Some aspects of the pathophysiology of rheumatoid arthritis.
Keywords:
rheumatoid arthritis, angiogenesis, mitochondrial dysfunction, free radical oxidation
Abstract
The review is devoted to the analysis of the main mechanisms of development of rheumatoid arthritis (RA). Chronic inflammatory process and local hypoxia of synovial tissues require an increased supply of oxygen, which necessitates the formation of new capillaries. A number of proangiogenic factors are activated, including vascular endothelial growth factor (VEGF), adhesion molecules, proinflammatory cytokines, chemokines, and matrix metalloproteinases. Under their influence, the proliferation of endothelial cells occurs, the formation of tubular structures associated with the basement membrane, and the formation of a new primitive vascular network. Mitochondrial dysfunction (MD) plays an important role in RA. Mitochondria at the site of inflammation provide the cell with increased production of energy and reactive oxygen species (ROS). In RA conditions, hypoxia, increased mitochondrial DNA (mtDNA) mutation rates, and excess ROS production are likely to initiate MD. This leads to the activation of autophagy, the formation of the NLRP3 inflammasome, and the release of aberrant mtDNA into the cytosol through a pore that opens in the outer mitochondrial membrane. Emitted mitochondrial structures are sensed as damage-associated molecular patterns (DAMPs), which activate an autoimmune inflammatory process. Activation of free radical oxidation is of great importance in the pathogenesis of RA. With developing hypoxia in the cells of the inflammatory focus, the balance of oxidative and antioxidant factors shifts towards excessive formation of ROS, which leads to the activation of T- and B-lymphocytes, macrophages, and promotes the formation of extracellular traps of neutrophils. All this significantly stimulates the course of autoimmune inflammation. Stimulation of the functional activity of fibroblast-like synoviocytes by free radicals enhances their production of pro-inflammatory cytokines, increases invasiveness and delays the apoptosis of these cells. In addition, excessive activation of radical oxidation contributes to articular cartilage damage and bone erosion through the activation of enzymes that degrade cartilage and extracellular bone matrix. The resulting imbalance between osteoblasts and osteoclasts in favor of the latter induces the process of bone resection.
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REFERENCES
1.Sprindzuk M.V. The angiogenesis. Morphologia.2010; 4 (3): 4-13 (in Russian). https://doi.org/10.26641/1997-9665.2010.3.4-132.
2. Shhava S.P. Vascular growth factors and neoangiogenesis during hypoxia and ischemia. Dal’nevo-stochnyi’i medicinskii zhurnal. 2007; (1): 127-131 (in Russian).
3.Vasilyev I.S., Vasilyev S.A., Abushkin I.A., Denis A.G., Sudeykina O.A., Lapin V.O. et al. Angiogenesis: literature review. Human, sport, medicine. 2017; 17 (1): 36-45 (in Russian). https://doi.org/10.14529/hsm170104
4.ChertokV.M., ZakharchukN.V., ChertokA.G. The cellular and molecular mechanisms of angi-ogenesis regulation in the brain. S.S.Korsakov Journal of Neurology and Psychiatry. 2017; 117 (8-2): 43-55 (in Russian). https://doi.org/10.17116/jnevro20171178243-55
5.Elshabrawy H.A., Chen Z., Volin M.V., Ravella S., Virupannavar S., Shahrara S. The patho-genic role of angiogenesis in rheumatoid arthritis. Angiogenesis. 2015; 18 (4): 433-448. https://doi.org/10.1007/s10456-015-9477-2
6.Wang Y., Wu H., Deng R. Angiogenesis as a potential treatment strategy for rheumatoid ar-thritis. Eur. J. Pharmacol. 2021, 910: 174500. https://doi.org/10.1016/j.ejphar.2021.174500
7.Guo X., Chen G. Hypoxia-inducible factor is critical for pathogenesis and regulation of im-mune cell functions in rheumatoid arthritis. Front. Immunol. 2020; 11: 1668. https://doi.org/10.3389/fimmu.2020.01668
8.Szekanecz Z., Besenyei T., Paragh G., Koch A.E. Angiogenesis in rheumatoid arthritis. Auto-immunity.2009; 42 (7): 563-573. https://doi.org/10.1080/08916930903143083
9.Komarova E.B. Markers of angiogenesis in patients with rheumatoid arthritis depending on its clinical characteristics. Sovremennaya Revmatologiya. 2017; 11 (1): 28-32 (in Russian). https://doi.org/10.14412/1996-7012-2017-1-28-32
10.Alexandrova L.A., Filippova N.A., Iman A., Subbotina T.F., Trofimov V.I. Interrelationship of the mediator of angiogenesis of VEGF-A with glutathione metabolism parameters and the clinical characteristics of systemic autoimmune diseases with joint damage. The Scientific Notes of IPP-SPSMU.2018; XXV (4): 64-69 (inRussian).
11.Zhao F., He Y., Zhao Z., He J., Huang H., Ai 1. et al. The Notch signaling-regulated angio-genesis in rheumatoid arthritis: pathogenic mechanisms and therapeutic potentials. Front. Immunol.2023; 14: 1272133. https://doi.org/10.3389/fimmu.2023.1272133
12.Gao W., Sweeney C., Connolly M., Kennedy A., Ng C.T., McCormic J. et al. Notch-1 medi-ates hypoxia-induced angiogenesis in rheumatoid arthritis. Arthritis Rheum. 2012; 64 (7): 2104-2113. https://doi.org/10.1002/art.34397
13.Fearon U., Canavan M., Biniecka M., Veale D.J. Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis. Nat. Rev. Rheumatol. 2016;12 (7): 385-397. https://doi.org/10.1038/nrrheum.2016.69
14.Friedman J.R., Nunnari J. Mitochondrial form and function. Nature.2014; 505 (7483): 335-343. https://doi.org/10.1038/nature12985
15.McGarry T., Biniecka M., Veale D.J., Fearon U. Hypoxia, oxidative stress and inflammation. Free Radic. Biol. Med. 2018, 125: 15-24. https://doi.org/10.1016/j.freeradbiomed.2018.03.042
16.Ma C., Wang J., Hong F., Yang S. Mitochondrial dysfunction in rheumatoid arthritis. Bio-molecules. 2022; 12 (9): 1216. https://doi.org/10.3390/biom12091216
17.Li M., Luo X., Long X., Jiang P., Jiang Q., Guo H., Chen Z. Potential role of mitochondria in synoviocytes. Clin. Rheumatol. 2021; 40 (2): 447-457. https://doi.org/10.1007/s10067-020-05263-5
