The role of immune factors in the etiopathogenesis of osteoarthritis
https://doi.org/10.18699/SSMJ20230206
Abstract
Osteoarthritis is caused by a complex interplay of genetic, metabolic, immunological, inflammatory, biochemical, and biomechanical factors. In recent years, a fairly large number of studies have been devoted to the role of cellular factors of the immune system in the development of osteoarthritis. The aim of the study was to analyze scientifc publications devoted to the study of cellular factors in the pathogenesis of osteoarthritis and to assess their signifcance in the development of joint pathology. Material and methods. The search for publications by keywords was carried out in the PubMed, Google Scholar, eLibrary databases and specialized journals related to therapy, rheumatology, traumatology and immunology from 2000 to 2022. Results and discussion. Summarizing modern ideas about the role of cellular factors of the immune system in the pathogenesis of osteoarthritis, it is necessary to note the presence of synovial inflammation, a key role in the development of which is assigned to macrophages. At the same time, patients with osteoarthritis are characterized by the predominance of classically activated macrophages with a pronounced pro-inflammatory effect. In addition, T lymphocytes also play an important role in the pathogenesis of joint damage. Among them, a special role is given to T helper cells, cytotoxic T lymphocytes and memory T cells. An imbalance of cytokines and chemokines produced by subpopulations of T lymphocytes is the reason for triggering a number of mechanisms for the onset and progression of osteoarthritis. A signifcant role in the development and progression of osteoarthritis is also assigned to neutrophils, which contribute to the development of inflammation. Neutrophil-produced elastase enhances cartilage degradation, chondrocyte apoptosis, unbalanced subchondral bone remodeling, and osteophyte formation. Conclusions. Knowledge of the role of cellular immune factors in the pathogenesis of osteoarthritis and ways to implement their effects determines the prospects for the use of immunotropic agents. Also, it should be taken into account that the occurrence and progression of osteoarthritis is due to the simultaneous combination of the influence of a wide range of various components, including risk factors, traumatic joint injury, etc.
About the Author
P. N. Fedulichev
V.I. Vernadsky Crimean Federal University
Russian Federation
Russian Federation
Pavel N. Fedulichev, candidate of medical sciences
295051, Simferopol, Lenina blvd., 5/7
References
1. Loeser R.F., Collins J.A., Diekman B.O. Ageing and the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 2016;12(7):412–420. doi: 10.1038/nrrheum.2016.65
2. Han D., Fang Y., Tan X., Jiang H., Gong X., Wang X., Hong W., Tu J., Wei W. The emerging role of fbroblast-like synoviocytes-mediated synovitis in osteoarthritis: An update. J. Cell. Mol. Med. 2020;24(17):9518–9532. doi: 10.1111/jcmm.15669
3. Lu H., Jia C., Wu D., Jin H., Lin Z., Pan J., Li X., Wang W. Fibroblast growth factor 21 (FGF21) alleviates senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the SIRT1-mTOR signaling pathway. Cell. Death Dis. 2021;12(10):865. doi: 10.1038/s41419-021-04157-x
4. Chou C.H., Jain V., Gibson J., Attarian D.E., Haraden C.A., Yohn C.B., Laberge R.M., Gregory S., Kraus V.B. Synovial cell cross-talk with cartilage plays a major role in the pathogenesis of osteoarthritis. Sci. Rep. 2020;10(1):10868. doi: 10.1038/s41598-020-67730-y
5. Li Y.S., Luo W., Zhu S.A., Lei G.H. T cells in osteoarthritis: alterations and beyond. Front. Immunol. 2017;8:356. doi: 10.3389/fmmu.2017.00356
