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Chinese Journal of Reparative and Reconstructive Surgery logoLink to Chinese Journal of Reparative and Reconstructive Surgery
. 2022 Nov;36(11):1420–1427. [Article in Chinese] doi: 10.7507/1002-1892.202206072

酒精性股骨头坏死发病机制和基因学研究进展

Progress of pathogenesis and genetics of alcohol-induced osteonecrosis of femoral head

伟 陈 1, 黎明 卿 1, 攀峰 吴 1, 举玉 唐 1,*
PMCID: PMC9681594  PMID: 36382462

Abstract

目的

综述酒精性股骨头坏死（alcohol-induced osteonecrosis of the femoral head，AIONFH）发病机制和基因学研究进展。

方法

广泛查阅国内外相关文献，阐述AIONFH的发病机制以及基因多态性与其易感性之间的关系，并总结疾病进展的相关因素以及近年研究的潜在药物和治疗靶点。

结果

AIONFH是由过量饮酒引起的一种难治性骨科疾病，致残率高，严重影响患者日常生活。AIONFH发病机制包括脂质代谢紊乱、内皮功能障碍、骨稳态失衡等，基因多态性以及非编码RNA等也参与其中。AIONFH发生过程中涉及的血液学指标及分子改变，可能作为疾病早期诊断标志物及潜在治疗靶点。

结论

AIONFH发病机制尚未完全阐明，基于遗传学的研究包括基因多态性、非编码RNA等，结合二代测序技术，有望为将来进行机制研究以及发现潜在治疗靶点提供方向。

Keywords: 酒精性股骨头坏死, 发病机制, 基因学

股骨头坏死（osteonecrosis of the femoral head，ONFH）是一种临床常见的关节疾病，根据致病原因可分为激素性、创伤性、酒精性和特发性。基于中国人群的流行病学调查显示，酒精性ONFH（alcohol-induced ONFH，AIONFH）患者约占所有患者的37%，其中86%为男性；与其他类型ONFH患者相比，AIONFH患者更年轻、对侧发病率更高、进展快、预后差[1-2]，且饮酒量与ONFH 风险成非线性正相关[3-4]。但AIONFH具体病因和发生机制目前尚未明确。

激素性ONFH的发病机制包括血管损伤、机械应力、骨内压力升高、脂肪细胞功能障碍、细胞凋亡缺陷和凝血功能障碍等[5]。有研究显示与激素诱导骨坏死作用相似，酒精可以促进脂肪生成，从而增加骨内压力，导致股骨头血流中断，同时抑制成骨和血管生成[6]。现针对AIONFH的发病机制、基因多态性、诊断标志物以及潜在的治疗药物进行综述，以期为后续该病的机制研究提供新思路。

1. AIONFH发病机制、基因多态性与相关性因素

1.1. 脂质代谢紊乱

1.1.1. 脂质代谢相关基因多态性

ApoB和ApoA1基因多态性已明确与AIONFH相关，Wang等[7]发现ApoB基因rs1042034、rs676210和rs673548位点多态性与AIONFH风险成负相关，而ApoA1基因rs632153位点多态性与AIONFH风险成正相关。有研究表明，RAB40C是一种与脂滴相关的Rab家族蛋白，与前脂肪细胞分化为脂肪细胞相关[8]。Liu等[9]发现RAB40C基因多态性与AIONFH相关，揭示了该基因的成脂功能在AIONFH发生中发挥作用。RETN基因的多态性对血浆抵抗素浓度有显著影响，而抵抗素含量与骨密度、高密度脂蛋白之间存在负相关[10-12]。Liu等[13]发现，RETN基因rs7408174和rs3745369位点多态性与AIONFH风险成正相关，而rs34861192和rs3219175位点多态性与AIONFH风险成负相关。此外，Lee等[14]也发现固醇调节元件结合因子1的IVS7+117A>G基因型与韩国人AIONFH风险成正相关。而Guo等[15]发现MIR137HG基因多态性与中国男性AIONFH易感性有关，其中rs7549905位点多态性与AIONFH风险成负相关，rs17371457位点多态性与低密度脂蛋白胆固醇水平成正相关。