18.López-Armada M.J., Fernández-Rodríguez J.A., Blanco F.J. Mitochondrial dysfunction oxi-dative stress in rheumatoid arthritis. Antioxidants; 2022, 11 (6): 1151. https://doi.org/10.3390/antiox11061151
19.Jing W., Liu C., Su C., Liu L., Chen P., Li X. et al. Role of reactive oxygen species and mito-chondrial damage in rheumatoid arthritis and targeted drugs. Front. Immunol. 2023; 14: 1107670. https://doi.org/10.3389/fimmu.2023.1107670
20.Grigoriev E.V., Salakhov R.R., Golubenko M.V., Ponasenko A.V., Shukevich D.L., Matveeva V.G. et al. Mitochondrial DNA as DAMP in critical conditions. Bulletin of SiberianMedicine. 2019; 18 (3): 134-143 (inRussian). https://doi.org/10.20538/1682-0363-2019-3-134-143
21.Saidov M.Z. DAMP-mediated inflammation and regulated cell death in immunoinflammatory rheumatic diseases. Medical Immunology.2023; 25 (1): 7-38 (in Russian). https://doi.org/10.15789/1563-0625-DMI-2557
22.Koenig A., Buskiewicz-Koenig I.A. Redox activation of mitochondrial DAMPs and the met-abolic consequences for development of autoimmunity. Antioxid. Redox Signal. 2022; 36 (7-9): 441-461. https://doi.org/10.1089/ars.2021.0073
23.Sharma P., Sampath H. Mitochondrial DNA integrity: role in health and disease. Cells. 2019, 8 (2): 100. https://doi.org/10.3390/cells8020100
24.Li Y., Shen Y., Hohensinner P., Ju J., Wen Z., Goodman S.B. et al. Deficient activity of the nuclease MRE11A induces T cell aging and promotes arthritogenic effector functions in patients with rheumatoid arthritis. Immunity. 2016; 45 (4): 903-916. https://doi.org/10.1016/j.immuni.2016.09.013
25.Biniecka M., Fox E., Gao W., Ng C.T., Veale D.J., Fearon U., O’Sullivan J. Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis. Arthritis Rheum. 2011; 63 (8): 2172-2182. https://doi.org/10.1002/art.30395
26.Harty L.C., Biniecka M., O’Sullivan J., Fox E., Mulhall K., Veale D.J. et al. Mitochondrial mutagenesis correlates with the local inflammatory environment in arthritis. Ann. Rheum. Dis. 2012; 71 (4): 582-588. https://doi.org/10.1136/annrheumdis-2011-200245
27.Ebanks B., Chakrabarti L. Mitochondrial ATP synthase is a target of oxidative stress in neu-rodegenerative diseases. Front. Mol. Biosci. 2022; 9: 854321. https://doi.org/10.3389/fmolb.2022.854321
28.Lawless C., Greaves L., Reeve A.K., Turnbull D.M., Vincent A.E. The rise and rise of mito-chondrial DNA mutations. Open Biol. 2020; 10 (5): 200061. https://doi.org/10.1098/rsob.200061
29.Li C-J. Oxidative stress and mitochondrial dysfunction in human diseases: pathophysiology, predictive biomarkers, therapeutic. Biomolecules. 2020; 10 (11): 1558. https://doi.org/10.3390/biom10111558
30.Collins L.V., Hajizadeh S., Holme E., Jonsson I-M., Tarkowski A. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J. Leukoc. Biol. 2004; 75: 995-1000. https://doi.org/10.1189/jlb.0703328
31.Choulaki C., Papadaki G., Repa A., Kampouraki E., Kambas K., Ritis K. et al. Enhanced ac-tivity of NLRP3 inflammasome in peripheral blood cells of patients with active rheumatoid ar-thritis. Arthritis Res. Ther. 2015; 17 (1): 257. https://doi.org/10.1186/s13075-015-0775-2
32.Zhang Y., Zheng Y., Li H. NLRP3 inflammasome plays an important role in the pathogenesis of collagen-induced arthritis. Mediat. Inflamm. 2016; 2016: 9656270. https://doi.org/10.1155/2016/9656270
33.Guo C., Fu R., Wang S., Huang Y., Li X., Zhou M. et al. NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis. Clin. Exp. Immunol. 2018; 194 (2): 231-243. https://doi.org/10.1111/cei.13167
34.Garanina E.E., Martynova E.V., Ivanov K.Y. Rizvanov A.A., Khaiboullina S.F. Inflammasomes: role in disease pathogenesis and therapeutic potential. Uchenye zapiski kazanskogo universiteta. 2020; 162 (1): 80-111 (in Russian). https://doi.org/10.26907/2542-064x.2020.1.80-111
35.Grebenchikov O.A., Zabelina T.S., Philippovskaya Zh.S., Gerasimenko O.N., Plotnikov E.Y., Likhvantsev V.V. Molecular mechanisms of oxidative stress. Intensive care herald. 2016; (3): 13-21 (in Russian).
36.Wang X., Fan D., Cao X., Ye Q., Wang Q., Zhang M. et al. The role of reactive oxygen spe-cies in the rheumatoid arthritis-associated synovial microenvironment. Antioxidants. 2022; 11 (6): 1153. https://doi.org/10.3390/antiox11061153
37.Zhdanova E.V., Kostolomova E.G., Volkova D.E., Zykov A.V. Cellular composition and cy-tokine profile of synovial fluid in rheumatoid arthritis. Medical Immunology. 2022; 24 (5): 1017-1026 (in Russian). https://doi.org/10.15789/1563-0625-CCA-2520
38.Ziyadullaev Sh.Sh., KhudaiberdievSh.Sh., Aripova T.U., Rizaev J.A., Kamalov Z.S., Sultonov I.I. et al. Immune changes in synovial fluid in rheumatoid arthritis. Immunologiya. 2023; 44 (5): 653-662 (in Russian). https://doi.org/10.33029/1816-2134-2023-44-5-653-662
39.Datta S., Kundu S., Ghosh P., De S., Ghosh A., Chatterjee M. Correlation of oxidant status with oxidative tissue damage in patients with rheumatoid arthritis. Clin. Rheumatol. 2014; 33 (11): 1557-1564. https://doi.org/10.1007/s10067-014-2597-z
40.Phull A-R., Nasir B., Haq I.U., Kim S.J. Oxidative stress, consequences and ROS mediated cellular signaling in rheumatoid arthritis. Chem. Biol. Interact. 2018; 281: 121-136. https://doi.org/10.1016/j.cbi.2017.12.024
41.Da Fonseca L.J.S., Nunes-Souza V., Goulart M.O.F., Rabelo L.A. Oxidative stress in rheuma-toid arthritis: what the future might hold regarding novel biomarkers and add-on therapies. Oxid. Med. Cell. Longev. 2019; 2019: 7536805. https://doi.org/10.1155/2019/7536805
42.de Paz N.M., Quevedo-Abeledo J.C., Gómez-Bernal F., de Vera-González A., Abreu-González P., Martín-González C. et al. Malondialdehyde serum levels in a full characterized se-ries of 430 rheumatoid patients. J. Clin. Med. 2024; 13:901. https://doi.org/10.3390/jcm13030901
43.Chávez M.D., Tse H.M. Targeting mitochondrial-derived reactive oxygen species in T cell-mediated autoimmune disease. Front. Immunol. 2021; 12: 703972. https://doi.org/10.3389/fimmu.2021.703972
