切换至 "中华医学电子期刊资源库"

中华关节外科杂志(电子版) ›› 2026, Vol. 20 ›› Issue (02) : 222 -226. doi: 10.3877/cma.j.issn.1674-134X.2026.02.011

综述

乙醛脱氢酶2在非创伤性股骨头坏死中的作用
张义1,2, 李冬来3, 张业勇2, 王功腾2, 李树锋2,()   
  1. 1 250355 济南,山东中医药大学第一临床医学院
    2 250014 济南,山东第一医科大学第一附属医院(山东省千佛山医院)骨外科,山东省风湿免疫病转化医学重点实验室
    3 250012 济南,山东大学齐鲁医学院骨科
  • 收稿日期:2025-03-27 出版日期:2026-04-01
  • 通信作者: 李树锋
  • 基金资助:
    山东省自然科学基金面上项目(ZR2022MH128)

Role of acetaldehyde dehydrogenase 2 in nontraumatic osteonecrosis of femoral head

Yi Zhang1,2, Donglai Li3, Yeyong Zhang2, Gongteng Wang2, Shufeng Li2,()   

  1. 1 First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
    2 Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University (Shandong Provincial Qianfoshan Hospital), Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan 250014, China
    3 Department of Orthopedics, Qilu Hospital of Shandong University, Jinan 250012, China
  • Received:2025-03-27 Published:2026-04-01
  • Corresponding author: Shufeng Li
引用本文:

张义, 李冬来, 张业勇, 王功腾, 李树锋. 乙醛脱氢酶2在非创伤性股骨头坏死中的作用[J/OL]. 中华关节外科杂志(电子版), 2026, 20(02): 222-226.

Yi Zhang, Donglai Li, Yeyong Zhang, Gongteng Wang, Shufeng Li. Role of acetaldehyde dehydrogenase 2 in nontraumatic osteonecrosis of femoral head[J/OL]. Chinese Journal of Joint Surgery(Electronic Edition), 2026, 20(02): 222-226.

非创伤性股骨头坏死(NT-ONFH)是一种常见的髋关节疾病,其发病机制复杂,与脂质代谢紊乱、氧化应激及酒精中毒等因素密切相关。乙醛脱氢酶2(ALDH2)是人体内酒精代谢的关键酶,其基因突变可通过降低酶活性导致乙醛或其他醛类物质在体内蓄积,进而可能促进NT-ONFH的发生发展。已有研究证实ALDH2基因多态性与NT-ONFH的发病存在着显著关联,携带突变等位基因(如ALDH2*2)的个体因酒精代谢能力下降,更易出现股骨头微循环障碍、成骨细胞凋亡及骨髓间充质干细胞分化异常,从而加速骨坏死进展。本文系统梳理了ALDH2及其基因突变对NT-ONFH影响的研究现状,从细胞和动物实验层面阐述其作用机制,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,同时分析现有研究的不足与局限,展望未来研究方向,旨在为深入揭示NT-ONFH发病机制及开发新型治疗策略提供理论依据。

Non-traumatic osteonecrosis of the femoral head (NT-ONFH) is a common hip joint disease with a complex pathogenesis closely related to lipid metabolism disorders, oxidative stress, and alcohol toxicity. Acetaldehyde dehydrogenase 2 (ALDH2), a key enzyme in alcohol metabolism in humans, can lead to the accumulation of acetaldehyde or other aldehydes in the body due to reduced enzyme activity caused by gene mutations, which may further promote the occurrence and development of NT-ONFH. Studies have confirmed a significant association between ALDH2 gene polymorphisms and the onset of NT-ONFH. Individuals carrying mutant alleles (e.g., ALDH2*2) exhibit reduced alcohol metabolism capacity, making them more susceptible to microcirculatory dysfunction in the femoral head, osteoblast apoptosis, and abnormal differentiation of bone marrow mesenchymal stem cells, which accelerates the progression of osteonecrosis. This article systematically summarized the current research status on the impact of ALDH2 and its gene mutations on NT-ONFH, elucidated the underlying mechanisms at the cellular and animal experimental levels, and summarized factors related to disease progression as well as potential drugs and therapeutic targets identified in recent studies. Additionally, it analyzed the limitations and shortcomings of existing research and prospects future research directions, aiming to provide a theoretical basis for further revealing the pathogenesis of NT-ONFH and developing novel therapeutic strategies.

