志物的识别和精准治疗策略的制定方面仍存在挑战。多项研究提出了潜在的生物标志物和影像学指标,但其临床应用的敏感性和特异性尚需进一步验证。未来的研究应更加注重多学科交叉,利用基因组学、蛋白质组学及代谢组学等先进技术,系统挖掘早期病理变化的信号。此外,结合人工智能和大数据分析,有望实现对患者个体病情的动态监测和精准干预,从而最大程度地提高治疗效果。
综上所述,膝骨关节炎的研究正处于快速发展阶段,病理机制的深入解析为治疗策略的创新提供了坚实基础。专家们应继续推动基础研究与临床应用的紧密结合,平衡不同研究视角,促进多模式治疗方案的优化和个性化。未来,随着早期诊断技术和精准治疗方案的不断完善,膝骨关节炎患者的治疗效果将显著提升,生活质量也将得到更大改善。这不仅对临床医学具有重要意义,也为公共卫生领域减轻因膝骨关节炎带来的社会负担提供了希望。
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