Молекулярно-генетические особенности иммунных механизмов остеоартроза

Введение. Остеоартроз (ОА) характеризуется гетерогенностью клинических проявлений, а в ряде случаев – тяжелым прогрессирующим течением. В связи с этим актуально определение новых молекулярных мишеней для лечения болезни.

Цель исследования – определить роль молекулярных, генетических и эпигенетических изменений при ОА, вовлеченных в патологические иммунные реакции, выявить специфические для болезни микроРНК в качестве потенциальных мишеней для таргетной терапии.

Материалы и методы. При подготовке обзора для поиска информации использованы научные платформы PubMed, Scopus, ResearchGate, RSCI. Поисковыми словами и словосочетаниями были следующие: osteoarthritis genes meta-analysis, osteoarthritis genes, miRNAs osteoarthritis.

Результаты. Получены данные о роли патологических иммунных реакций в механизмах развития ОА с изменением экспрессии инфильтрирующими суставы иммунными клетками 34 специфических генов, вовлеченных в функционирование иммунной системы. В клинических исследованиях определена ассоциация аллельных вариантов генов C5AR1, FCGR2B, HLA-DR2, HLA-DR5, IL1B, IL1RN, IL4R, IL6, IL10, IL17, TYROBP, TLR3, TLR4, TLR7, TLR9, TLR10, участвующих в регуляции функционирования иммунной системы. Выявлены изменения экспрессии 11 специфических микроРНК, вовлеченных в воспалительные и дегенеративные процессы при ОА.

Заключение. Молекулярно-генетические исследования позволяют находить новые маркеры патологических иммунных реакций при ОА, которые могут быть использованы для лечения и предотвращения быстрого прогрессирования болезни, а также для проектирования таргетной терапии с применением в качестве мишеней специфических генов. Выявлена важная роль нарушений экспрессии генов, участвующих в функционировании иммунной системы, в патогенезе болезни. Ассоциированные с ОА микроРНК, вовлеченные в патогенез иммунных реакций, могут стать перспективными инструментами для таргетной терапии болезни. Анализ рассмотренных материалов свидетельствует о том, что использование микроРНК, воздействующих на сопричастные патогенезу ОА ретроэлементы, может стать основой не только для подавления прогрессирования патологии, но и для замедления процессов старения.

1. Chen J., Chen S., Cai D. et al. The role of Sirt6 in osteoarthritis and its effect on macrophage polarization. Bioengineered 2022;13(4):9677–89. DOI: 10.1080/21655979.2022.2059610

2. Gilbert S.J., Blain E.J., Mason D.J. Interferon-gamma modulates articular chondrocyte and osteoblast metabolism through protein kinase R-independent and dependent mechanisms. Biochem Biophys Rep 2022;32:101323. DOI: 10.1016/j.bbrep.2022.101323

3. Vos T., Flaxman A.D., Naghavi M. et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2012;380:2163–96. DOI: 10.1016/S0140-6736(12)61729-2

4. Середа А.П., Кочиш А.А., Черный А.А. и др. Эпидемиология эндопротезирования тазобедренного и коленного суставов и перипротезной инфекции в Российской Федерации. Травматология и ортопедия России 2021;27(3):84–93. DOI: 10.21823/2311-2905-2021-27-3-84-93

5. De Cecco M., Ito T., Petrashen A.P. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 2019;566(7742):73–8. DOI: 10.1038/s41586-018-0784-9

6. Gorbunova V., Seluanov A., Mita P. et al. The role of retrotransposable elements in ageing and age-associated diseases. Nature 2021;596(7870):43–53. DOI: 10.1038/s41586-021-03542-y

7. Van Meter M., Kashyap M., Rezazadeh S. et al. SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age. Nat Commun 2014;5:5011. DOI: 10.1038/ncomms6011