[1]
Huang ZQ, Fu FY, Li WL, et al. Current treatment modalities for osteonecrosis of femoral head in mainland China: a cross-sectional study[J]. Orthop Surg, 2020, 12(6): 1776-1783.
[2]
刘君政, 周俊鹏, 李永伟, 等. 2003—2022年股骨头坏死研究的全球趋势[J]. 中华骨与关节外科杂志, 2023, 16(2): 138-145.
[3]
Zhao D, Zhang F, Wang B, et al. Guidelines for clinical diagnosis and treatment of osteonecrosis of the femoral head in adults(2019 version)[J]. J Orthop Translat, 2020, 21: 100-110.
[4]
Solomon L. Clinical and therapeutic concepts in ischemic femur head necrosis[J]. Orthopade, 1990, 19(4): 200-207.
[5]
Yoon BH, Jones LC, Chen CH, et al. Etiologic classification criteria of ARCO on femoral head osteonecrosis part 1: glucocorticoid-associated osteonecrosis[J]. J Arthroplasty, 2019, 34(1): 163-168.e1.
[6]
Yoon BH, Jones LC, Chen CH, et al. Etiologic classification criteria of ARCO on femoral head osteonecrosis part 2: alcohol-associated osteonecrosis[J]. J Arthroplasty, 2019, 34(1): 169-174.e1.
[7]
Cui Q, Wang GJ, Balian G. Pluripotential marrow cells produce adipocytes when transplanted into steroid-treated mice[J]. Connect Tissue Res, 2000, 41(1): 45-56.
[8]
郭坤亮. 内源性糖皮质激素在酒精性股骨头缺血坏死发病机制中的作用[D]. 重庆: 重庆医科大学, 2003.
[9]
Phemister DB. Bone growth and repair[J]. Ann Surg, 1935, 102(2): 261-285.
[10]
Li H, Borinskaya S, Yoshimura K, et al. Refined geographic distribution of the oriental ALDH2*504Lys(nee 487Lys)variant[J]. Ann Hum Genet, 2009, 73(Pt 3): 335-345.
[11]
Kubo T, Ueshima K, Saito M, et al. Clinical and basic research on steroid-induced osteonecrosis of the femoral head in Japan[J]. J Orthop Sci, 2016, 21(4): 407-413.
[12]
George G, Lane JM. Osteonecrosis of the femoral head[J/OL]. JAAOS Glob Res Rev, 2022, 6(5): e21.00176. DOI: 10.5435/jaaosglobal-d-21-00176.
[13]
Mont MA, Cherian JJ, Sierra RJ, et al. Nontraumatic osteonecrosis of the femoral head: where do we stand today? A ten-year update[J]. J Bone Joint Surg Am, 2015, 97(19): 1604-1627.
[14]
Kubo Y, Drescher W, Fragoulis A, et al. Adverse effects of oxidative stress on bone and vasculature in corticosteroid-associated osteonecrosis: potential role of nuclear factor erythroid 2-related factor 2 in cytoprotection[J]. Antioxid Redox Signal, 2021, 35(5): 357-376.
[15]
Betteridge DJ. What is oxidative stress?[J]. Metabolism, 2000, 49(2): 3-8.
[16]
Kim T-H, Hong JM, Oh B, et al. Genetic association study of polymorphisms in the catalase gene with the risk of osteonecrosis of the femoral head in the Korean population[J]. Osteoarthritis Cartilage, 2008, 16(9): 1060-1066.
[17]
Ichiseki T, Matsumoto T, Nishino M, et al. Oxidative stress and vascular permeability in steroid-induced osteonecrosis model[J]. J Orthop Sci, 2004, 9(5): 509-515.
[18]
Ichiseki T, Kaneuji A, Katsuda S, et al. DNA oxidation injury in bone early after steroid administration is involved in the pathogenesis of steroid-induced osteonecrosis[J]. Rheumatology, 2005, 44(4): 456-460.