44.Zhi L., Ustyugova I.V., Chen Z., Zhang Q., Wu M.X. Enhanced Th17 differentiation and ag-gravated arthritis in IEX-1-deficient mice by mitochondrial reactive oxygen species-mediated signaling. J. Immunol. 2012; 189: 1639-1647. https://doi.org/10.4049/jimmunol.1200528
45.Abimannan T., Peroumal D., Parida J.R., Barik P.K., Padhan P., Devadas S. Oxidative stress modulates the cytokine response of differentiated Th17 and Th1 cells. Free Radic. Biol. Med. 2016; 99: 352-363. https://doi.org/10.1016/j.freeradbiomed.2016.08.026
46.Zhang H., Wang L., Chu Y. Reactive oxygen species: the signal regulator of B cell. Free Radic. Biol. Med. 2019; 142: 16-22. https://doi.org/10.1016/j.freeradbiomed.2019.06.004
47.Kristyanto H., Blomberg N.J., Slot L.M., van der Voort E.I.H., Kerkman P.F., Bakker A. et al. Persistently activated, proliferative memory autoreactive b cells promote inflammation in rheumatoid arthritis. Sci. Transl. Med. 2020; 12 (570): eaaz5327. https://doi.org/10.1126/scitranslmed.aaz5327
48.Bassoy E.Y., Walch M., Martinvalet D. Reactive oxygen species: do they play a role in adap-tive immunity? Front. Immuol. 2021; 12: 755856. https://doi.org/10.3389/fimmu.2021.755856
69.Khamaladze I., Saxena A., Nandakumar K.S., Holmdahl R. B-cell epitope spreading and in-flammation in a mouse model of arthritis associated with a deficiency in reactive oxygen species production. Eur. J. Immunol. 2015; 45 (8): 2243-2251. https://doi.org/10.1002/eji.201545518
50.Wheeler M.L., Defranco A.L. Prolonged production of reactive oxygen species in response to B cell receptor stimulation promotes B cell activation and proliferation. J. Immunol. 2012; 189 (9): 4405-4416. https://doi.org/10.4049/jimmunol.1201433
51.Berman-Riu M., Cunill V., Clemente A., López-Gómez A., Pons J., Ferrer J.M. Dysfunctional mitochondria, disrupted levels of reactive oxygen species, and autophagy in B cells from common variable immunodeficiency patients. Front. Immunol. 2024; 15: 1362995. https://doi.org/10.3389/fimmu.2024.1362995
52.Rosati E., Sabatini R., Ayroldi E., Tabilio A., Bartoli A., Bruscoli S. et al. Apoptosis of hu-man primary B lymphocytes is inhibited by N-acetyl-L-cysteine. J. Leukoc. Biol. 2004; 76 (1): 152-161. https://doi.org/10.1189/jlb.0403148
53.Vorobjeva N.V. Neutrophil extracellular traps: new aspects. Vestnik Moskovskogo universiteta. Seriya 16. Biologiya. 2020; 75 (4): 210-225 (in Russian).
54.Cecchi I., Arias de la Rosa I., Menegatti E., Roccatello D., Collantes-Estevez E., Lopez-Pedrera C. et al. Neutrophils: novel key players in rheumatoid arthritis. Current and future thera-peutic targets. Autoimmun. Rev. 2018; 17 (11): 1138-1149. https://doi.org/10.1016/j.autrev.2018.06,006
55.Wright H.L., Lyon M., Chapman E.A., Moots R.J., Edwards S.W. Rheumatoid arthritis syno-vial fluid neutrophils drive inflammation through production of chemokines, reactive oxygen species, and neutrophil extracellular traps. Front. Immunol. 2020; 11: 584116. https://doi.org/10.3389/fimmu.2020.584116
56.Bedouhène S., Dang PM-C., Hurtado-Nedelec M., El-Benna J. Neutrophil degranulation of azurophil and specific granules. Methods Mol. Biol. 2020; 2087: 215-222. https://doi.org/10.1007/978-1-0716-0154-9_16
57.Kaushal J., Kamboj A., Anupam K., Tandon A., Sharma A., Bhatnagar A. Interplay of redox imbalance with matrix gelatinases in neutrophils and their association with disease severity in rheumatoid arthritis patients. ClinImmunol. 2022; 237: 108965. https://doi.org/10.1016/j.clim.2022.108965
58.Song W., Ye J., Pan N., Tan C., Herrmann M. Neutrophil extracellular traps tied to rheuma-toid arthritis: points to ponder. Front. Immunol. 2020; 11: 578129. https://doi.org/10.3389/fimmu.2020.578129
59.Bedina S.A., Mozgovaya E.E., Trofimenko A.S., Spitsyna S.S., Mamus M.A. Formation of extracellular traps by circulating neutrophils and monocytes in rheumatoid arthritis patients: a study of new citrullinated autoantigen. Medical Immunology. 2021; 23 (5): 1165-1170 (in Rus-sian). https://doi.org/10.15789/1563-0625-FOE-2301
60. Bedina S.A., Mozgovaya E.E., Trofimenko A.S., Spicina S.S., Mamus M.A. Neutrophil ex-tracellular traps: features of their formation in rheumatoid arthritis and osteoarthritis. Medical Immunology. 2024; 26 (1): 175-180 (in Russian). https://doi.org/10.15789/1563-0625-NET-2672
61.Khandrup R., Carmona-Rivera C., Vivekanandan-Giri A., Zizinski A., Yalavarthi S., Knight J.S. et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci. Transl. Med. 2013; 5 (178): 178ra40. https://doi.org/10.1126/scitranslmed.3005580
62.Chowdhury C.S., Giaglis S., Walker U.A., Buser A., Hahn S., Hasler P. Enhanced neutrophil extracellular trap generation in rheumatoid arthritis: analysis of underlying signal transduction pathways and potential diagnostic utility. Arthritis Res. Ther. 2014; 16 (3): R122. https://doi.org/10.1186/ar4579
63.Ye H., Yang Q., Guo H., Wang X., Cheng L., Han B. et al. Internalisation of neutrophils ex-tracellular traps by macrophages aggravate rheumatoid arthritis via Rab5a. RMD Open. 2024; 10 (1): e003847. https://doi.org/10.1136/rmdopen-2023-003847
64.Yang X., Chang Y., Wei W. Emerging role of targeting macrophages in rheumatoid arthritis: focus on polarization, metabolism and apoptosis. Cell Prolif. 2020; 53 (7): e12854. https://doi.org/10.1111/cpr.12854
65.Ross E.A., Devitt A., Johnson J.R. Macrophages: the good, the bad, and the gluttony. Front. Immunol. 2021; 12: 708186. https://doi.org/10.3389/fimmu.2021.708186
66.Cutolo M., Campitiello R., GotelliE., Soldano S. The role of M1/M2 macrophage polarization in rheumatoid arthritis synovitis. Front. Immunol. 2022;13: 867260. https://doi.org/10.3389/fimmu.2022.867260
67.Nandakumar K.S., Fang Q., Ågren I.W., Bejmo Z.F. Aberrant activation of immune and non-immune cells contributes to joint inflammation and bone degradation in rheumatoid arthritis. Int. J. Mol. Sci. 2023; 24 (21): 15883. https://doi.org/10.3390/ijms242115883
68.Dumas A., Knaus U.G. Raising the ‘good’ oxidants for immune protection. Front. Immunol. 2021; 12: 698042. https://doi.org/10.3389/fimmu.2021.698042