8. Zhou F., Mei J., Han X. et al. Kinsenoside attenuates osteoarthritis by repolarizing macrophages through inactivating NF-κB/MAPK signaling and protecting chondrocytes. Acta Pharm Sin B 2019;9(5):973–85. DOI: 10.1016/j.apsb.2019.01.015

9. Knights A.J., Redding S.J., Maerz T. Inflammation in osteoarthritis: the latest progress and ongoing challenges. Curr Opin Rheumatol 2023;35(2):128–34. DOI: 10.1097/BOR.0000000000000923

10. Simon T.C., Jeffries M.A. The epigenomic landscape in osteoarthritis. Curr Rheumatol Rep 2017;19(6):30. DOI: 10.1007/s11926-017-0661-9

11. Mustafin R.N., Khusnutdinova E.K. Non-coding parts of genomes as the basis of epigenetic heredity. Vavilov Journal of Genetics and Breeding 2017;21(6):742–9.

12. Wei G., Qin S., Li W. et al. MDTE DB: a database for microRNAs derived from Transposable element. IEEE/ACM Trans Comput Biol Bioinform 2016;13(6):1155–60. DOI: 10.1109/TCBB.2015.2511767

13. Johnson R., Guigo R. The RIDL hypothesis: transposable elements as functional domains of long noncoding RNAs. RNA 2014;20(7):959–76. DOI: 10.1261/rna.044560.114

14. Uhalte E.C., Wilkinson J.M., Southam L., Zeggini E. Pathways to understanding the genomic aetiology of osteoarthritis. Hum Mol Genet 2017;26:R193–201. DOI: 10.1093/hmg/ddx302

15. Zhang J., Zhang S., Zhou Y. et al. KLF9 and EPYC acting as feature genes for osteoarthritis and their association with immune infiltration. J Orthop Surg Res 2022;17(1):365. DOI: 10.1186/s13018-022-03247-6

16. Xu W.D., Huang Q., Huang A.F. Emerging role of galectin family in inflammatory autoimmune diseases. Autoimmun Rev 2021;20(7):102847. DOI: 10.1016/j.autrev.2021.102847

17. Colasanti T., Sabatinelli D., Mancone C. et al. Homocysteinylated alpha 1 antitrypsin as an antigenic target of autoantibodies in seronegative rheumatoid arthritis patients. J Autoimmun 2020;113:102470. DOI: 10.1016/j.jaut.2020.102470

18. Kenny J., Mullin B.H., Tomlinson W. et al. Age-dependent genetic regulation of osteoarthritis: independent effects of immune system genes. Arthritis Res Ther 2023;25(1):232. DOI: 10.1186/s13075-023-03216-2

19. Goldmann K., Spiliopoulou A., Iakovliev A. et al. Expression quantitative trait loci analysis in rheumatoid arthritis identifies tissue specific variants associated with severity and outcome. Ann Rheum Dis 2024;83(3):288–99. DOI: 10.1136/ard-2023-224540

20. Szulc M., Swatkowska-Stodulska R., Pawlowska E., Derwich M. Vitamin D metabolism and its role in temporomandibular joint osteoarthritis and autoimmune thyroid diseases. Int J Mol Sci 2023;24(4):4080. DOI: 10.3390/ijms24044080

21. Jian J., Li G., Hettinghouse A., Liu C. Progranulin: A key player in autoimmune diseases. Cytokine 2018;101:48–55. DOI: 10.1016/j.cyto.2016.08.007

22. Akhter S., Tasnim F.M., Islam M.N. et al. Role of Th17 and Il-17 cytokines on inflammatory and auto-immune diseases. Curr Pharm Des 2023;29(26):2078–90. DOI: 10.2174/1381612829666230904150808

23. Saetan N., Honsawek S., Tanavalee S. et al. Association of plasma and synovial fluid interferon-γ inducible protein-10 with radiographic severity in knee osteoarthritis. Clin Biochem 2011;44(14-15):1218–22. DOI: 10.1016/j.clinbiochem.2011.07.010