[19]
Okura T, Seki T, Suzuki K, et al. Serum levels of carotenoids in patients with osteonecrosis of the femoral head are lower than in healthy, community-living people[J/OL]. J Orthop Surg, 2018, 26(2): 2309499018770927. DOI: 10.1177/2309499018770927.
[20]
Chen K, Liu Y, He J, et al. Steroid-induced osteonecrosis of the femoral head reveals enhanced reactive oxygen species and hyperactive osteoclasts[J]. Int J Biol Sci, 2020, 16(11): 1888-1900.
[21]
Vasiliou V, Pappa A, Estey T. Role of human aldehyde dehydrogenases in endobiotic and xenobiotic metabolism[J]. Drug Metab Rev, 2004, 36(2): 279-299.
[22]
Oyama T, Isse T, Kagawa N, et al. Tissue-distribution of aldehyde dehydrogenase 2 and effects of the ALDH2 gene-disruption on the expression of enzymes involved in alcohol metabolism[J]. Front Biosci, 2005, 10: 951-960.
[23]
Seamon J, Keller T, Saleh J, et al. The pathogenesis of nontraumatic osteonecrosis[J/OL]. Arthritis, 2012, 2012: 601763. DOI: 10.1155/2012/601763.
[24]
Prieto-Alhambra D, Turkiewicz A, Reyes C, et al. Smoking and alcohol intake but not muscle strength in young men increase fracture risk at middle age: a cohort study linked to the Swedish national patient registry[J]. J Bone Miner Res, 2020, 35(3): 498-504.
[25]
Nielsen HK, Lundby L, Rasmussen K, et al. Alcohol decreases serum osteocalcin in a dose-dependent way in normal subjects[J]. Calcif Tissue Int, 1990, 46(3): 173-178.
[26]
Rico H, Cabranes JA, Cabello J, et al. Low serum osteocalcin in acute alcohol intoxication: a direct toxic effect of alcohol on osteoblasts[J]. Bone Miner, 1987, 2(3): 221-225.
[27]
Friday KE, Howard GA. Ethanol inhibits human bone cell proliferation and function in vitro[J]. Metabolism, 1991, 40(6): 562-565.
[28]
Giuliani N, Girasole G, Vescovi PP, et al. Ethanol and acetaldehyde inhibit the formation of early osteoblast progenitors in murine and human bone marrow cultures[J]. Alcohol Clin Exp Res, 1999, 23(2): 381-385.
[29]
Li L, Ding Y, Liu B, et al. Transcriptome landscape of the late-stage alcohol-induced osteonecrosis of the human femoral head[J/OL]. Bone, 2021, 150: 116012. DOI: 10.1016/j.bone.2021.116012.
[30]
Chen CH, Kraemer BR, Lee L, et al. Annotation of 1350 common genetic variants of the 19 ALDH multigene family from global human genome aggregation database(gnomAD)[J/OL]. Biomolecules, 2021, 11(10): 1423. DOI: 10.3390/biom11101423.
[31]
Vasiliou V, Nebert DW. Analysis and update of the human aldehyde dehydrogenase(ALDH)gene family[J]. Hum Genomics, 2005, 2(2): 138-143.
[32]
Stewart MJ, Malek K, Crabb DW. Distribution of messenger RNAs for aldehyde dehydrogenase 1, aldehyde dehydrogenase 2, and aldehyde dehydrogenase 5 in human tissues[J]. J Investig Med, 1996, 44(2): 42-46.
[33]
Ma H, Li J, Gao F, et al. Aldehyde dehydrogenase 2 ameliorates acute cardiac toxicity of ethanol: role of protein phosphatase and forkhead transcription factor[J]. J Am Coll Cardiol, 2009, 54(23): 2187-2196.