1.1.2. 脂质组学

代谢组学逐渐成为研究热点，脂质组学为其中一个分支，已有研究从其入手探索ONFH的疾病标志物，以期揭示ONFH的病理生理过程。Yan等[16]通过对不同类型ONFH患者血浆样品进行超高效液相色谱-三重四级杆质谱分析，发现AIONFH患者血浆中差异表达的脂质种类比其他类型ONFH患者更多，且一半属于三脂酰甘油类化合物亚类，提示AIONFH的发生与脂质代谢紊乱更为密切。

1.2. 血液循环系统紊乱

1.2.1. 内皮细胞与血管新生异常

高剂量酒精通过调节VEGF、bFGF和缺氧诱导因子等血管生成相关基因的表达，对血管生成产生不利影响[17-18]。Ma等[19]发现VEGFA基因rs2010963位点多态性仅存在于AIONFH患者中，激素性ONFH患者中没有，提示VEGFA基因多态性与AIONFH的发生有关。沈莹姗等[20]发现激素性ONFH股骨头内坏死区、硬化区和正常区的骨组织以及血清中VEGF蛋白水平均高于AIONFH患者，提示AIONFH病理过程中的血管生成减少。饥饿素能抑制血管内皮细胞（endothelial cells，ECs）凋亡，改善受损的内皮功能，促进血管生成[21]。而Li等[22]发现在非创伤性ONFH患者血清中，饥饿素水平明显低于正常对照组，且与血管性血友病因子（von Willebrand factor，vWF）成负相关，证实了饥饿素联合vWF可能参与了非创伤性ONFH的发病过程。

ACKR1/DARC是一种非特异性炎症趋化因子受体，广泛表达于ECs，不仅可以增加白细胞外渗，还具有抑制血管新生的作用[23-25]。Liao等[26]发现存在于AIONFH患者股骨头血窦和微小静脉中的ECs，根据ACKR1表达水平，可以分为高表达ACKR1的ECs（ACKR1+ECs）和低表达ACKR1的ECs（ACKR1–ECs），并发现ACKR1+ECs具有更强的免疫细胞招募能力和较弱的血管形成能力。选择素E可调节造血干细胞的休眠和增殖，当发生血管损伤时可在ACKR1+ECs与基质细胞之间发挥通讯作用[27]。因此，当酒精滥用等致病因素造成血管损伤后，ACKR1+ECs可通过选择素E途径与BMSCs接触，从而改变其分化趋势，促进AIONFH的发生。S100钙结合蛋白A9可调节内皮祖细胞的管状形成，增加ECs的通透性并促进凋亡，造成动脉功能障碍[28-30]；而其对于血管的这种影响促进了ONFH的发生，且表达水平与激素性ONFH及AIONFH进展密切相关[31]。

有研究表明，基质金属蛋白酶20（matrix metalloproteinase 20，MMP-20）基因可以调控老年性黄斑变性的血管新生[32]。An等[33]探讨了MMP-20的基因多态性与中国汉族男性AIONFH发病风险的关系，发现rs1711423和rs1784418位点多态性与AIONFH风险成负相关，而rs10895322、rs1784424、rs3781788、rs7126560、rs1573954、rs1711399和rs2292730位点多态性与AIONFH遗传易感性密切相关。