24. Li S., Ren Y., Peng D. et al. TIM-3 genetic variations affect susceptibility to osteoarthritis by interfering with interferon gamma in CD4+ T cells. Inflammation 2015;38(5):1857–63. DOI: 10.1007/s10753-015-0164-7

25. Guo Q., Chen X., Chen J. et al. STING promotes senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the NF-κB signaling pathway. Cell Death Dis 2021;12(1):13. DOI: 10.1038/s41419-020-03341-9

26. de Groen R.A., Liu B.S., Boonstra A. Understanding IFNλ in rheumatoid arthritis. Arthritis Res Ther 2014;16(1):102. DOI: 10.1186/ar4445

27. Lee Y.H., Song G.G. Association between the interferon-γ + 874 T/A polymorphism and susceptibility to systemic lupus erythematosus and rheumatoid arthritis: A meta-analysis. Int J Immunogenet 2022;49(6):365–71. DOI: 10.1111/iji.12599

28. Toro-Domínguez D., Carmona-Sáez P., Alarcón-Riquelme M.E. Shared signatures between rheumatoid arthritis, systemic lupus erythematosus and Sjögren’s syndrome uncovered through gene expression meta-analysis. Arthritis Res Ther 2014;16(6):489. DOI: 10.1186/s13075-014-0489-x

29. Xu J., Chen K., Yu Y. et al. Identification of immune-related risk genes in osteoarthritis based on bioinformatics analysis and machine learning. J Pers Med 2023;13(2):367. DOI: 10.3390/jpm13020367

30. Li J., Wang G., Xv X. et al. Identification of immune-associated genes in diagnosing osteoarthritis with metabolic syndrome by integrated bioinformatics analysis and machine learning. Front Immunol 2023;14:1134412. DOI: 10.3389/fimmu.2023.1134412

31. Gomes da Silva I.I.F., Barbosa A.D., Souto F.O. et al. MYD88, IRAK3 and rheumatoid arthritis pathogenesis: analysis of differential gene expression in CD14+ monocytes and the inflammatory cytokine levels. Immunobiology 2021;226(6):152152. DOI: 10.1016/j.imbio.2021.152152

32. Zhang Q., Sun C., Liu X. et al. Mechanism of immune infiltration in synovial tissue of osteoarthritis: a gene expression-based study. J Orthop Surg Res 2023;18(1):58. DOI: 10.1186/s13018-023-03541-x

33. Pan L., Yang F., Cao X. et al. Identification of five hub immune genes and characterization of two immune subtypes of osteoarthritis. Front Endocrinol (Lausanne) 2023;14:1144258. DOI: 10.3389/fendo.2023.1144258

34. Cheng P., Gong S., Guo C. et al. Exploration of effective biomarkers and infiltrating Immune cells in osteoarthritis based on bioinformatics analysis. Artif Cells Nanomed Biotechnol 2023;51(1):242–54. DOI: 10.1080/21691401.2023.2185627

35. Xia D., Wang J., Yang S. et al. Identification of key genes and their correlation with immune infiltration in osteoarthritis using integrative bioinformatics approaches and machine-learning strategies. Medicine (Baltimore) 2023;102(46):e35355. DOI: 10.1097/MD.0000000000035355

36. Qin J., Zhang J., Wu J.J. et al. Identification of autophagy-related genes in osteoarthritis articular cartilage and their roles in immune infiltration. Front Immunol 2023;14:1263988. DOI: 10.3389/fimmu.2023.1263988

37. Wang L., Ye S., Qin J. et al. Ferroptosis-related genes LPCAT3 and PGD are potential diagnostic biomarkers for osteoarthritis. J Orthop Surg Res 2023;18(1):699. DOI: 10.1186/s13018-023-04128-2