69.Hu Z., Li Y., Zhang L., Jiang Y., Long C., Yang Q., Yang M. Metabolic changes in fibro-blast-like synoviocytes in rheumatoid arthritis: state of the art review. Front. Immunol. 2024; 15: 1250884. https://doi.org/10.3389/fimmu.2024.1250884
70.Kullman F., Widmann T., Kirner A., Jüsten H.P., Wessinghage D., DietmaierW. et al. Mi-crosatellite analysis in rheumatoid arthritis synovial fibroblasts. Ann. Rheum. Dis. 2000; 59 (5): 386-389. https://doi.org/10.1036/ard.59.5.386
71.Pap T., Aupperle K.R., Gay S., Firestein G.S., Gay R.E. Invasiveness of synovial fibroblasts is regulated by p53 in the SCID mouse in vivo model of cartilage invasion. Arthritis Rheum. 2001; 44 (3): 676-681. https://doi.org/10.1002/1529-0131(200103)44:3<676::AID-ANR117>3.0.CO;2-6
72.Yamanishi Y., Boyle D.L., Green D.R., Keystone E.C., Connor A., Zollman S. et al. p53 tu-mor suppressor gene mutations in fibroblast-like synoviocytes from erosion synovium and non-erosion synovium in rheumatoid arthritis. Arthritis Res. Ther. 2005; 7 (1): R12-R18. https://doi.org/10.1186/ar1448
73.Taghadosi M., Adib M., Jamshidi A., Mahmoudi M., Farhadi E. The p53 status in rheumatoid arthritis with focus on fibroblast-like synoviocytes. Immunol. Res. 2021; 69 (3): 225-238. https://doi.org/10.1007/s12026-021-09202-7
74.Ekwall A-KH., Whitaker J.W., Hammaker D., Bugbee W.D., Wang W., Firestein G.S. The rheumatoid arthritis risk gene LBH regulates growth in fibroblast-like synoviocytes. Arthritis Rheumatol. 2015; 67 (5): 1193-1202. https://doi.org/10.1002/art.39060
75.Al-Azab M., Qaed E., Ouyang X., Elkhider A., Walana W., Li H. et al. TL1A/TNFR2-mediated mitochondrial dysfunction of fibroblast-kike synoviocytes increases inflammatory re-sponse in patients with rheumatoid arthritis via reactive oxygen species generation. FEBS J.2020; 287 (14): 3088-3104. https://doi.org/10.1111/febs.15181
76.Balogh E., Veale D.J., McGarry T., Orr C., Szekanecz Z., Ng C-T.et al. Oxidative stress im-pairs energy metabolism in primary cells and synovial tissue of patients with rheumatoid arthritis. Arthritis Res. Ther. 2018; 20 (1): 95. https://doi.org/10.1186/s13075-018-1582-1
77.Henrotin Y.E., Bruckner P., Pujol J.P. The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthr. Cartil. 2003; 11 (10): 747-755. https://doi.org/10.1016/s1063-4584(03)00150-x
78.Tu J., Hong W., Zhang P., Wang X., Korner H., Wei W. Ontology and function of fibroblast-like and macrophage-like synoviocytes: how do they talk to each other and can they be targeted for rheumatoid arthritis therapy? Front. Immunol. 2018; 98: 1467. https://doi.org/10.3389/fimmu.2018.01467
79.Zhu L., Wang H., Wu Y., He Z., Qin Y., Shen Q. The autophagy level is increased in the syn-ovial tissues of patients with active rheumatoid arthritis and is correlated with disease severity. Mediators Inflamm. 2017; 2017:7623145. https://doi.org/10.1155/2017/7623145
80.Redza-Dutordoir M., Averill-Bates D.A. Interactions between reactive oxygen species and autophagy: special issue: death mechanisms in cellular homeostasis. Biochim. Biophys. Acta Mol. Cell. Res. 2021; 1868 (8): 119041. https://doi.org/10.1016/j.bbamcr.2021.119041
81.Karami J., Masoumi M., Khorramdelazad H., Bashiri H., Darvishi P., Sereshki H.A. et al. Role of autophagy in the pathogenesis of rheumatoid arthritis: latest evidence and therapeutic approaches. Life Sci. 2020; 254: 117734. https://doi.org/10.1016/j.lfs.2020.117734
82.Ding J.T., Hong F-F., Yang S-L. Roles of autophagy in rheumatoid arthritis. Clin. Exp. Rheumatol. 2022; 40 (11): 2179-2187. https://doi.org/10.55563/clinexprheumatol/exg1ic
83.Busteed S., Bennett M.W., Molloy C., Houston A., Stone M.A. Shanahan F., Molloy M.G., O’Connell J. Bcl-x(L) expression in vivo in rheumatoid synovium. Clin. Rheumatol. 2006; 25 (6): 789-793. https://doi.org/10.1007/s10067-005-0191-0
84.Wu J., Feng Z., Chen L., Li H., Bian H., Geng J. et al. TNF antagonist sensitizes synovial fi-broblasts to ferroptotic cell death in collagen-induced arthritis mouse models. Nat. Commun. 2022; 13: 676. https://doi.org/10.1038/s41467-021-27948-4
85.Bolduc J.A., Collins J.A., Loeser R.F. Reactive oxygen species, aging and articular cartilage homeostasis. Free Radic. Biol. Med. 2019; 132: 73-82. https://doi.org/10.1016/j.freeradbiomed.2018.08.038
86.Kan S., Duan M., Liu Y., Wang C., Xie J. Role of mitochondria in physiology of chondro-cytes and diseases of osteoarthritis and rheumatoid arthritis. Cartilage. 2021;13 (Suppl 2): 1102S-1121S. https://doi.org/10.1177/19476035211063858
87.Hitchon C.A., El-Gabalawy H.S. Oxidation in rheumatoid arthritis. Arthritis Res. Ther.2004; 6 (6): 265-278. https://doi.org/10.1186/ar1447
88.Matsuda K., Shiba N., Hiraoka K. New insights into role of synovial fibroblasts leading to joint destruction in rheumatoid arthritis. Int. J. Mol. Sci. 2023; 24 (6): 5173. https://doi.org/10.3390/ijms24065173
89.Burrage P.S., Mix K.S., Brinckerhoff C.E. Matrix metalloproteinases: role in arthritis. Front. Diosci. 2006; 11: 529-543. https://doi.org/10.2741/1817
124.Wu Q., Zhong Z.M., Zhu S.Y., Liao C.R., Pan Y., Zeng J.H. et al. Advanced oxidation pro-tein products induce chondrocyte apoptosis via receptor for advanced glycation end products-mediated, redox-dependent intrinsic apoptosis pathway. Apoptosis. 2016; 21 (1): 36-50. https://doi.org/10.1007/s10495-015-1191-4
90.Ye W., Zhu S., Liao C., Xiao J., Wu Q., Lin Z. et al. Advanced oxidation protein products induce apoptosis of human chondrocyte through reactive oxygen species-mediated mitochondrial dysfunction and endoplasmic reticulum stress pathways. Fundam. Clin. Pharmacol. 2017; 31 (1): 64-74. https://doi.org/10.1111/fcp.12229
91.Tao H., Ge G., Liang X., Zhang W., Sun H., Li M. et al. ROS signaling cascades: dual regula-tions for osteoclast and osteoblast. ActaBiochim. Biophys. Sin. (Shanghai). 2020; 52 (10): 1055-1062. https://doi.org/10.1093/abbs/gmaa098
1.Sprindzuk M.V. The angiogenesis. Morphologia.2010; 4 (3): 4-13 (in Russian). https://doi.org/10.26641/1997-9665.2010.3.4-132.