6. Watanabe S., Alexander M., Misharin A.V., Budinger G.R.S. The role of macrophages in the resolution of inflammation. J. Clin. Invest. 2019;129(7):2619–2628. doi: 10.1172/JCI124615
7. Gómez-Aristizábal A., Gandhi R., Mahomed N.N., Marshall K.W., Viswanathan S. Synovial fluid monocyte/macrophage subsets and their correlation to patient-reported outcomes in osteoarthritic patients: a cohort study. Arthritis Res. Ther. 2019;21(1):26. doi: 10.1186/s13075-018-1798-2
8. Kraus V.B., McDaniel G., Huebner J.L., Stabler T.V., Pieper C.F., Shipes S.W., Petry N.A., Low P.S., Shen J., McNearney T.A., Mitchell P. Direct in vivo evidence of activated macrophages in human osteoarthritis. Osteoarthritis Cartilage. 2016;24(9):1613–1621. doi: 10.1016/j.joca.2016.04.010
9. Orecchioni M., Ghosheh Y., Pramod A.B., Ley K. Macrophage polarization: different gene signatures in M1(LPS+) vs. classically and M2(LPS-) vs. alternatively activated macrophages. Front. Immunol. 2019;10:1084. doi: 10.3389/fmmu.2019.01084
10. Dey A., Allen J., Hankey-Giblin P.A. Ontogeny and polarization of macrophages in inflammation: blood monocytes versus tissue macrophages. Front. Immunol. 2015;5:683. doi: 10.3389/fmmu.2014.00683
11. Ma W.T., Gao F., Gu K., Chen D.K. The role of monocytes and macrophages in autoimmune diseases: a comprehensive review. Front. Immunol. 2019;10:1140. doi: 10.3389/fmmu.2019.01140
12. Chen Y., Jiang W., Yong H., He M., Yang Y., Deng Z., Li Y. Macrophages in osteoarthritis: pathophysiology and therapeutics. Am. J. Transl. Res. 2020;12(1):261–268.
13. Davies L.C., Taylor P.R. Tissue-resident macrophages: then and now. Immunology. 2015;144(4):541–548. doi: 10.1111/imm.12451
14. Fahy N., de Vries-van Melle M.L., Lehmann J., Wei W., Grotenhuis N., Farrell E., van der Kraan P.M., Murphy J.M., Bastiaansen-Jenniskens Y.M., van Osch G.J. Human osteoarthritic synovium impacts chondrogenic differentiation of mesenchymal stem cells via macrophage polarisation state. Osteoarthritis Cartilage. 2014;22(8):1167–1175. doi: 10.1016/j.joca.2014.05.021
15. Wynn T.A., Vannella K.M. Macrophages in tissue repair, regeneration, and fbrosis. Immunity. 2016;44(3):450–462. doi: 10.1016/j.immuni.2016.02.015
16. Gu Q., Yang H., Shi Q. Macrophages and bone inflammation. J. Orthop. Translat. 2017;10:86–93. doi:10.1016/j.jot.2017.05.002
17. Madsen D.H., Leonard D., Masedunskas A., Moyer A., Jürgensen H.J., Peters D.E., Amornphimoltham P., Selvaraj A., Yamada S.S., Brenner D.A., …Bugge T.H. M2-like macrophages are responsible for collagen degradation through a mannose receptor-mediated pathway. J. Cell. Biol. 2013;202(6):951–966. doi: 10.1083/jcb.201301081
18. Dai M., Sui B., Xue Y., Liu X., Sun J. Cartilage repair in degenerative osteoarthritis mediated by squid type II collagen via immunomodulating activation of M2 macrophages, inhibiting apoptosis and hypertrophy of chondrocytes. Biomaterials. 2018;180:91–103. doi:10.1016/j.biomaterials.2018.07.011
19. Hoeksema M.A., Glass C.K. Nature and nurture of tissue-specifc macrophage phenotypes. Atherosclerosis. 2019;281:159–167. doi: 10.1016/j.atherosclerosis.2018.10.005
20. Temple-Wong M.M., Ren S., Quach P., Hansen B.C., Chen A.C., Hasegawa A., D’Lima D.D., Koziol J., Masuda K., Lotz M.K., Sah R.L. Hyaluronan concentration and size distribution in human knee synovial fluid: variations with age and cartilage degeneration. Arthritis Res. Ther. 2016;18:18. doi: 10.1186/s13075-016-0922-4
21. Balazs E.A. Viscosupplementation for treatment of osteoarthritis: from initial discovery to current status and results. Surg. Technol. Int. 2004;12:278–289.
