尹瀚翔,金潇枭,胡佳威,田龍珠,阳春华

铜死亡是近年来发现的一种新的依赖性细胞死亡形式，称为铜依赖性细胞死亡。与细胞凋亡、自噬或焦亡不同，铜死亡的特征是铜可以结合和破坏DNA，结合并激活E2D2诱导的蛋白质泛素化和降解。铜死亡参与多种生理和病理过程，自发现以来，铜死亡越来越多地涉及骨相关疾病。本文重点介绍了铜死亡的最新研究进展和展望，总结了铜死亡的调控机制，讨论了铜死亡在股骨头坏死、骨质疏松症（OP）、骨关节炎（OA）、类风湿性关节炎（RA）和骨肉瘤（OS）等骨相关疾病发病机制中的作用及其治疗潜力。

铜稳态；铜死亡；细胞死亡；骨相关疾病

[1] Migliorini F,Maffulli N,Baroncini A,Eschweiler J,Tingart M,Betsch M.Prognostic factors in the management of osteonecrosis of the femoral head:A systematic review.Surgeon.2023 Apr;21(2):85-98. [2] Li D,Gao Z,Li Q,Liu X,Liu H.Cuproptosis-a potential target for the treatment of osteoporosis.Front Endocrinol(Lausanne).2023 May 5;14:1135181. [3] Chen L,Min J,Wang F.Copper homeostasis and cuproptosis in health and disease.Signal Transduct Target Ther.2022 Nov 23;7(1):378. [4] Tsvetkov P,Coy S,Petrova B,Dreishpoon M,Verma A,Abdusamad M,Rossen J,Joesch-Cohen L,Humeidi R,Spangler RD,Eaton JK,Frenkel E,Kocak M,Corsello SM,Lutsenko S,Kanarek N,Santagata S,Golub TR.Copper induces cell death by targeting lipoylated TCA cycle proteins.Science.2022 Mar 18;375(6586):1254-1261. [5] Gao L,Zhang A.Copper-instigated modulatory cell mortality mechanisms and progress in oncological treatment investigations.Front Immunol.2023 Aug 2;14:1236063. [6] Blades B,Ayton S,Hung YH,Bush AI,La Fontaine S.Copper and lipid metabolism:A reciprocal relationship.Biochim Biophys Acta Gen Subj.2021 Nov;1865(11):129979. [7] Ruiz LM,Libedinsky A,Elorza AA.Role of Copper on Mitochondrial Function and Metabolism.Front Mol Biosci.2021 Aug 24;8:711227. [8] Li M,Song Q,Bai Y,Hua F,Wu T,Liu J.Comprehensive analysis of cuproptosis in immune response and prognosis of osteosarcoma.Front Pharmacol.2022 Oct 3;13:992431. [9] Han J,Luo J,Wang C,Kapilevich L,Zhang XA.Roles and mechanisms of copper homeostasis and cuproptosis in osteoarticular diseases.Biomed Pharmacother.2024 May;174:116570. [10] Xiong C,Ling H,Hao Q,Zhou X.Cuproptosis:p53-regulated metabolic cell death?Cell Death Differ.2023 Apr;30(4):876-884. [11] Glyn-Jones S,Palmer AJ,Agricola R,Price AJ,Vincent TL,Weinans H,Carr AJ.Osteoarthritis.Lancet.2015 Jul 25;386(9991):376-87. [12] Jeon OH,David N,Campisi J,Elisseeff JH.Senescent cells and osteoarthritis:a painful connection.J Clin Invest.2018 Apr 2;128(4):1229-1237. [13] Zhou X,Cao H,Yuan Y,Wu W.Biochemical Signals Mediate the Crosstalk between Cartilage and Bone in Osteoarthritis.Biomed Res Int.2020 Apr 6;2020:5720360. [14] Bellia F,Lanza V,Naletova I,Tomasello B,Ciaffaglione V,Greco V,Sciuto S,Amico P,Inturri R,Vaccaro S,Campagna T,Attanasio F,TabbìG,Rizzarelli E.Copper(II)Complexes with Carnosine Conjugates of Hyaluronic Acids at Different Dipeptide Loading Percentages Behave as Multiple SOD Mimics and Stimulate Nrf2 Translocation and Antioxidant Response in In Vitro Inflammatory Model.Antioxidants(Basel).2023 Aug 18;12(8):1632. [15] Yu B,Sun W,Lin J,Fan C,Wang C,Zhang Z,Wang Y,Tang Y,Lin Y,Zhou D.Using Cu-Based Metal-Organic Framework as a Comprehensive and Powerful Antioxidant Nanozyme for Efficient Osteoarthritis Treatment.Adv Sci(Weinh).2024 Apr;11(13):e2307798. [16] Zhou J,Liu C,Sun Y,Francis M,Ryu MS,Grider A,Ye K.Genetically predicted