[34]
Luckey SW, Petersen DR. Metabolism of 4-hydroxynonenal by rat kupffer cells[J]. Arch Biochem Biophys, 2001, 389(1): 77-83.
[35]
Ohsawa I, Nishimaki K, Yasuda C, et al. Deficiency in a mitochondrial aldehyde dehydrogenase increases vulnerability to oxidative stress in PC12 cells[J]. J Neurochem, 2003, 84(5): 1110-1117.
[36]
Vasiliou V, Pappa A. Polymorphisms of human aldehyde dehydrogenases[J]. Pharmacology, 2000, 61(3): 192-198.
[37]
Brooks PJ, Enoch MA, Goldman D, et al. The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption[J/OL]. PLoS Med, 2009, 6(3): e1000050. DOI: 10.1371/journal.pmed.1000050.
[38]
Rizzo WB, Carney G. Sjögren-Larsson syndrome: Diversity of mutations and polymorphisms in the fatty aldehyde dehydrogenase gene(ALDH3A2)[J]. Hum Mutat, 2005, 26(1): 1-10.
[39]
Kaur R, Paria P, Saini AG, et al. Metabolic epilepsy in hyperprolinemia type II due to a novel nonsense ALDH4A1 gene variant[J]. Metab Brain Dis, 2021, 36(6): 1413-1417.
[40]
Motte J, Fisse AL, Grüter T, et al. Novel variants in a patient with late-onset hyperprolinemia type II: diagnostic key for status epilepticus and lactic acidosis[J/OL]. BMC Neurol, 2019, 19(1): 345. DOI: 10.1186/s12883-019-1583-0.
[41]
Lowe ED, Gao GY, Johnson LN, et al. Structure of daidzin, a naturally occurring anti-alcohol-addiction agent, in complex with human mitochondrial aldehyde dehydrogenase[J]. J Med Chem, 2008, 51(15): 4482-4487.
[42]
Larson HN, Weiner H, Hurley TD. Disruption of the coenzyme binding site and dimer interface revealed in the crystal structure of mitochondrial aldehyde dehydrogenase “Asian” variant[J]. J Biol Chem, 2005, 280(34): 30550-30556.
[43]
Chen CH, Ferreira JCB, Joshi AU, et al. Novel and prevalent non-East Asian ALDH2 variants; Implications for global susceptibility to aldehydes’ toxicity[J/OL]. EBio Medicine, 2020, 55: 102753. DOI: 10.1016/j.ebiom.2020.102753.
[44]
Hoshi H, Hao W, Fujita Y, et al. Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis[J]. J Bone Miner Res, 2012, 27(9): 2015-2023.
[45]
Shimizu Y, Sakai A, Menuki K, et al. Reduced bone formation in alcohol-induced osteopenia is associated with elevated p21 expression in bone marrow cells in aldehyde dehydrogenase 2-disrupted mice[J]. Bone, 2011, 48(5): 1075-1086.
[46]
Yamaguchi J, Hasegawa Y, Kawasaki M, et al. ALDH2 polymorphisms and bone mineral density in an elderly Japanese population[J]. Osteoporos Int, 2006, 17(6): 908-913.
[47]
Okuma KF, Menuki K, Tsukamoto M, et al. Disruption of the aldehyde dehydrogenase 2 gene results in no increase in trabecular bone mass due to skeletal loading in association with impaired cell cycle regulation through p21 expression in the bone marrow cells of mice[J]. Calcif Tissue Int, 2017, 101(3): 328-340.
[48]