22. Ni S., Miao K., Zhou X., Xu N., Li C., Zhu R., Sun R., Wang Y. The involvement of follistatin-like protein 1 in osteoarthritis by elevating NF-κB-mediated inflammatory cytokines and enhancing fbroblast like synoviocyte proliferation. Arthritis Res. Ther. 2015;17(1):91. doi: 10.1186/s13075-015-0605-6
23. Kapoor M., Martel-Pelletier J., Lajeunesse D., Pelletier J.P., Fahmi H. Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat.Rev. Rheumatol. 2011;7(1):33–42. doi: 10.1038/nrrheum.2010.196
24. Nanus D.E., Badoume A., Wijesinghe S.N., Halsey A.M., Hurley P., Ahmed Z., Botchu R., Davis E.T., Lindsay M.A., Jones S.W. Synovial tissue from sites of joint pain in knee osteoarthritis patients exhibits a differential phenotype with distinct fbroblast subsets. EBioMedicine. 2021;72:103618. doi: 10.1016/j.ebiom.2021.103618
25. Raphael I., Nalawade S., Eagar T.N., Forsthuber T.G. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 2015;74(1):5–17. doi: 10.1016/j.cyto.2014.09.011
26. Zhang L., Li Y.G., Li Y.H., Qi L., Liu X.G., Yuan C.Z., Hu N.W., Ma D.X., Li Z.F., Yang Q., Li W., Li J.M. Increased frequencies of Th22 cells as well as Th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis. PLoS One. 2012;7(4):e31000. doi: 10.1371/journal.pone.0031000
27. Haynes M.K., Hume E.L., Smith J.B. Phenotypic characterization of inflammatory cells from osteoarthritic synovium and synovial fluids. Clin. Immunol. 2002;105(3):315–325. doi: 10.1006/clim.2002.5283
28. Schmitt E., Klein M., Bopp T. Th9 cells, new players in adaptive immunity. Trends Immunol. 2014;35(2):61–68. doi: 10.1016/j.it.2013.10.004
29. Kundu-Raychaudhuri S., Abria C., Raychaudhuri S.P. IL-9, a local growth factor for synovial T cells in inflammatory arthritis. Cytokine. 2016;79:45–51. doi: 10.1016/j.cyto.2015.12.020
30. Qi C., Shan Y., Wang J., Ding F., Zhao D., Yang T., Jiang Y. Circulating T helper 9 cells and increased serum interleukin-9 levels in patients with knee osteoarthritis. Clin. Exp. Pharmacol. Physiol. 2016;43(5):528–534. doi: 10.1111/1440-1681.12567
31. Kar S., Gupta R., Malhotra R., Sharma V., Farooque K., Kumar V., Chakraborty S., Mitra D.K. Interleukin-9 facilitates osteoclastogenesis in rheumatoid arthritis. Int. J. Mol. Sci. 2021;22(19):10397. doi: 10.3390/ijms221910397
32. Ignatenko T.S., Maylyan E.A., Kapanadze G.D. Concentrations of several cytokines in blood serum in women with autoimmune thyroiditis. Krymskiy zhurnal eksperimental’noy i klinicheskoy meditsiny = Crimea Journal of Experimental and Clinical Medicine. 2021;(2):28–33. [In Russian]. doi: 10.37279/2224-6444-2021-11-2-28-33
33. Zhang L., Li J.M., Liu X.G., Ma D.X., Hu N.W., Li Y.G., Li W., Hu Y., Yu S., Qu X., … Wang G.H. Elevated Th22 cells correlated with Th17 cells in patients with rheumatoid arthritis. J. Clin. Immunol. 2011;31(4):606–614. doi: 10.1007/s10875-011-9540-8
34. Guo S.Y., Ding Y.J., Li L., Zhang T., Zhang Z.Z., Zhang E.S. Correlation of CD4+ CD25+ Foxp3+ Treg with the recovery of joint function after total knee replacement in rats with osteoarthritis. Genet. Mol. Res. 2015;14(3):7290–7296. doi: 10.4238/2015.July.3.4