1.2.2. 凝血与造血功能紊乱

饮酒可造成内皮损伤，导致血管内凝血，股骨头血供减少，这可能是AIONFH的发病机制[34-35]。研究发现，内皮激活相关标志物（如vWF）与ONFH的进展成正相关，非创伤性ONFH患者血清vWF、PAI-1水平显著高于正常人群，而韩国人群中TFPI基因的单倍型“GAAT”与AIONFH显著相关，这些都表明凝血异常在ONFH发生发展中的复杂作用[22, 36-37]。Notch信号通路在调节骨稳态过程中起着重要作用，然而L3MBTL3作为Notch的竞争性抑制因子会抑制Notch信号通路，参与骨代谢相关疾病的发生[38-39]。PTPN9作为蛋白酪氨酸激酶亚家族成员之一，通过抑制VEGF受体信号和ECs功能，与血管内血栓形成密切相关[40]。Xiong等[41]探讨了L3MBTL3和PTPN9基因多态性与中国汉族人群AIONFH易感性之间的关系，结果表明L3MBTL3基因rs2068957位点多态性与AIONFH风险成正相关，而PTPN9基因rs75393192位点多态性与AIONFH风险成负相关，PTPN9基因的单倍型“GC”可显著降低AIONFH的易感性。

1.3. 骨代谢紊乱

1.3.1. 破骨细胞

骨保护素（osteoprotegerin，OPG）具有多种功能，包括抑制破骨细胞成熟、抑制血管钙化、促进肿瘤生长和转移等。Wang等[42]研究发现，AIONFH患者外周血白细胞OPG、RANK和RANKL基因的多个CpG位点处于异常甲基化状态，提示OPG/RANKL/RANK基因甲基化水平可能作为AIONFH的潜在预测因子，同时揭示了表观遗传机制可能参与破骨细胞分化过程。Li等[43-44]认为中国北方地区男性OPG和RANKL基因多态性与AIONFH密切相关，其中OPG基因rs1032128、rs11573828位点多态性和RANKL基因rs2200287位点多态性与AIONFH风险成正相关，而OPG基因rs11573856、rs3134056和rs1564861位点多态性与AIONFH风险成负相关。MMP-2可促进破骨细胞迁移、附着和骨基质降解[45-46]。Yu等[47]发现MMP-2基因多态性与AIONFH风险相关，其中rs243849位点的“T”等位基因增加了AIONFH的风险，而rs7201和rs243832位点的“CC”可降低风险。

1.3.2. 成骨细胞

Visfatin/Nampt是人体广泛存在的酶，具有分解代谢和促炎作用[48-49]。Liao等[26]发现AIONFH患者股骨头中的ACKR1+ECs可能通过Visfatin途径与软骨细胞、成骨细胞、纤维软骨细胞进行通讯，参与的主要受体ITGA5和ITGB1与成骨标志基因表达成负相关，与成软骨标志基因表达成正相关。此外，也有研究表明饥饿素对成骨细胞的增殖和分化具有促进作用，并可以抑制TNF-α诱导的破骨细胞分化和成骨细胞凋亡，但是AIONFH患者饥饿素水平降低，提示饥饿素可能参与了AIONFH的发生过程[22, 50-51]。

近年研究发现，Piezo家族机械敏感通道是与骨发育和成骨细胞分化相关的关键机械刺激传感蛋白，能感应骨骼机械应力并将其转化为细胞内信号，从而调控成骨细胞的功能和骨形成[52]。魏腾飞等[53]发现AIONFH患者股骨头内Piezo1蛋白表达水平低于激素性ONFH患者，提示AIONFH患者的成骨细胞活性更低，揭示了其不同于激素性ONFH的骨修复特点，同时也为进一步研究股骨头坏死骨组织细胞中的生物力学信号转导机制奠定了基础。