2. Shhava S.P. Vascular growth factors and neoangiogenesis during hypoxia and ischemia. Dal’nevo-stochnyi’i medicinskii zhurnal. 2007; (1): 127-131 (in Russian).
3.Vasilyev I.S., Vasilyev S.A., Abushkin I.A., Denis A.G., Sudeykina O.A., Lapin V.O. et al. Angiogenesis: literature review. Human, sport, medicine. 2017; 17 (1): 36-45 (in Russian). https://doi.org/10.14529/hsm170104
4.ChertokV.M., ZakharchukN.V., ChertokA.G. The cellular and molecular mechanisms of angi-ogenesis regulation in the brain. S.S.Korsakov Journal of Neurology and Psychiatry. 2017; 117 (8-2): 43-55 (in Russian). https://doi.org/10.17116/jnevro20171178243-55
5.Elshabrawy H.A., Chen Z., Volin M.V., Ravella S., Virupannavar S., Shahrara S. The patho-genic role of angiogenesis in rheumatoid arthritis. Angiogenesis. 2015; 18 (4): 433-448. https://doi.org/10.1007/s10456-015-9477-2
6.Wang Y., Wu H., Deng R. Angiogenesis as a potential treatment strategy for rheumatoid ar-thritis. Eur. J. Pharmacol. 2021, 910: 174500. https://doi.org/10.1016/j.ejphar.2021.174500
7.Guo X., Chen G. Hypoxia-inducible factor is critical for pathogenesis and regulation of im-mune cell functions in rheumatoid arthritis. Front. Immunol. 2020; 11: 1668. https://doi.org/10.3389/fimmu.2020.01668
8.Szekanecz Z., Besenyei T., Paragh G., Koch A.E. Angiogenesis in rheumatoid arthritis. Auto-immunity.2009; 42 (7): 563-573. https://doi.org/10.1080/08916930903143083
9.Komarova E.B. Markers of angiogenesis in patients with rheumatoid arthritis depending on its clinical characteristics. Sovremennaya Revmatologiya. 2017; 11 (1): 28-32 (in Russian). https://doi.org/10.14412/1996-7012-2017-1-28-32
10.Alexandrova L.A., Filippova N.A., Iman A., Subbotina T.F., Trofimov V.I. Interrelationship of the mediator of angiogenesis of VEGF-A with glutathione metabolism parameters and the clinical characteristics of systemic autoimmune diseases with joint damage. The Scientific Notes of IPP-SPSMU.2018; XXV (4): 64-69 (inRussian).
11.Zhao F., He Y., Zhao Z., He J., Huang H., Ai 1. et al. The Notch signaling-regulated angio-genesis in rheumatoid arthritis: pathogenic mechanisms and therapeutic potentials. Front. Immunol.2023; 14: 1272133. https://doi.org/10.3389/fimmu.2023.1272133
12.Gao W., Sweeney C., Connolly M., Kennedy A., Ng C.T., McCormic J. et al. Notch-1 medi-ates hypoxia-induced angiogenesis in rheumatoid arthritis. Arthritis Rheum. 2012; 64 (7): 2104-2113. https://doi.org/10.1002/art.34397
13.Fearon U., Canavan M., Biniecka M., Veale D.J. Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis. Nat. Rev. Rheumatol. 2016;12 (7): 385-397. https://doi.org/10.1038/nrrheum.2016.69
14.Friedman J.R., Nunnari J. Mitochondrial form and function. Nature.2014; 505 (7483): 335-343. https://doi.org/10.1038/nature12985
15.McGarry T., Biniecka M., Veale D.J., Fearon U. Hypoxia, oxidative stress and inflammation. Free Radic. Biol. Med. 2018, 125: 15-24. https://doi.org/10.1016/j.freeradbiomed.2018.03.042
16.Ma C., Wang J., Hong F., Yang S. Mitochondrial dysfunction in rheumatoid arthritis. Bio-molecules. 2022; 12 (9): 1216. https://doi.org/10.3390/biom12091216
17.Li M., Luo X., Long X., Jiang P., Jiang Q., Guo H., Chen Z. Potential role of mitochondria in synoviocytes. Clin. Rheumatol. 2021; 40 (2): 447-457. https://doi.org/10.1007/s10067-020-05263-5
18.López-Armada M.J., Fernández-Rodríguez J.A., Blanco F.J. Mitochondrial dysfunction oxi-dative stress in rheumatoid arthritis. Antioxidants; 2022, 11 (6): 1151. https://doi.org/10.3390/antiox11061151
19.Jing W., Liu C., Su C., Liu L., Chen P., Li X. et al. Role of reactive oxygen species and mito-chondrial damage in rheumatoid arthritis and targeted drugs. Front. Immunol. 2023; 14: 1107670. https://doi.org/10.3389/fimmu.2023.1107670
20.Grigoriev E.V., Salakhov R.R., Golubenko M.V., Ponasenko A.V., Shukevich D.L., Matveeva V.G. et al. Mitochondrial DNA as DAMP in critical conditions. Bulletin of SiberianMedicine. 2019; 18 (3): 134-143 (inRussian). https://doi.org/10.20538/1682-0363-2019-3-134-143
21.Saidov M.Z. DAMP-mediated inflammation and regulated cell death in immunoinflammatory rheumatic diseases. Medical Immunology.2023; 25 (1): 7-38 (in Russian). https://doi.org/10.15789/1563-0625-DMI-2557
22.Koenig A., Buskiewicz-Koenig I.A. Redox activation of mitochondrial DAMPs and the met-abolic consequences for development of autoimmunity. Antioxid. Redox Signal. 2022; 36 (7-9): 441-461. https://doi.org/10.1089/ars.2021.0073
23.Sharma P., Sampath H. Mitochondrial DNA integrity: role in health and disease. Cells. 2019, 8 (2): 100. https://doi.org/10.3390/cells8020100
24.Li Y., Shen Y., Hohensinner P., Ju J., Wen Z., Goodman S.B. et al. Deficient activity of the nuclease MRE11A induces T cell aging and promotes arthritogenic effector functions in patients with rheumatoid arthritis. Immunity. 2016; 45 (4): 903-916. https://doi.org/10.1016/j.immuni.2016.09.013
25.Biniecka M., Fox E., Gao W., Ng C.T., Veale D.J., Fearon U., O’Sullivan J. Hypoxia induces mitochondrial mutagenesis and dysfunction in inflammatory arthritis. Arthritis Rheum. 2011; 63 (8): 2172-2182. https://doi.org/10.1002/art.30395
26.Harty L.C., Biniecka M., O’Sullivan J., Fox E., Mulhall K., Veale D.J. et al. Mitochondrial mutagenesis correlates with the local inflammatory environment in arthritis. Ann. Rheum. Dis. 2012; 71 (4): 582-588. https://doi.org/10.1136/annrheumdis-2011-200245
27.Ebanks B., Chakrabarti L. Mitochondrial ATP synthase is a target of oxidative stress in neu-rodegenerative diseases. Front. Mol. Biosci. 2022; 9: 854321. https://doi.org/10.3389/fmolb.2022.854321
28.Lawless C., Greaves L., Reeve A.K., Turnbull D.M., Vincent A.E. The rise and rise of mito-chondrial DNA mutations. Open Biol. 2020; 10 (5): 200061. https://doi.org/10.1098/rsob.200061