35. Na H.S., Park J.S., Cho K.H., Kwon J.Y., Choi J., Jhun J., Kim S.J., Park S.H., Cho M.L. Interleukin-1-interleukin-17 signaling axis induces cartilage destruction and promotes experimental osteoarthritis. Front. Immunol. 2020;11:730. doi: 10.3389/fmmu.2020.00730
36. Sinkeviciute D., Aspberg A., He Y., BayJensen A.C., Önnerfjord P. Characterization of the interleukin-17 effect on articular cartilage in a translational model: an explorative study. BMC Rheumatol. 2020;4:30. doi: 10.1186/s41927-020-00122-x
37. Moradi B., Schnatzer P., Hagmann S., Rosshirt N., Gotterbarm T., Kretzer J.P., Thomsen M., Lorenz H.M., Zeifang F., Tretter T. CD4⁺CD25⁺/highCD-127low/⁻ regulatory T cells are enriched in rheumatoid arthritis and osteoarthritis joints-analysis of frequency and phenotype in synovial membrane, synovial fluid and peripheral blood. Arthritis Res. Ther. 2014;16(2):R97.doi: 10.1186/ar4545 38. Ueno H., Banchereau J., Vinuesa C.G. Pathophysiology of T follicular helper cells in humans and mice. Nat. Immunol. 2015;16(2):142–152. doi:10.1038/ni.3054
38. Crotty S. Follicular helper CD4 T cells (TFH). Annu. Rev. Immunol. 2011;29:621–663. doi: 10.1146/annurev-immunol-031210-101400
39. Chu Y., Wang F., Zhou M., Chen L., Lu Y. A preliminary study on the characterization of follicular helper T (Tfh) cells in rheumatoid arthritis synovium. Acta Histochem. 2014;116(3):539–543. doi: 10.1016/j.acthis.2013.10.009
40. Shan Y., Qi C., Liu Y., Gao H., Zhao D., Jiang Y. Increased frequency of peripheral blood follicular helper T cells and elevated serum IL-21 levels in patients with knee osteoarthritis. Mol. Med. Rep. 2017;15(3):1095–1102. doi: 10.3892/mmr.2017.6132
41. Zhu W., Zhang X., Jiang Y., Liu X., Huang L., Wei Q., Huang Y., Wu W., Gu J. Alterations in peripheral T cell and B cell subsets in patients with osteoarthritis. Clin. Rheumatol. 2020;39(2):523–532. doi: 10.1007/s10067-019-04768-y
42. Hsieh J.L., Shiau A.L., Lee C.H., Yang S.J., Lee B.O., Jou I.M., Wu C.L., Chen S.H., Shen P.C. CD8+ T cell-induced expression of tissue inhibitor of metalloproteinses-1 exacerbated osteoarthritis. Int. J. Mol. Sci. 2013;14(10):19951–19970. doi: 10.3390/ijms141019951
43. Kriegova E., Manukyan G., Mikulkova Z., Gabcova G., Kudelka M., Gajdos P., Gallo J. Gender-related differences observed among immune cells in synovial fluid in knee osteoarthritis. Osteoarthritis Cartilage. 2018;26(9):1247–1256. doi: 10.1016/j.joca.2018.04.016
44. Hsueh M.F., Zhang X., Wellman S.S., Bolognesi M.P., Kraus V.B. Synergistic roles of macrophages and neutrophils in osteoarthritis progression. Arthritis Rheumatol. 2021;73(1):89–99. doi: 10.1002/art.41486
45. Chaney S., Vergara R., Qiryaqoz Z., Suggs K., Akkouch A. The involvement of neutrophils in the pathophysiology and treatment of osteoarthritis. Biomedicines. 2022;10(7):1604. doi: 10.3390/biomedicines10071604
46. Maylyan E.A. Cytokine levels in postmenopausal women depending on IL-6, TNFSF11 and TNFRSF11B genes polymorphisms. Nauchnyye vedomosti Belgorodskogo gosudarstvennogo universiteta. Seriya: Meditsina. Farmatsiya = Scientifc Statements of Belgorod State University. Series: Medicine. Pharmacy.2018;41(2):235–244. [In Russian]. doi: 10.18413/2075-4728-2018-41-2-235-244