38. Xu L., Wang Z., Wang G. Screening of biomarkers associated with osteoarthritis aging genes and immune correlation studies. Int J Gen Med 2024;17:205–24. DOI: 10.2147/IJGM.S447035

39. Yang L., Chen Z., Guo H. et al. Extensive cytokine analysis in synovial fluid of osteoarthritis patients. Cytokine 2021;143:155546. DOI: 10.1016/j.cyto.2021.155546

40. Liu Y., Lu T., Liu Z. et al. Six macrophage-associated genes in synovium constitute a novel diagnostic signature for osteoarthritis. Front Immunol 2022;13:936606. DOI: 10.3389/fimmu.2022.936606

41. Zhang B., Gu J., Wang Y. et al. TNF-α stimulated exosome derived from fibroblast-like synoviocytes isolated from rheumatoid arthritis patients promotes HUVEC migration, invasion and angiogenesis by targeting the miR-200a-3p/KLF6/ VEGFA axis. Autoimmunity 2023;56(1):2282939. DOI: 10.1080/08916934.2023.2282939

42. Ye Y., Bao C., Fan W. Overexpression of miR-101 may target DUSP1 to promote the cartilage degradation in rheumatoid arthritis. J Comput Biol 2019;26(10):1067–79. DOI: 10.1089/cmb.2019.0021

43. Chen M., Li M., Zhang N. et al. Mechanism of miR-218-5p in autophagy, apoptosis and oxidative stress in rheumatoid arthritis synovial fibroblasts is mediated by KLF9 and JAK/ STAT3 pathways. J Investig Med 2021;69(4):824–32. DOI: 10.1136/jim-2020-001437

44. Cortes-Altamirano J.L., Morraz-Varela A., Reyes-Long S. et al. Chemical mediators’ expression associated with the modulation of pain in rheumatoid arthritis. Curr Med Chem 2020;27(36): 6208–18. DOI: 10.2174/0929867326666190816225348

45. Morel J., Roch-Bras F., Molinari N. et al. HLA-DMA*0103 and HLA-DMB*0104 alleles as novel prognostic factors in rheumatoid arthritis. Ann Rheum Dis 2004;63(12):1581–6. DOI: 10.1136/ard.2003.012294

46. Rong H., He X., Wang L. et al. Association between IL1B polymorphisms and the risk of rheumatoid arthritis. Int Immunopharmacol 2020;83:106401. DOI: 10.1016/j.intimp.2020.106401

47. Liu X., Peng L., Li D. et al. The impacts of IL1R1 and IL1R2 genetic variants on rheumatoid arthritis risk in the chinese han population: a case-control study. Int J Gen Med 2021;14:2147–59. DOI: 10.2147/IJGM.S291395

48. Hernández-Bello J., Oregón-Romero E., Vázquez-Villamar M. et al. Aberrant expression of interleukin-10 in rheumatoid arthritis: relationship with IL-10 haplotypes and autoantibodies. Cytokine 2017;95:88–96. DOI: 10.1016/j.cyto.2017.02.022

49. Mandik-Nayak L., DuHadaway J.B., Mulgrew J. et al. RhoB blockade selectively inhibits autoantibody production in autoimmune models of rheumatoid arthritis and lupus. Dis Model Mech 2017;10(11):1313–22. DOI: 10.1242/dmm.029835

50. Fida S., Myers M.A., Whittingham S. et al. Autoantibodies to the transcriptional factor SOX13 in primary biliary cirrhosis compared with other diseases. J Autoimmun 2002;19(4):251–7. DOI: 10.1006/jaut.2002.0622

51. Lee Y.H., Song G.G. Associations between TNFAIP3 polymorphisms and rheumatoid arthritis: a systematic review and meta-analysis update with trial sequential analysis. Public Health Genomics 2022;12:1–11. DOI: 10.1159/000526212

52. Okada Y., Wu D., Trynka G. et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature 2014;506(7488):376–81. DOI: 10.1038/nature12873

