基于铁死亡理论探讨传统中医治疗骨关节炎的研究进展
Research Progress of Traditional Chinese Medicine Treatment of Osteoarthritis Based on the Ferroptosis Theory
DOI: 10.12677/jcpm.2024.34365, PDF,   
作者: 杨昕宇, 宗泰丞, 易红赤*：云南中医药大学第一临床医学院，云南 昆明；廖建青, 郑远志, 魏庆中：云南中医药大学第一附属医院骨三科，云南 昆明
关键词: 铁死亡；骨关节炎；中医药；研究进展；Ferroptosis； Osteoarthritis； Traditional Chinese Medicine； Research Progress
摘要: 骨关节炎(OA)是一种关节退行性改变为特征的与年龄相关的骨病，OA发生的本质是由于软骨细胞的退变、关节滑膜增生、骨赘形成等导致关节生物力学的改变，从而引起的关节肿胀、畸形与疼痛。铁死亡作为一种非凋亡性细胞死亡形式，根本原因是细胞内脂质活性氧和大量铁离子的大量堆积导致细胞结构、功能受损。研究表明OA的发生发展与铁死亡密不可分，抑制软骨细胞铁死亡可以达到促进软骨细胞增殖，利用铁死亡机制以清除老化的软骨细胞达到减轻关节炎症反应的效果。本文整理了铁死亡相关的调控机制，探讨传统中医治疗通过铁死亡理论途径对OA治疗的现状和进展，为有效治疗OA提供前期理论依据，未来治疗OA提供新思路。
Abstract: Osteoarthritis (OA) is an age-related bone disease characterized by joint degenerative changes. The essence of OA is the joint biomechanical changes caused by the degeneration of chondrocytes, joint synovial hyperplasia, and osteophyte formation, resulting in joint swelling, deformity and pain. Ferroptosis, as a form of non-apoptotic cell death, is fundamentally due to the damage to cell structure and function caused by the accumulation of lipid reactive oxygen species and a large number of iron ions in the cell. Studies have shown that the occurrence and development of OA are closely related to ferroptosis. Inhibiting the ferroptosis of chondrocytes can promote the proliferation of chondrocytes, and using the ferroptosis mechanism to remove aging chondrocytes can reduce the effect of joint inflammation. This paper sorted out the regulatory mechanism related to ferroptosis and discussed the current status and progress of OA treatment by traditional Chinese medicine through ferroptosis theory. It provides a theoretical basis for the effective treatment of OA in the early stage and a new idea for the future treatment of OA.
文章引用：杨昕宇, 廖建青, 郑远志, 魏庆中, 宗泰丞, 易红赤. 基于铁死亡理论探讨传统中医治疗骨关节炎的研究进展[J]. 临床个性化医学, 2024, 3(4): 2559-2566. https://doi.org/10.12677/jcpm.2024.34365

参考文献

[1] Piva, S.R., Susko, A.M., Khoja, S.S., Josbeno, D.A., Fitzgerald, G.K. and Toledo, F.G.S. (2015) Links between Osteoarthritis and Diabetes: Implications for Management from a Physical Activity Perspective. Clinics in Geriatric Medicine, 31, 67-87. [Google Scholar] [CrossRef] [PubMed]
[2] Global Burden of Disease Collaborative Network (2020) Global Burden of Disease Study 2019 (GBD 2019) Results.
[3] Zhao, Y., Li, Y., Zhang, R., Wang, F., Wang, T. and Jiao, Y. (2020) The Role of Erastin in Ferroptosis and Its Prospects in Cancer Therapy. OncoTargets and Therapy, 13, 5429-5441. [Google Scholar] [CrossRef] [PubMed]
[4] Yang, W.S., SriRamaratnam, R., Welsch, M.E., Shimada, K., Skouta, R., Viswanathan, V.S., et al. (2014) Regulation of Ferroptotic Cancer Cell Death by Gpx4. Cell, 156, 317-331. [Google Scholar] [CrossRef] [PubMed]
[5] Dolma, S., Lessnick, S.L., Hahn, W.C. and Stockwell, B.R. (2003) Identification of Genotype-Selective Antitumor Agents Using Synthetic Lethal Chemical Screening in Engineered Human Tumor Cells. Cancer Cell, 3, 285-296. [Google Scholar] [CrossRef] [PubMed]
[6] Wieland, H.A., Michaelis, M., Kirschbaum, B.J. and Rudolphi, K.A. (2005) Osteoarthritis—An Untreatable Disease? Nature Reviews Drug Discovery, 4, 331-344. [Google Scholar] [CrossRef] [PubMed]
[7] 刘诗卉, 李冬冬, 张宏坤, 等. 细胞死亡在NAFLD发生发展中的研究进展[J]. 齐齐哈尔医学院学报, 2024, 45(16): 1578-1582.