47. Ignatenko G.A., Nemsadze I.G., Mirovich E.D., Churilov A.V., Maylyan E.A., Glazkov I.S., Rumyantseva Z.S. The role of cytokines in bone remodeling and the pathogenesis of postmenopausal osteoporosis. Meditsinskiy vestnik Yuga Rossii = Medical Herald of the South of Russia. 2020;11(2):6–18. [In Russian]. doi: 10.21886/2219-8075-2020-11-2-6-18
48. Ignatenko G.A., Maylyan E.A., Nemsadze I.G., Rumyantseva Z.S., Churilov A.V., Glazkov I.S., Mirovich E.D. Role of cytokines in bone tissue remodeling in norm and pathology. Tavricheskiy Mediko-biologicheskiy vestnik = Tauric Medico-Biological Bulletin. 2020;23(1):133–139. [In Russian]. doi: 10.37279/2070-8092-2020-23-1-133-139
49. Neve A., Corrado A., Cantatore F.P. Osteoblast physiology in normal and pathological conditions. Cell Tissue Res. 2011;343(2):289–302. doi: 10.1007/s00441-010-1086-1
50. Fattori V., Amaral F.A., Verri W.A. Jr. Neutrophils and arthritis: Role in disease and pharmacological perspectives. Pharmacol. Res. 2016;112:84–98. doi:10.1016/j.phrs.2016.01.027
51. Wilkinson D.J., Falconer A.M.D., Wright H.L., Lin H., Yamamoto K., Cheung K., Charlton S.H., Arques M.D.C., Janciauskiene S., Refaie R., … Rowan A.D. Matrix metalloproteinase-13 is fully activated by neutrophil elastase and inactivates its serpin inhibitor, alpha-1 antitrypsin: Implications for osteoarthritis. FEBS J. 2022;289(1):121–139. doi: 10.1111/febs.16127
52. Wang G., Jing W., Bi Y., Li Y., Ma L., Yang H., Zhang Y. Neutrophil elastase induces chondrocyte apoptosis and facilitates the occurrence of osteoarthritis via caspase signaling pathway. Front. Pharmacol. 2021;12:666162. doi: 10.3389/fphar.2021.666162
53. Donell S. Subchondral bone remodelling in osteoarthritis. EFORT Open Rev. 2019;4(6):221–229. doi: 10.1302/2058-5241.4.180102
54. Tamassia N., Bianchetto-Aguilera F., Arruda-Silva F., Gardiman E., Gasperini S., Calzetti F., Cassatella M.A. Cytokine production by human neutrophils: Revisiting the “dark side of the moon”. Eur.J. Clin. Invest. 2018;48 Suppl 2:e12952. doi: 10.1111/eci.12952
55. Molnar V., Matišić V., Kodvanj I., Bjelica R., Jeleč Ž., Hudetz D., Rod E., Čukelj F., Vrdoljak T., Vidović D., … Primorac D. Cytokines and chemokines involved in osteoarthritis pathogenesis. Int. J. Mol. Sci. 2021;22(17):9208. doi: 10.3390/ijms22179208
56. Scanzello C.R. Chemokines and inflammation in osteoarthritis: Insights from patients and animal models. J. Orthop. Res. 2017;35(4):735–739. doi:10.1002/jor.23471
57. Kasten K.R., Prakash P.S., Unsinger J., Goetzman H.S., England L.G., Cave C.M., Seitz A.P., Mazuski C.N., Zhou T.T., Morre M., … Caldwell C.C.Interleukin-7 (IL-7) treatment accelerates neutrophil recruitment through gamma delta T-cell IL-17 production in a murine model of sepsis. Infect. Immun. 2010;78(11):4714–4722. doi: 10.1128/IAI.00456-10
58. Maylyan E.A., Churilov A.V., Dzhelomanova E.S., Lesnichenko D.A. Levels of several cytokines in women with menopausal syndrome. Problemy ekologicheskoy i meditsinskoy genetiki i klinicheskoy immunologii = Problems of Ecological and Medical Genetics and Clinical Immunology. 2022; 169(1):33–41. [In Russian].