53. Mousavi M.J., Shayesteh M.R.H., Jamalzehi S. et al. Association of the genetic polymorphisms in inhibiting and activating molecules of immune system with rheumatoid arthritis: a systematic review and meta-analysis. J Res Med Sci 2021;26:22. DOI: 10.4103/jrms.JRMS_567_20

54. Budhiparama N.C., Lumban-Gaol I., Sudoyo H. et al. Interleukin-1 genetic polymorphisms in knee osteoarthritis: What do we know? A meta-analysis and systematic review. J Orthop Surg (Hong Kong) 2022;30(1):23094990221076652. DOI: 10.1177/23094990221076652

55. Deng X., Ye K., Tang J. et al. Association of rs1800795 and rs1800796 polymorphisms in interleukin-6 gene and osteoarthritis risk: evidence from a meta-analysis. Nucleosides Nucleotides Nucleic Acids 2023;42:328–42. DOI: 10.1080/15257770.2022.2147541

56. Lu F., Liu P., Zhang Q. et al. Association between the polymorphism of IL-17A and IL-17F gene with knee osteoarthritis risk: a meta-analysis based on case-control studies. J Orthop Surg Res 2019;14(1):445. DOI: 10.1186/s13018-019-1495-0

57. Rogoveanu O.C., Calina D., Cucu M.G. et al. Association of cytokine gene polymorphisms with osteoarthritis susceptibility. Exp Ther Med 2018;16(3):2659–64. DOI: 10.3892/etm.2018.6477

58. Moos V., Menard J., Sieper J. et al. Association of HLA-DRB1*02 with osteoarthritis in a cohort of 106 patients. Rheumatology (Oxford) 2002;41(6):666–9. DOI: 10.1093/rheumatology/41.6.666

59. Jurynec M.J., Sawitzke A.D., Beals T.C. et al. A hyperactivating proinflammatory RIPK2 allele associated with early-onset osteoarthritis. Hum Mol Genet 2018;27(13):2383–91. DOI: 10.1093/hmg/ddy132

60. Yang H.Y., Lee H.S., Lee C.H. et al. Association of a functional polymorphism in the promoter region of TLR-3 with osteoarthritis: A two-stage case-control study. J Orthop Res 2013;31:680–5. DOI: 10.1002/jor.22291

61. Stefik D., Vranic V., Ivkovic N. et al. Potential impact of polymorphisms in Toll-like receptors 2, 3, 4, 7, 9, miR-146a, miR-155, and miR-196a genes on osteoarthritis susceptibility. Biology 2023;12:458. DOI: 10.3390/biology12030458

62. Yi X., Xu E., Xiao Y., Cai X. Evaluation of the relationship between common variants in the TLR-9 gene and hip osteoarthritis susceptibility. Genet Test Mol Biomark 2019;23(6):373–9. DOI: 10.1089/gtmb.2019.0010

63. Tang H., Cheng Z., Ma W. et al. TLR10 and NFKBIA contributed to the risk of hip osteoarthritis: systematic evaluation based on Han Chinese population. Sci Rep 2018;8:10243. DOI: 10.1038/s41598-018-28597-2

64. Wang X., Ning Y., Zhou B. et al. Integrated bioinformatics analysis of the osteoarthritis-associated microRNA expression signature. Mol Med Rep 2018;17(1):1833–8. DOI: 10.3892/mmr.2017.8057

65. Mohebi N., Damavandi E., Rostamian A.R. et al. Comparison of plasma levels of MicroRNA-155-5p, MicroRNA-210-3p, and MicroRNA-16-5p in rheumatoid arthritis patients with healthy controls in a case-control study. Iran J Allergy Asthma Immunol 2023;22(4):354–65. DOI: 10.18502/ijaai.v22i4.13608