1.3.3. BMSCs分化失衡

酒精可以直接诱导脂肪生成，减少BMSCs的成骨效应，并产生细胞内脂质沉积，导致骨细胞死亡[54]。在这一过程中，mTOR信号通路可能是骨稳态的重要中介，酒精可激活mTOR信号通路导致BMSCs成骨-成脂分化异常，下调骨钙素、Ⅰ型胶原和成骨细胞特异性转录因子2（runt-related transcription factor 2，RUNX2）的表达[55-58]。有研究发现，酒精可以诱导氧化应激和内质网应激抑制Wnt/β-catenin信号通路，还可以调节PETN/Akt/Gsk3β/β-catenin信号通路，从而抑制BMSCs的增殖和成骨分化，抑制血管生成，并促进BMSCs成脂分化[59-61]。Dkk1作为一种Wnt抑制剂，可以阻碍Wnt、卷曲受体和低密度脂蛋白受体相关蛋白5共受体复合体的形成[62]。Ko等[63]发现AIONFH患者骨组织Bad和Dkk1基因表达及血清Dkk1丰度均显著高于股骨颈骨折患者，提示骨细胞凋亡与Dkk1表达增强相关。这些研究结果表明，Wnt信号通路在AIONFH发病机制中发挥重要作用。还有研究表明，酒精可通过调节AMPK途径影响胆固醇和血脂的稳态，并通过AMPK和PI3K/AKT/HIF-1α信号通路影响BMSCs的分化方向[64-67]。此外，多种间接途径，包括雌激素、生长激素-IGF、甲状旁腺素-维生素D轴，都可能介导长期饮酒对骨组织的有害影响[68-69]。

COUP-TFⅡ是核受体超家族成员之一，抑制Wnt和RUNX2的活性，激活PPARγ和Sox9的表达，从而促进BMSCs向脂肪细胞和软骨细胞谱系分化[70-71]。相反的，miR-194作为COUP-TFⅡ的关键负调节因子也参与了BMSCs的成骨过程[72]。而Wang等[73]的研究首次证实了COUP-TFⅡ表达增加介导了BMSCs分化失衡并向ONFH发展，可能为ONFH的治疗提供新靶点。Li等[74]发现通过下调PPARγ和上调降钙素基因相关肽表达，可有效抑制BMSCs成脂分化，促进成骨分化，降低AIONFH发生率。因此，我们认为酒精可通过刺激COUP-TFⅡ/PPARγ/Wnt轴造成BMSCs的成骨-成脂分化紊乱，从而促进AIONFH的发生。

1.4. 非编码RNA的作用

miRNA通过参与破骨细胞、成骨细胞和骨细胞的增殖、分化和凋亡，影响血管生成及BMSCs成脂分化等途径，在ONFH等骨相关疾病中发挥重要作用[75]。Hong等[76]利用基因芯片技术研究了AIONFH患者血清中差异表达的miRNA，发现AIONFH患者血清和骨组织中miR-127-3p、miR-628-3p和miR-1表达下调，而miR-885-5p、miR-483-3p和miR-483-5p表达上调，且相关的预测靶基因IGF-2、PDGFA、RUNX2、PTEN和VEGF等也可能发生了改变，提示miRNA的变化可作为AIONFH早期诊断标志物和潜在治疗靶点。

在非创伤性ONFH患者中，环状RNA（circular RNA，circRNA）在血浆和股骨头局部表达增加与影像学进展和髋关节功能变差有关，因此circRNA可以作为潜在的生物标志物，反映疾病严重程度和预测预后[77]。Guo等[78]通过对比AIONFH患者与正常人群血液中Carmen基因差异，发现Carmen基因多态性与45岁以下人群AIONFH风险成负相关。而Li等[79]通过全基因组转录组分析发现，长链非编码RNA（long non-coding RNA，lncRNA）的表达特征可以区分AIONFH与其他类型的ONFH，提示lncRNA可能成为AIONFH诊断和治疗的潜在生物标志物。

钱晓芬等[80]通过对AIONFH患者外周血进行基因测序，筛选出具有差异表达的mRNA和lncRNA，构建了包含3个lncRNA（SNHG3、MUC19、LINC00476）、5个miRNA（hsa-miR-146b-5p、hsa-miR-139-5p、hsa-miR-126-3p、hsa-miR-193a-3p、hsa-miR-135a-5p）和11个mRNA（PEX5、ACTR3B、CHMP4B、CSMD1、MTRF1、ZNF3、HTR7、NR5A2、SYT14、CASK、ING5）的竞争性内源RNA网络，涉及干细胞分化、炎症反应、神经内分泌、基因多态性等多种生物学过程，为进一步研究AIONFH分子机制及治疗靶点提供了新思路。