59. Maylyan E.A., Chaykovskaya I.V., Soboleva A.A., Lesnichenko D.A., Kostetskaya N.I. Levels of several cytokines in serum and oral fluid in postmenopausal women with chronic generalized periodontitis and osteoporosis. Aktual’nyye problemy meditsiny = Challenges in Modern Medicine. 2021. 44 (1): 79–91. [In Russian]. doi: 10.52575/2687-0940-2021-44-1-79-91
60. Scanzello C.R., Goldring S.R. The role of synovitis in osteoarthritis pathogenesis. Bone. 2012;51(2):249–257. doi: 10.1016/j.bone.2012.02.012
61. de Luca P., Kouroupis D., Viganò M., PeruccaOrfei C., Kaplan L., Zagra L., de Girolamo L., Correa D., Colombini A. Human diseased articular cartilage contains a mesenchymal stem cell-like population of chondroprogenitors with strong immunomodulatory responses. J. Clin. Med. 2019;8(4):423. doi: 10.3390/jcm8040423
62. Hamilton J.L., Nagao M., Levine B.R., Chen D., Olsen B.R., Im H.J. Targeting VEGF and its receptors for the treatment of osteoarthritis and associated pain. J. Bone. Miner. Res. 2016;31(5):911–924. doi: 10.1002/jbmr.2828
63. de Lange-Brokaar B.J., Kloppenburg M., Andersen S.N., Dorjée A.L., Yusuf E., Herb-van Toorn L., Kroon H.M., Zuurmond A.M., Stojanovic-Susulic V., Bloem J.L., … Ioan-Facsinay A. Characterization of synovial mast cells in knee osteoarthritis: association with clinical parameters. Osteoarthritis Cartilage. 2016;24(4):664–671. doi: 10.1016/j.joca.2015.11.011
64. Wang Q., Lepus C.M., Raghu H., Reber L.L., Tsai M.M., Wong H.H., von Kaeppler E., Lingampalli N., Bloom M.S., Hu N., … Robinson W.H. IgEmediated mast cell activation promotes inflammation and cartilage destruction in osteoarthritis. Elife. 2019;8:e39905. doi: 10.7554/eLife.39905
65. Sousa-Valente J., Calvo L., Vacca V., Simeoli R., Arévalo J.C., Malcangio M. Role of TrkA signalling and mast cells in the initiation of osteoarthritis pain in the monoiodoacetate model. Osteoarthritis Cartilage.2018;26(1):84–94. doi: 10.1016/j.joca.2017.08.006
66. Enomoto H., Inoki I., Komiya K., Shiomi T., Ikeda E., Obata K., Matsumoto H., Toyama Y., Okada Y. Vascular endothelial growth factor isoforms and their receptors are expressed in human osteoarthritic cartilage. Am. J. Pathol. 2003;162(1):171–181. doi: 10.1016/s0002-9440(10)63808-4
67. Kennedy A., Ng C.T., Biniecka M., Saber T., Taylor C., O’Sullivan J., Veale D.J., Fearon U. Angiogenesis and blood vessel stability in inflammatory arthritis. Arthritis Rheum. 2010;62(3):711–721. doi: 10.1002/art.27287
68. Kim H.R., Lee J.H., Kim K.W., Kim B.M., Lee S.H. The relationship between synovial fluid VEGF and serum leptin with ultrasonographic fndings in knee osteoarthritis. Int. J. Rheum. Dis. 2016;19(3):233–240. doi: 10.1111/1756-185X.12486
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Fedulichev P.N. The role of immune factors in the etiopathogenesis of osteoarthritis. Сибирский научный медицинский журнал. 2023;43(2):61-73. (In Russ.) https://doi.org/10.18699/SSMJ20230206
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