[8] Vabulas, R.M. (2021) Ferroptosis-Related Flavoproteins: Their Function and Stability. International Journal of Molecular Sciences, 22, Article No. 430. [Google Scholar] [CrossRef] [PubMed]
[9] 郑苏莹, 方泽浩, 金晶, 等. 铁死亡的调控机制及其在血液系统疾病中的研究进展[J]. 中国细胞生物学学报, 2022, 44(6): 1165-1173.
[10] 张玉莲, 桑希生. 浅析历节病与骨痹[J]. 中医药学报, 2011, 39(1): 5-7.
[11] 张伟冬. 基于“益肾活血除痹法”探讨腰腿痛宁胶囊治疗骨关节炎的临床和实验研究[D]: [博士学位论文]. 长春: 长春中医药大学, 2024.
[12] Dixon, S.J. and Stockwell, B.R. (2013) The Role of Iron and Reactive Oxygen Species in Cell Death. Nature Chemical Biology, 10, 9-17. [Google Scholar] [CrossRef] [PubMed]
[13] Gao, M., Monian, P., Quadri, N., Ramasamy, R. and Jiang, X. (2015) Glutaminolysis and Transferrin Regulate Ferroptosis. Molecular Cell, 59, 298-308. [Google Scholar] [CrossRef] [PubMed]
[14] Feng, H., Schorpp, K., Jin, J., Yozwiak, C.E., Hoffstrom, B.G., Decker, A.M., et al. (2020) Transferrin Receptor Is a Specific Ferroptosis Marker. Cell Reports, 30, 3411-3423.e7. [Google Scholar] [CrossRef] [PubMed]
[15] 文皓楠, 王凯, 海云翔, 等. 铁死亡在骨代谢中的调控机制[J]. 中国药理学通报, 2024, 40(4): 625-629.
[16] Mortensen, M.S., Ruiz, J. and Watts, J.L. (2023) Polyunsaturated Fatty Acids Drive Lipid Peroxidation during Ferroptosis. Cells, 12, Article No. 804. [Google Scholar] [CrossRef] [PubMed]
[17] Ayala, A., Muñoz, M.F. and Argüelles, S. (2014) Lipid Peroxidation: Production, Metabolism, and Signaling Mechanisms of Malondialdehyde and 4-Hydroxy-2-Nonenal. Oxidative Medicine and Cellular Longevity, 2014, Article ID: 360438. [Google Scholar] [CrossRef] [PubMed]
[18] Nimse, S.B. and Pal, D. (2015) Free Radicals, Natural Antioxidants, and Their Reaction Mechanisms. RSC Advances, 5, 27986-28006. [Google Scholar] [CrossRef] 
[19] 陈芳, 胡韬韬, 陈丹, 等. 抗霉素诱导肾小管上皮细胞铁死亡的实验研究[J]. 内科急危重症杂志, 2018, 24(4): 320-323.
[20] 喻浩宸, 陈锐, 郭世朋, 等. 柳氮磺吡啶诱导乳腺癌ZR-75-1细胞发生铁死亡及其机制研究[J]. 肿瘤, 2018, 38(10): 933-941.
[21] 宣文婷, 杨泽勇, 季雅茹, 等. p53抑制铁死亡抵抗HT22细胞谷氨酸神经毒性[J]. 中国药理学通报, 2019, 35(5): 654-660.
[22] 王嘉璐, 熊昌源, 陈建锋, 等. 电针对膝骨关节炎软骨细胞的作用机制研究进展[J]. 江西中医药大学学报, 2024, 36(4): 114-117, 122.