66. Yang L., Yang S., Ren C. et al. Deciphering the roles of miR-16-5p in malignant solid tumors. Biomed Pharmacother 2022;148:112703. DOI: 10.1016/j.biopha.2022.112703

67. Liu X., Ni S., Li C. et al. Circulating microRNA-23b as a new biomarker for rheumatoid arthritis. Gene 2019;712:143911. DOI: 10.1016/j.gene.2019.06.001

68. Cheng Q., Chen X., Wu H., Du Y. Three hematologic/immune system-specific expressed genes are considered as the potential biomarkers for the diagnosis of early rheumatoid arthritis through bioinformatics analysis. J Transl Med 2021;19(1):18. DOI: 10.1186/s12967-020-02689-y

69. Zeng Z., Li Y., Pan Y. et al. Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nat Commun 2018;9(1):5395. DOI: 10.1038/s41467-018-07810-w

70. Law Y.Y., Lee W.F., Hsu C.J. et al. miR-let-7c-5p and miR-149-5p inhibit proinflammatory cytokine production in osteoarthritis and rheumatoid arthritis synovial fibroblasts. Aging (Albany NY) 2021;13(13):17227–36. DOI: 10.18632/aging.203201

71. Liu H., Yan L., Li X. et al. MicroRNA expression in osteoarthritis: a meta-analysis. Clin Exp Med 2023;23(7):3737–49. DOI: 10.1007/s10238-023-01063-8

72. Bae S.C., Lee Y.H. miR-146a levels in rheumatoid arthritis and their correlation with disease activity: a meta-analysis. Int J Rheum Dis 2018;21(7):1335–42. DOI: 10.1111/1756-185X.13338

73. Zheng J., Wang Y., Hu J. Study of the shared gene signatures of polyarticular juvenile idiopathic arthritis and autoimmune uveitis. Front Immunol 2023;14:1048598. DOI: 10.3389/fimmu.2023.1048598

74. Tavasolian F., Hosseini A.Z., Soudi S., Naderi M. miRNA-146a improves immunomodulatory effects of MSC-derived exosomes in rheumatoid arthritis. Curr Gene Ther 2020;20(4):297–312. DOI: 10.2174/1566523220666200916120708

75. Li Z., Zhao W., Wang M. et al. Role of microRNAs deregulation in initiation of rheumatoid arthritis: a retrospective observational study. Medicine (Baltimore) 2024;103(3):e36595. DOI: 10.1097/MD.0000000000036595

76. Semerci Sevimli T., Sevimli M., Qomi Ekenel E. et al. Comparison of exosomes secreted by synovial fluid-derived mesenchymal stem cells and adipose tissue-derived mesenchymal stem cells in culture for microRNA-127-5p expression during chondrogenesis. Gene 2023;865:147337. DOI: 10.1016/j.gene.2023.147337

77. Yin M., Zhang Z., Wang Y. Anti-tumor effects of miR-34a by regulating immune cells in the tumor microenvironment. Cancer Medicine 2023;12(10):11602–10. DOI: 10.1002/cam4.5826

78. Zhu J., Yang S., Qi Y. et al. Stem cell-homing hydrogel-based miR-29b-5p delivery promotes cartilage regeneration by suppressing senescence in an osteoarthritis rat model. Sci Adv 2022;8(13):eabk0011. DOI: 10.1126/sciadv.abk0011

79. Zhang Y., Li S., Jin P. et al. Dual functions of microRNA-17 in maintaining cartilage homeostasis and protection against osteoarthritis. Nat Commun 2022;13(1):2447. DOI: 10.1038/s41467-022-30119-8

80. Farghadan M., Zavaran-Hosseini A., Farhadi E. et al. MicroRNA-211-5p overexpression effect on endoplasmic reticulum stress and apoptotic genes in fibroblast-like synoviocytes of rheumatoid arthritis. Iran J Allergy Asthma Immunol 2022;21(4):418–28. DOI: 10.18502/ijaai.v21i4.10289