circulating levels of copper and zinc are associated with osteoarthritis but not with rheumatoid arthritis.Osteoarthritis Cartilage.2021 Jul;29(7):1029-1035. [17] Wang J,Jing Z,Yin C,Wang Z,Zeng S,Ma X,Zheng Y,Cai H,Liu Z.Coatless modification of 3D-printed Ti6Al4V implants through tailored Cu ion implantation combined with UV photofunctionalization to enhance cell attachment,osteogenesis and angiogenesis.Colloids Surf B Biointerfaces.2024 Jun;238:113891. [18] Li Y,Pan Q,Xu J,He X,Li HA,Oldridge DA,Li G,Qin L.Overview of methods for enhancing bone regeneration in distraction osteogenesis:Potential roles of biometals.J Orthop Translat.2021 Feb 2;27:110-118. [19] Smolen JS,Aletaha D,McInnes IB.Rheumatoid arthritis.Lancet.2016 Oct 22;388(10055):2023-2038. [20] Zhao J,Jiang P,Guo S,Schrodi SJ,He D.Apoptosis,Autophagy,NETosis,Necroptosis,and Pyroptosis Mediated Programmed Cell Death as Targets for Innovative Therapy in Rheumatoid Arthritis.Front Immunol.2021 Dec 24;12:809806. [21] Huang Z,Tan B,Ye H,Fu F,Wang R,Chen W.Dynamic evolution of osseous structure in osteonecrosis of the femoral head and dynamic collapse risks:a preliminary CT image study.J Orthop Surg Res.2020 Nov 17;15(1):539. [22] Lin Y,Xiao W,Bal BS,Rahaman MN.Effect of copper-doped silicate 13-93 bioactive glass scaffolds on the response of MC3T3-E1 cells in vitro and on bone regeneration and angiogenesis in rat calvarial defects in vivo.Mater Sci Eng C Mater Biol Appl.2016 Oct 1; 67:440-452. [23] Hammadi Jasim N,Adel Kareem D,Majeed Al Ali MF,Abbas BA.Effect of Long-Term Treatment with Dexamethasone on the Liver and Kidney Histopathology,as well as Blood Biochemistry in Male Rabbits(Lepus Cuniculus).Arch Razi Inst.2022 Feb 28;77(1):333-343. [24] Li B,Lei Y,Hu Q,Li D,Zhao H,Kang P.Porous copper-and lithium-doped nano-hydroxyapatite composite scaffold promotes angiogenesis and bone regeneration in the repair of glucocorticoids-induced osteonecrosis of the femoral head.Biomed Mater.2021 Sep 28;16(6). [25] Liu J,Hong M,Li Y,Chen D,Wu Y,Hu Y.Programmed Cell Death Tunes Tumor Immunity.Front Immunol.2022 Mar 30;13:847345. [26] Ye L,Yu C,Xia J,Ni K,Zhang Y,Ying X,Xie D,Jin Y,Sun R,Tang R,Fan S,Yao S.Multifunctional nanomaterials via cell cuproptosis and oxidative stress for treating osteosarcoma and OS-induced bone destruction.Mater Today Bio.2024 Feb 15;25:100996. [27] Li H,Xiao Z,Quarles LD,Li W.Osteoporosis:Mechanism,Molecular Target and Current Status on Drug Development.Curr Med Chem.2021;28(8):1489-1507. [28] Rucker RB,Kosonen T,Clegg MS,Mitchell AE,Rucker BR,Uriu-Hare JY,Keen CL.Copper,lysyl oxidase,and extracellular matrix protein cross-linking.Am J Clin Nutr.1998 May;67(5 Suppl):996S-1002S. [29] Zha K,Tan M,Hu Y,Hu W,Zhang S,Zhao Y,Lin Z,Zhang W,Xue H,Mi B,Zhou W,Feng Q,Cao F,Liu G.Regulation of metabolic microenvironment with a nanocomposite hydrogel for improved bone fracture healing.Bioact Mater.2024 Apr 24;37:424-438. [30] Bernhardt A,Bacova J,Gbureck U,Gelinsky M.Influence of Cu2+on Osteoclast Formation and Activity In Vitro.Int J Mol Sci.2021 Feb 28;22(5):2451.

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