[23] Yao, X., Sun, K., Yu, S., Luo, J., Guo, J., Lin, J., et al. (2021) Chondrocyte Ferroptosis Contribute to the Progression of Osteoarthritis. Journal of Orthopaedic Translation, 27, 33-43. [Google Scholar] [CrossRef] [PubMed]
[24] Wang, F., Liao, Y., Zhang, M., Zhu, Y., Wang, W., Cai, H., et al. (2021) N6-Methyladenosine Demethyltransferase Fto-Mediated Autophagy in Malignant Development of Oral Squamous Cell Carcinoma. Oncogene, 40, 3885-3898. [Google Scholar] [CrossRef] [PubMed]
[25] Tang, D., Chen, X., Kang, R. and Kroemer, G. (2020) Ferroptosis: Molecular Mechanisms and Health Implications. Cell Research, 31, 107-125. [Google Scholar] [CrossRef] [PubMed]
[26] 喻浩宸. 柳氮磺吡啶诱导乳腺癌细胞发生铁死亡及其机制的研究[D]: [硕士学位论文]. 重庆: 重庆医科大学, 2019.
[27] Mancuso, R.I., Foglio, M.A. and Olalla Saad, S.T. (2020) Artemisinin-Type Drugs for the Treatment of Hematological Malignancies. Cancer Chemotherapy and Pharmacology, 87, 1-22. [Google Scholar] [CrossRef] [PubMed]
[28] 杨霞, 宁宗. 铁死亡在呼吸系统疾病中的研究进展[J]. 中国比较医学杂志, 2020, 30(12): 125-129.
[29] Xie, Y., Song, X., Sun, X., Huang, J., Zhong, M., Lotze, M.T., et al. (2016) Identification of Baicalein as a Ferroptosis Inhibitor by Natural Product Library Screening. Biochemical and Biophysical Research Communications, 473, 775-780. [Google Scholar] [CrossRef] [PubMed]
[30] Bogdan, A.R., Miyazawa, M., Hashimoto, K. and Tsuji, Y. (2016) Regulators of Iron Homeostasis: New Players in Metabolism, Cell Death, and Disease. Trends in Biochemical Sciences, 41, 274-286. [Google Scholar] [CrossRef] [PubMed]
[31] Sun, X., Ou, Z., Xie, M., Kang, R., Fan, Y., Niu, X., et al. (2015) HSPB1 as a Novel Regulator of Ferroptotic Cancer Cell Death. Oncogene, 34, 5617-5625. [Google Scholar] [CrossRef] [PubMed]
[32] Ruan, Q., Wang, C., Zhang, Y. and Sun, J. (2024) Ruscogenin Attenuates Cartilage Destruction in Osteoarthritis through Suppressing Chondrocyte Ferroptosis via Nrf2/SLC7A11/GPX4 Signaling Pathway. Chemico-Biological Interactions, 388, Article ID: 110835. [Google Scholar] [CrossRef] [PubMed]
[33] 王福林, 郝仲德. 中医分型辨治配合综合治疗骨性关节炎的临床研究[C]//甘肃省中医药学会. 甘肃省中医药学会2009年学术研讨会论文专辑. 定西: 定西市中医院, 2009: 4.
[34] 郭冰清. 黄芩素对erastin诱导成骨细胞铁死亡的影响及潜在机制[D]: [硕士学位论文]. 南京: 南京中医药大学, 2021.
[35] Lapchak, P.A., Maher, P., Schubert, D. and Zivin, J.A. (2007) Baicalein, an Antioxidant 12/15-Lipoxygenase Inhibitor Improves Clinical Rating Scores Following Multiple Infarct Embolic Strokes. Neuroscience, 150, 585-591. [Google Scholar] [CrossRef] [PubMed]
[36] Luo, H. and Zhang, R. (2021) Icariin Enhances Cell Survival in Lipopolysaccharide Induced Synoviocytes by Suppressing Ferroptosis via the Xc/GPX4 Axis. Experimental and Therapeutic Medicine, 21, Article No. 72.