29.Li C-J. Oxidative stress and mitochondrial dysfunction in human diseases: pathophysiology, predictive biomarkers, therapeutic. Biomolecules. 2020; 10 (11): 1558. https://doi.org/10.3390/biom10111558
30.Collins L.V., Hajizadeh S., Holme E., Jonsson I-M., Tarkowski A. Endogenously oxidized mitochondrial DNA induces in vivo and in vitro inflammatory responses. J. Leukoc. Biol. 2004; 75: 995-1000. https://doi.org/10.1189/jlb.0703328
31.Choulaki C., Papadaki G., Repa A., Kampouraki E., Kambas K., Ritis K. et al. Enhanced ac-tivity of NLRP3 inflammasome in peripheral blood cells of patients with active rheumatoid ar-thritis. Arthritis Res. Ther. 2015; 17 (1): 257. https://doi.org/10.1186/s13075-015-0775-2
32.Zhang Y., Zheng Y., Li H. NLRP3 inflammasome plays an important role in the pathogenesis of collagen-induced arthritis. Mediat. Inflamm. 2016; 2016: 9656270. https://doi.org/10.1155/2016/9656270
33.Guo C., Fu R., Wang S., Huang Y., Li X., Zhou M. et al. NLRP3 inflammasome activation contributes to the pathogenesis of rheumatoid arthritis. Clin. Exp. Immunol. 2018; 194 (2): 231-243. https://doi.org/10.1111/cei.13167
34.Garanina E.E., Martynova E.V., Ivanov K.Y. Rizvanov A.A., Khaiboullina S.F. Inflammasomes: role in disease pathogenesis and therapeutic potential. Uchenye zapiski kazanskogo universiteta. 2020; 162 (1): 80-111 (in Russian). https://doi.org/10.26907/2542-064x.2020.1.80-111
35.Grebenchikov O.A., Zabelina T.S., Philippovskaya Zh.S., Gerasimenko O.N., Plotnikov E.Y., Likhvantsev V.V. Molecular mechanisms of oxidative stress. Intensive care herald. 2016; (3): 13-21 (in Russian).
36.Wang X., Fan D., Cao X., Ye Q., Wang Q., Zhang M. et al. The role of reactive oxygen spe-cies in the rheumatoid arthritis-associated synovial microenvironment. Antioxidants. 2022; 11 (6): 1153. https://doi.org/10.3390/antiox11061153
37.Zhdanova E.V., Kostolomova E.G., Volkova D.E., Zykov A.V. Cellular composition and cy-tokine profile of synovial fluid in rheumatoid arthritis. Medical Immunology. 2022; 24 (5): 1017-1026 (in Russian). https://doi.org/10.15789/1563-0625-CCA-2520
38.Ziyadullaev Sh.Sh., KhudaiberdievSh.Sh., Aripova T.U., Rizaev J.A., Kamalov Z.S., Sultonov I.I. et al. Immune changes in synovial fluid in rheumatoid arthritis. Immunologiya. 2023; 44 (5): 653-662 (in Russian). https://doi.org/10.33029/1816-2134-2023-44-5-653-662
39.Datta S., Kundu S., Ghosh P., De S., Ghosh A., Chatterjee M. Correlation of oxidant status with oxidative tissue damage in patients with rheumatoid arthritis. Clin. Rheumatol. 2014; 33 (11): 1557-1564. https://doi.org/10.1007/s10067-014-2597-z
40.Phull A-R., Nasir B., Haq I.U., Kim S.J. Oxidative stress, consequences and ROS mediated cellular signaling in rheumatoid arthritis. Chem. Biol. Interact. 2018; 281: 121-136. https://doi.org/10.1016/j.cbi.2017.12.024
41.Da Fonseca L.J.S., Nunes-Souza V., Goulart M.O.F., Rabelo L.A. Oxidative stress in rheuma-toid arthritis: what the future might hold regarding novel biomarkers and add-on therapies. Oxid. Med. Cell. Longev. 2019; 2019: 7536805. https://doi.org/10.1155/2019/7536805
42.de Paz N.M., Quevedo-Abeledo J.C., Gómez-Bernal F., de Vera-González A., Abreu-González P., Martín-González C. et al. Malondialdehyde serum levels in a full characterized se-ries of 430 rheumatoid patients. J. Clin. Med. 2024; 13:901. https://doi.org/10.3390/jcm13030901
43.Chávez M.D., Tse H.M. Targeting mitochondrial-derived reactive oxygen species in T cell-mediated autoimmune disease. Front. Immunol. 2021; 12: 703972. https://doi.org/10.3389/fimmu.2021.703972
44.Zhi L., Ustyugova I.V., Chen Z., Zhang Q., Wu M.X. Enhanced Th17 differentiation and ag-gravated arthritis in IEX-1-deficient mice by mitochondrial reactive oxygen species-mediated signaling. J. Immunol. 2012; 189: 1639-1647. https://doi.org/10.4049/jimmunol.1200528
45.Abimannan T., Peroumal D., Parida J.R., Barik P.K., Padhan P., Devadas S. Oxidative stress modulates the cytokine response of differentiated Th17 and Th1 cells. Free Radic. Biol. Med. 2016; 99: 352-363. https://doi.org/10.1016/j.freeradbiomed.2016.08.026
46.Zhang H., Wang L., Chu Y. Reactive oxygen species: the signal regulator of B cell. Free Radic. Biol. Med. 2019; 142: 16-22. https://doi.org/10.1016/j.freeradbiomed.2019.06.004
47.Kristyanto H., Blomberg N.J., Slot L.M., van der Voort E.I.H., Kerkman P.F., Bakker A. et al. Persistently activated, proliferative memory autoreactive b cells promote inflammation in rheumatoid arthritis. Sci. Transl. Med. 2020; 12 (570): eaaz5327. https://doi.org/10.1126/scitranslmed.aaz5327
48.Bassoy E.Y., Walch M., Martinvalet D. Reactive oxygen species: do they play a role in adap-tive immunity? Front. Immuol. 2021; 12: 755856. https://doi.org/10.3389/fimmu.2021.755856
69.Khamaladze I., Saxena A., Nandakumar K.S., Holmdahl R. B-cell epitope spreading and in-flammation in a mouse model of arthritis associated with a deficiency in reactive oxygen species production. Eur. J. Immunol. 2015; 45 (8): 2243-2251. https://doi.org/10.1002/eji.201545518
50.Wheeler M.L., Defranco A.L. Prolonged production of reactive oxygen species in response to B cell receptor stimulation promotes B cell activation and proliferation. J. Immunol. 2012; 189 (9): 4405-4416. https://doi.org/10.4049/jimmunol.1201433
51.Berman-Riu M., Cunill V., Clemente A., López-Gómez A., Pons J., Ferrer J.M. Dysfunctional mitochondria, disrupted levels of reactive oxygen species, and autophagy in B cells from common variable immunodeficiency patients. Front. Immunol. 2024; 15: 1362995. https://doi.org/10.3389/fimmu.2024.1362995
52.Rosati E., Sabatini R., Ayroldi E., Tabilio A., Bartoli A., Bruscoli S. et al. Apoptosis of hu-man primary B lymphocytes is inhibited by N-acetyl-L-cysteine. J. Leukoc. Biol. 2004; 76 (1): 152-161. https://doi.org/10.1189/jlb.0403148
53.Vorobjeva N.V. Neutrophil extracellular traps: new aspects. Vestnik Moskovskogo universiteta. Seriya 16. Biologiya. 2020; 75 (4): 210-225 (in Russian).