Sakata R. A case-control study of association between life-style, alcohol dehydrogenase 2 and aldehyde dehydrogenase 2 genotype and idiopathic osteonecrosis of the femoral head[J]. Kurume Med J, 2003, 50(3-4): 121-130.
[49]
Ohta S, Ohsawa I, Kamino K, et al. Mitochondrial ALDH2 deficiency as an oxidative stress[J]. Ann N Y Acad Sci, 2004, 1011: 36-44.
[50]
Guo Y, Tan LJ, Lei SF, et al. Genome-wide association study identifies ALDH7A1 as a novel susceptibility gene for osteoporosis[J/OL]. PLoS Genet, 2010, 6(1): e1000806. DOI: 10.1371/journal.pgen.1000806.
[51]
Perez-Miller S, Younus H, Vanam R, et al. Alda-1 is an agonist and chemical chaperone for the common human aldehyde dehydrogenase 2 variant[J]. Nat Struct Mol Biol, 2010, 17(2): 159-164.
[52]
Lin X, Zhu D, Wang K, et al. Activation of aldehyde dehydrogenase 2 protects ethanol-induced osteonecrosis of the femoral head in rat model[J/OL]. Cell Prolif, 2022, 55(6): e13252. DOI: 10.1111/cpr.13252.
[53]
Tsai SH, Hsu LA, Tsai HY, et al. Aldehyde dehydrogenase 2 protects against abdominal aortic aneurysm formation by reducing reactive oxygen species, vascular inflammation, and apoptosis of vascular smooth muscle cells[J]. FASEB J, 2020, 34(7): 9498-9511.
[1] 何琪, 周月惠, 薛宇轩, 吉宇通, 王海彬, 周驰. 卫虚-血瘀-髓痿理论治疗激素性股骨头坏死的价值[J/OL]. 中华关节外科杂志(电子版), 2026, 20(01): 87-96.
[2] 王宏达, 单兴宇, 张浩强, 田志敏, 李焕玺, 何淳诺, 庄凯鹏, 周胜虎, 甄平. 人工骨修复材料在股骨头坏死修复中的应用[J/OL]. 中华关节外科杂志(电子版), 2026, 20(01): 77-86.
[3] 黄嘉楠, 杨均政, 张华, 陈柏豪, 陈楚仪, 何琪, 陈鹏. 环状RNA调控激素性股骨头坏死的机制与研究进展[J/OL]. 中华关节外科杂志(电子版), 2025, 19(06): 755-760.
[4] 张耀林, 徐永清. 蚓激酶治疗股骨头坏死的作用机制及应用研究[J/OL]. 中华关节外科杂志(电子版), 2025, 19(06): 728-734.
[5] 中国康复医学会骨与关节康复专业委员会, 中国中医药研究促进会骨伤科分会, 程立明, 李泰贤, 何伟, 刘又文, 何海军, 王卫国, 钱东阳, 王荣田, 陈卫衡. 股骨头坏死血管介入治疗中国专家共识[J/OL]. 中华关节外科杂志(电子版), 2025, 19(06): 654-660.
[6] 张耀林, 王腾, 杨曦, 罗欢, 徐永清. 骨形态发生蛋白2在股骨头坏死保髋治疗的研究进展[J/OL]. 中华关节外科杂志(电子版), 2025, 19(04): 472-477.
[7] 林志强, 李嘉欢, 张凯, 李文帅, 刘健, 邓泽群, 乔永杰, 周胜虎. 骨髓间充质干细胞在激素性股骨头坏死发病机制的研究进展[J/OL]. 中华关节外科杂志(电子版), 2025, 19(04): 464-471.
[8] 翟禹樵, 鲜思平, 陈明灿, 蒋珊. 动力交叉钉治疗股骨颈骨折后早期股骨头坏死风险预测[J/OL]. 中华关节外科杂志(电子版), 2025, 19(04): 402-408.
[9] 王章正, 莫亮, 何伟, 周驰, 陈镇秋, 方斌, 刘予豪. 股骨头坏死疼痛时间与软骨退变程度的病理学研究[J/OL]. 中华关节外科杂志(电子版), 2025, 19(01): 65-75.
[10] 王静, 赵乐, 曾健康, 李培杰, 谭飞, 李嘉欢, 乔永杰, 周胜虎. 富血小板血浆治疗早期股骨头坏死的研究进展[J/OL]. 中华关节外科杂志(电子版), 2024, 18(06): 773-777.
[11] 马小杰, 张贵慧, 李润泽, 王秋入, 陈带领, 马清伟, 张磊, 陈长军. 对硒代甲硫氨酸逆转糖皮质激素介导的成骨细胞凋亡和成骨阻抑治疗大鼠激素性股骨头坏死的机制探索[J/OL]. 中华损伤与修复杂志(电子版), 2025, 20(05): 412-420.
[12] 张耕毓, 唐冲, 张昆, 张辉, 张清华, 刘家帮. 股骨头坏死髓芯减压术的文献计量学分析及单中心病例报道[J/OL]. 中华临床医师杂志(电子版), 2024, 18(08): 771-780.
[13] 印于, 俞斌, 冯文聪, 杨俊, 倪才方, 朱晓黎, 李智, 李明明. 动脉化疗栓塞联合锥形束断层扫描引导乙醇注射治疗危险部位小肝癌的疗效与安全性[J/OL]. 中华介入放射学电子杂志, 2026, 14(02): 157-163.
[14] 周子竣, 姜华, 刘珍银, 李海波, 张靖. 乙醇-碘海醇混合液与乙醇-碘化油悬浮液在兔肾动脉栓塞中的使用比较研究[J/OL]. 中华介入放射学电子杂志, 2026, 14(02): 150-156.
[15] 刘浪, 蒋贻洲, 庞宁东, 姜华, 牛传强, 刘录, 张靖, 李海波. 无水乙醇联合Glubran-2 胶治疗Puig Ⅲ型静脉畸形的疗效分析[J/OL]. 中华介入放射学电子杂志, 2025, 13(01): 44-48.
阅读次数
全文


摘要


AI


AI小编
你好!我是《中华医学电子期刊资源库》AI小编,有什么可以帮您的吗?