[37] He, Q., Yang, J., Pan, Z., Zhang, G., Chen, B., Li, S., et al. (2023) Biochanin a Protects against Iron Overload Associated Knee Osteoarthritis via Regulating Iron Levels and Nrf2/System Xc-/GPX4 Axis. Biomedicine & Pharmacotherapy, 157, Article ID: 113915. [Google Scholar] [CrossRef] [PubMed]
[38] Chen, K., Yu, Y., Wang, Y., Zhu, Y., Qin, C., Xu, J., et al. (2024) Systematic Pharmacology and Experimental Validation to Reveal the Alleviation of Astragalus membranaceus Regulating Ferroptosis in Osteoarthritis. Drug Design, Development and Therapy, 18, 259-275. [Google Scholar] [CrossRef] [PubMed]
[39] 王浩, 周富丽, 朱仁弟, 等. 槲皮素对Erastin诱导的软骨细胞铁死亡的影响[J]. 中国药理学通报, 2024, 40(10): 1945-1952.
[40] 陈凡, 周富丽, 陈勇, 等. 姜黄素可能通过上调Prdx6蛋白表达抑制软骨细胞铁死亡[J]. 安徽医科大学学报, 2023, 58(12): 2106-2112.
[41] Zhou, Y., Jia, Z., Wang, J., Huang, S., Yang, S., Xiao, S., et al. (2023) Curcumin Reverses Erastin-Induced Chondrocyte Ferroptosis by Upregulating Nrf2. Heliyon, 9, e20163. [Google Scholar] [CrossRef] [PubMed]
[42] 朱仁弟, 屈彪, 周仁鹏, 等. 金雀根通过阻断TRPM7抑制Erastin诱导的软骨细胞铁死亡[J]. 中国临床药理学与治疗学, 2024, 29(7): 800-808.
[43] Ruan, Q., Wang, C., Zhang, Y. and Sun, J. (2023) Brevilin a Attenuates Cartilage Destruction in Osteoarthritis Mouse Model by Inhibiting Inflammation and Ferroptosis via SIRT1/Nrf2/GPX4 Signaling Pathway. International Immunopharmacology, 124, Article ID: 110924. [Google Scholar] [CrossRef] [PubMed]
[44] 钱佳佳. 基于蛋白组学研究温经通络汤调控血管新生治疗膝骨关节炎的作用机制[D]: [博士学位论文]. 南京: 南京中医药大学, 2021.
[45] Li, Z., Dai, A., Yang, M., Chen, S., Deng, Z. and Li, L. (2022) P38mapk Signaling Pathway in Osteoarthritis: Pathological and Therapeutic Aspects. Journal of Inflammation Research, 15, 723-734. [Google Scholar] [CrossRef] [PubMed]
[46] 王爱武, 刘娅, 雒琪, 等. 独活寄生汤抗炎、镇痛作用的药效学研究[J]. 中国实验方剂学杂志, 2008, 14(12): 61-64.
[47] 张斌山. 独活寄生汤对风寒湿痹型关节炎患者关节液中炎症因子、氧化应激及脂肪细胞因子的影响[J]. 中国实验方剂学杂志, 2017, 23(6): 186-191.
[48] 许丽梅, 董丹宇, 薛维婳, 等. 从铁死亡探讨独活寄生汤防治骨关节炎的机制[J]. 中医学报, 2023, 38(12): 2554-2559.
[49] Xu, J., Ruan, Z., Guo, Z., Hou, L., Wang, G., Zheng, Z., et al. (2024) Inhibition of SAT1 Alleviates Chondrocyte Inflammation and Ferroptosis by Repressing ALOX15 Expression and Activating the Nrf2 Pathway. Bone & Joint Research, 13, 110-123. [Google Scholar] [CrossRef] [PubMed]
[50] 刘渊, 邓健, 孙雪莲, 等. 足阳明经筋手法治疗对膝关节骨性关节炎患者股四头肌力学性能及软骨细胞铁死亡的影响[J]. 中华中医药杂志, 2022, 37(9): 5504-5507.
[51] 李路, 张立德. 电针双侧足三里、三阴交穴治疗脾气虚证大鼠和对机体铁代谢影响实验研究[J]. 辽宁中医药大学学报, 2015, 17(7): 81-85.