54.Cecchi I., Arias de la Rosa I., Menegatti E., Roccatello D., Collantes-Estevez E., Lopez-Pedrera C. et al. Neutrophils: novel key players in rheumatoid arthritis. Current and future thera-peutic targets. Autoimmun. Rev. 2018; 17 (11): 1138-1149. https://doi.org/10.1016/j.autrev.2018.06,006
55.Wright H.L., Lyon M., Chapman E.A., Moots R.J., Edwards S.W. Rheumatoid arthritis syno-vial fluid neutrophils drive inflammation through production of chemokines, reactive oxygen species, and neutrophil extracellular traps. Front. Immunol. 2020; 11: 584116. https://doi.org/10.3389/fimmu.2020.584116
56.Bedouhène S., Dang PM-C., Hurtado-Nedelec M., El-Benna J. Neutrophil degranulation of azurophil and specific granules. Methods Mol. Biol. 2020; 2087: 215-222. https://doi.org/10.1007/978-1-0716-0154-9_16
57.Kaushal J., Kamboj A., Anupam K., Tandon A., Sharma A., Bhatnagar A. Interplay of redox imbalance with matrix gelatinases in neutrophils and their association with disease severity in rheumatoid arthritis patients. ClinImmunol. 2022; 237: 108965. https://doi.org/10.1016/j.clim.2022.108965
58.Song W., Ye J., Pan N., Tan C., Herrmann M. Neutrophil extracellular traps tied to rheuma-toid arthritis: points to ponder. Front. Immunol. 2020; 11: 578129. https://doi.org/10.3389/fimmu.2020.578129
59.Bedina S.A., Mozgovaya E.E., Trofimenko A.S., Spitsyna S.S., Mamus M.A. Formation of extracellular traps by circulating neutrophils and monocytes in rheumatoid arthritis patients: a study of new citrullinated autoantigen. Medical Immunology. 2021; 23 (5): 1165-1170 (in Rus-sian). https://doi.org/10.15789/1563-0625-FOE-2301
60. Bedina S.A., Mozgovaya E.E., Trofimenko A.S., Spicina S.S., Mamus M.A. Neutrophil ex-tracellular traps: features of their formation in rheumatoid arthritis and osteoarthritis. Medical Immunology. 2024; 26 (1): 175-180 (in Russian). https://doi.org/10.15789/1563-0625-NET-2672
61.Khandrup R., Carmona-Rivera C., Vivekanandan-Giri A., Zizinski A., Yalavarthi S., Knight J.S. et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci. Transl. Med. 2013; 5 (178): 178ra40. https://doi.org/10.1126/scitranslmed.3005580
62.Chowdhury C.S., Giaglis S., Walker U.A., Buser A., Hahn S., Hasler P. Enhanced neutrophil extracellular trap generation in rheumatoid arthritis: analysis of underlying signal transduction pathways and potential diagnostic utility. Arthritis Res. Ther. 2014; 16 (3): R122. https://doi.org/10.1186/ar4579
63.Ye H., Yang Q., Guo H., Wang X., Cheng L., Han B. et al. Internalisation of neutrophils ex-tracellular traps by macrophages aggravate rheumatoid arthritis via Rab5a. RMD Open. 2024; 10 (1): e003847. https://doi.org/10.1136/rmdopen-2023-003847
64.Yang X., Chang Y., Wei W. Emerging role of targeting macrophages in rheumatoid arthritis: focus on polarization, metabolism and apoptosis. Cell Prolif. 2020; 53 (7): e12854. https://doi.org/10.1111/cpr.12854
65.Ross E.A., Devitt A., Johnson J.R. Macrophages: the good, the bad, and the gluttony. Front. Immunol. 2021; 12: 708186. https://doi.org/10.3389/fimmu.2021.708186
66.Cutolo M., Campitiello R., GotelliE., Soldano S. The role of M1/M2 macrophage polarization in rheumatoid arthritis synovitis. Front. Immunol. 2022;13: 867260. https://doi.org/10.3389/fimmu.2022.867260
67.Nandakumar K.S., Fang Q., Ågren I.W., Bejmo Z.F. Aberrant activation of immune and non-immune cells contributes to joint inflammation and bone degradation in rheumatoid arthritis. Int. J. Mol. Sci. 2023; 24 (21): 15883. https://doi.org/10.3390/ijms242115883
68.Dumas A., Knaus U.G. Raising the ‘good’ oxidants for immune protection. Front. Immunol. 2021; 12: 698042. https://doi.org/10.3389/fimmu.2021.698042
69.Hu Z., Li Y., Zhang L., Jiang Y., Long C., Yang Q., Yang M. Metabolic changes in fibro-blast-like synoviocytes in rheumatoid arthritis: state of the art review. Front. Immunol. 2024; 15: 1250884. https://doi.org/10.3389/fimmu.2024.1250884
70.Kullman F., Widmann T., Kirner A., Jüsten H.P., Wessinghage D., DietmaierW. et al. Mi-crosatellite analysis in rheumatoid arthritis synovial fibroblasts. Ann. Rheum. Dis. 2000; 59 (5): 386-389. https://doi.org/10.1036/ard.59.5.386
71.Pap T., Aupperle K.R., Gay S., Firestein G.S., Gay R.E. Invasiveness of synovial fibroblasts is regulated by p53 in the SCID mouse in vivo model of cartilage invasion. Arthritis Rheum. 2001; 44 (3): 676-681. https://doi.org/10.1002/1529-0131(200103)44:3<676::AID-ANR117>3.0.CO;2-6
72.Yamanishi Y., Boyle D.L., Green D.R., Keystone E.C., Connor A., Zollman S. et al. p53 tu-mor suppressor gene mutations in fibroblast-like synoviocytes from erosion synovium and non-erosion synovium in rheumatoid arthritis. Arthritis Res. Ther. 2005; 7 (1): R12-R18. https://doi.org/10.1186/ar1448
73.Taghadosi M., Adib M., Jamshidi A., Mahmoudi M., Farhadi E. The p53 status in rheumatoid arthritis with focus on fibroblast-like synoviocytes. Immunol. Res. 2021; 69 (3): 225-238. https://doi.org/10.1007/s12026-021-09202-7