1.5. 酒精代谢相关生化指标

研究表明，外周血和器官中的乙醇脱氢酶（alcohol dehydrogenase，ADH）和乙醛脱氢酶（acetaldehyde dehydrogenase，ALDH）的遗传变异会导致AIONFH[81]。Li等[79]通过对晚期AIONFH患者全基因组进行测序，发现一种编码ADH的ADH1B基因显著上调，且ADH1B蛋白主要在AIONFH患者股骨头的血管平滑肌细胞、基质细胞和脂肪细胞中表达，而ALDH的表达没有明显改变。ALDH2作为酒精代谢过程中的关键酶，能将乙醛氧化成无毒乙酸，而只存在于东亚人群中的ALDH2*504Lys变异使ALDH2活性降低，增加了酒精的有害作用[82]。上述研究提示过量饮酒人群的股骨头局部可能积累了过量乙醛，而乙醛蓄积的细胞毒性可以直接影响血管和细胞外基质，导致血管平滑肌细胞结构损伤和功能障碍，从而导致AIONFH发生。因此，降低局部过量乙醛引起的细胞毒性可能是一种有前景的AIONFH治疗措施。

Hamada等[83]通过检测AIONFH患者血液，发现血清γ-谷氨酰转移酶（γ-glutamyltransferase，GGT）显著升高，以临界值36.5 U/L作为AIONFH的诊断标准，灵敏度为76%，特异度为80%。研究表明，持续酗酒可导致单侧ONFH患者对侧股骨头受累[84]。因此，在患有单侧ONFH且伴有高“GGT”水平的情况下，无论患者自述饮酒行为是否达到AIONFH诊断标准，都应嘱其戒酒，以预防对侧股骨头发生坏死。

1.6. 免疫细胞

Wang等[61]的研究揭示了酒精与骨免疫的关系，即酒精通过激活T淋巴细胞来促进破骨细胞因子（如IL-17、RANKL）的分泌，通过减少B淋巴细胞下调OPG。而Ma等[85]通过对ONFH患者外周血T、B淋巴细胞亚群分析，发现AIONFH患者的淋巴细胞总数和T淋巴细胞均显著低于特发性ONFH患者，且T淋巴细胞百分比降低与骨坏死分期进展相关，提示T、B淋巴细胞等免疫调节细胞在AIONFH发病机制中起重要作用。

2. 疾病进展相关因素

Yang等[86]的一项病例对照研究发现，ABO血型与ONFH发生无相关性，但与ONFH的进展密切相关，其中A型血患者进展最快，O型血患者进展最慢。Liu等[87]发现非创伤性ONFH患者血浆血管活性肠肽浓度明显低于正常人，且与Ficat分期、疼痛视觉模拟评分（VAS）、TNF-α及IL-1β水平成负相关，与Harris评分成正相关，这提示血浆血管活性肠肽浓度降低与影像学进展和临床严重程度相关，可作为ONFH早期诊断标志物。Wu等[31]发现S100钙结合蛋白A9水平随着ONFH的Ficat和Arlet分期进展而升高，并与患者激素用药史和饮酒史相关。Ma等[85]发现在不同分期AIONFH患者外周血中，国际骨循环研究协会（ARCO） Ⅳ期者的T淋巴细胞百分比明显低于Ⅱ、Ⅲ期患者。郑小龙等[88]比较了AIONFH患者和正常人血液中骨转换标志物的差异，发现AIONFH患者骨转换标志物均明显升高，其中Ⅰ型胶原氨基端延长肽与分期进展成正相关，提示其在一定程度上可以反映AIONFH发展进程。

相关研究报道，低氧相关转录因子BHLHE40和CREB3L1及其调控子在纤维软骨细胞中具有特异性活性[89-90]。Liao等[26]发现AIONFH患者股骨头中存在大量纤维软骨细胞以及ACKR1+ECs，并且随着疾病进展而增加，提示骨髓微环境中低氧程度加剧及内皮细胞ACKR1表达水平增加与AIONFH进展密切相关。