74.Ekwall A-KH., Whitaker J.W., Hammaker D., Bugbee W.D., Wang W., Firestein G.S. The rheumatoid arthritis risk gene LBH regulates growth in fibroblast-like synoviocytes. Arthritis Rheumatol. 2015; 67 (5): 1193-1202. https://doi.org/10.1002/art.39060
75.Al-Azab M., Qaed E., Ouyang X., Elkhider A., Walana W., Li H. et al. TL1A/TNFR2-mediated mitochondrial dysfunction of fibroblast-kike synoviocytes increases inflammatory re-sponse in patients with rheumatoid arthritis via reactive oxygen species generation. FEBS J.2020; 287 (14): 3088-3104. https://doi.org/10.1111/febs.15181
76.Balogh E., Veale D.J., McGarry T., Orr C., Szekanecz Z., Ng C-T.et al. Oxidative stress im-pairs energy metabolism in primary cells and synovial tissue of patients with rheumatoid arthritis. Arthritis Res. Ther. 2018; 20 (1): 95. https://doi.org/10.1186/s13075-018-1582-1
77.Henrotin Y.E., Bruckner P., Pujol J.P. The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthr. Cartil. 2003; 11 (10): 747-755. https://doi.org/10.1016/s1063-4584(03)00150-x
78.Tu J., Hong W., Zhang P., Wang X., Korner H., Wei W. Ontology and function of fibroblast-like and macrophage-like synoviocytes: how do they talk to each other and can they be targeted for rheumatoid arthritis therapy? Front. Immunol. 2018; 98: 1467. https://doi.org/10.3389/fimmu.2018.01467
79.Zhu L., Wang H., Wu Y., He Z., Qin Y., Shen Q. The autophagy level is increased in the syn-ovial tissues of patients with active rheumatoid arthritis and is correlated with disease severity. Mediators Inflamm. 2017; 2017:7623145. https://doi.org/10.1155/2017/7623145
80.Redza-Dutordoir M., Averill-Bates D.A. Interactions between reactive oxygen species and autophagy: special issue: death mechanisms in cellular homeostasis. Biochim. Biophys. Acta Mol. Cell. Res. 2021; 1868 (8): 119041. https://doi.org/10.1016/j.bbamcr.2021.119041
81.Karami J., Masoumi M., Khorramdelazad H., Bashiri H., Darvishi P., Sereshki H.A. et al. Role of autophagy in the pathogenesis of rheumatoid arthritis: latest evidence and therapeutic approaches. Life Sci. 2020; 254: 117734. https://doi.org/10.1016/j.lfs.2020.117734
82.Ding J.T., Hong F-F., Yang S-L. Roles of autophagy in rheumatoid arthritis. Clin. Exp. Rheumatol. 2022; 40 (11): 2179-2187. https://doi.org/10.55563/clinexprheumatol/exg1ic
83.Busteed S., Bennett M.W., Molloy C., Houston A., Stone M.A. Shanahan F., Molloy M.G., O’Connell J. Bcl-x(L) expression in vivo in rheumatoid synovium. Clin. Rheumatol. 2006; 25 (6): 789-793. https://doi.org/10.1007/s10067-005-0191-0
84.Wu J., Feng Z., Chen L., Li H., Bian H., Geng J. et al. TNF antagonist sensitizes synovial fi-broblasts to ferroptotic cell death in collagen-induced arthritis mouse models. Nat. Commun. 2022; 13: 676. https://doi.org/10.1038/s41467-021-27948-4
85.Bolduc J.A., Collins J.A., Loeser R.F. Reactive oxygen species, aging and articular cartilage homeostasis. Free Radic. Biol. Med. 2019; 132: 73-82. https://doi.org/10.1016/j.freeradbiomed.2018.08.038
86.Kan S., Duan M., Liu Y., Wang C., Xie J. Role of mitochondria in physiology of chondro-cytes and diseases of osteoarthritis and rheumatoid arthritis. Cartilage. 2021;13 (Suppl 2): 1102S-1121S. https://doi.org/10.1177/19476035211063858
87.Hitchon C.A., El-Gabalawy H.S. Oxidation in rheumatoid arthritis. Arthritis Res. Ther.2004; 6 (6): 265-278. https://doi.org/10.1186/ar1447
88.Matsuda K., Shiba N., Hiraoka K. New insights into role of synovial fibroblasts leading to joint destruction in rheumatoid arthritis. Int. J. Mol. Sci. 2023; 24 (6): 5173. https://doi.org/10.3390/ijms24065173
89.Burrage P.S., Mix K.S., Brinckerhoff C.E. Matrix metalloproteinases: role in arthritis. Front. Diosci. 2006; 11: 529-543. https://doi.org/10.2741/1817
124.Wu Q., Zhong Z.M., Zhu S.Y., Liao C.R., Pan Y., Zeng J.H. et al. Advanced oxidation pro-tein products induce chondrocyte apoptosis via receptor for advanced glycation end products-mediated, redox-dependent intrinsic apoptosis pathway. Apoptosis. 2016; 21 (1): 36-50. https://doi.org/10.1007/s10495-015-1191-4
90.Ye W., Zhu S., Liao C., Xiao J., Wu Q., Lin Z. et al. Advanced oxidation protein products induce apoptosis of human chondrocyte through reactive oxygen species-mediated mitochondrial dysfunction and endoplasmic reticulum stress pathways. Fundam. Clin. Pharmacol. 2017; 31 (1): 64-74. https://doi.org/10.1111/fcp.12229
91.Tao H., Ge G., Liang X., Zhang W., Sun H., Li M. et al. ROS signaling cascades: dual regula-tions for osteoclast and osteoblast. ActaBiochim. Biophys. Sin. (Shanghai). 2020; 52 (10): 1055-1062. https://doi.org/10.1093/abbs/gmaa098
Published
30-09-2025
How to Cite
Rykunova A. Y., Zverev Y. F. Some aspects of the pathophysiology of rheumatoid arthritis. // Patologicheskaya Fiziologiya i Eksperimental’naya Terapiya (Pathological physiology and experimental therapy). 2025. VOL. 69. № 3. PP. 101–112.
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