Liu等[13]发现RETN基因rs3745368位点多态性与AIONFH的临床分期相关。Guo等[15]发现MIR137HG基因rs9440302和rs7554283位点多态性可以显著增加ARCO Ⅲ、Ⅳ期AIONFH患者易感性。Yan等[16]通过脂质组学分析发现3，4-二羟基苯甲酸可能是疾病进展的预测因子。

3. 潜在药物及治疗靶点

阿仑膦酸钠等双磷酸盐类药物已被证明对于ONFH有效[91-93]。普伐他汀作为常见的降脂药物，临床尚未用于ONFH患者，但基于AIONFH动物模型中的研究已证实其有益作用[94-97]。此外，辛伐他汀联合阿仑膦酸钠可抑制TLR4/NF-κB信号通路，抑制炎症反应，上调脂联素和骨钙素表达水平，对AIONFH有治疗作用[98]。

研究表明，甜菜碱可促进成骨细胞胞质钙内流、ERK激活和IGF-1产生，抑制mTOR信号通路，从而促进成骨基因表达，减轻AIONFH大鼠股骨头的骨坏死性损害[58, 99]。而大黄酸、蛇床子素、虫草素以及新型Akt激活剂SC-79可作用于Wnt/β-catenin信号通路，逆转酒精不利影响，可以作为预防AIONFH进展的潜在治疗方法[60, 100-102]。Wang等[103]发现葛根素可以抑制BMSCs向成脂细胞分化，降低PPARγ基因表达，从而预防AIONFH。有研究报道，麝香酮具有血管扩张和血管生成作用，可诱导CYP450、CYP1A2和CYP3A11酶的表达[104-107]，提高这些酶的水平有利于酒精代谢，也有助于降低AIONFH发生率。此外，Guo等[108]的研究还证实了麝香酮可通过促进ALP活性和Ⅰ型胶原、骨钙素基因的表达，发挥对AIONFH的保护作用。

Chen等[109]的细胞和动物实验发现敲除DKK1基因可促进BMSCs成骨并抑制脂肪生成，且在大鼠股骨头注射DKK1基因敲除的慢病毒可有效延缓AIONFH进展，因此靶向DKK1激活Wnt/β-Catenin通路可能是一种预防AIONFH的潜在治疗策略。杜振宁等[110]的细胞实验探讨了血红素氧合酶1（heme oxygenase 1，HO-1）和BMP-2对酒精作用下成骨细胞凋亡的影响，结果发现成骨细胞中过表达HO-1可降低酒精作用后成骨细胞凋亡率，同时上调HO-1和BMP-2表达后上述作用更明显，提示联合使用HO-1和BMP-2可能对AIONFH的骨修复具有有益作用。

4. 结语与展望

过量饮酒可导致ONFH，其中涉及的机制复杂，目前还未完全阐明。脂质代谢紊乱、内皮功能障碍、骨稳态失衡等参与的发病机制是近年来主要研究方向，其中遗传学层面，包括基因多态性以及非编码RNA等，也被证明参与了AIONFH发生发展。

虽然关于AIONFH发生机制的研究呈增多趋势，但目前依然缺乏延缓疾病进展的有效手段。研究表明，持续酗酒可导致单侧ONFH患者对侧股骨头受累[84]。因此，戒酒是防止疾病发生发展的有效手段。目前对于AIONFH的早期诊断主要基于影像学改变，缺乏先于影像学改变的诊断方法，饮酒人群的血液学指标变化是否可以预测AIONFH发生值得继续探讨。

利益冲突　在课题研究和文章撰写过程中不存在利益冲突；经费支持没有影响文章观点及其报道

作者贡献声明　陈伟：文献收集、分析总结、撰写文章；卿黎明、唐举玉：综述构思设计；卿黎明、吴攀峰：文章校对

Funding Statement

国家自然科学基金资助项目（81871577）

National Natural Science Foundation of China (81871577)

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