Толл-подобные рецепторы как компонент патофизиологии остеоартрита: противовоспалительное, анальгетическое и нейропротекторное действие

Толл-подобные рецепторы (Toll-like receptors, TLR) реагируют на бактериальные липополисахариды (ЛПС) и участвуют в формировании врожденного иммунитета. Избыточная активность TLR приводит к хронизации воспаления и к развитию ряда коморбидных патологий, включая остеоартрит (ОА). Компьютерный анализ текстов 52 312 публикаций, посвященных TLR, позволил систематически описать механизмы биологического действия TLR и их влияние на патофизиологию ОА. Выделены механизмы, посредством которых медленнодействующие препараты на основе стандартизированных форм хондроитина сульфата (ХС), обладающие симптом-модифицирующим и структурно-модифицирующим эффектом, могут способствовать снижению активности TLR и использоваться в терапии ОА. Сделанные выводы подтверждаются результатами хемореактомного анализа TLR, а также клиническими и экспериментальными данными.

1. Abdelwahab A, Palosaari S, Abdelwahab SA, et al. Differential synovial tissue expression of TLRs in seropositive and seronegative rheumatoid arthritis: A preliminary report. Autoimmunity. 2021 Feb;54(1):23-34. doi: 10.1080/08916934.2020.1864729. Epub 2020 Dec 30.

2. Park H, Hong J, Yin Y, et al. TAP2, a peptide antagonist of Toll-like receptor 4, attenuates pain and cartilage degradation in a monoiodoacetate-induced arthritis rat model. Sci Rep.2020 Oct 15;10(1):17451. doi: 10.1038/s41598-020-74544-5

3. Herrero-Beaumont G, Perez-Baos S, Sanchez-Pernaute O, et al. Targeting chronic innate inflammatory pathways, the main road to prevention of osteoarthritis progression. Biochem Pharmacol. 2019 Jul;165:24-32. doi: 10.1016/j.bcp.2019.02.030. Epub 2019 Feb 27.

4. Barreto G, Manninen M, Eklund K. Osteoarthritis and Toll-Like Receptors: When Innate Immunity Meets Chondrocyte Apoptosis. Biology (Basel). 2020 Mar 30;9(4):65. doi: 10.3390/biology9040065

5. Torshin IYu, Rudakov KV. Combinatorial analysis of the solvability properties of the problems of recognition and completeness of algorithmic models. Part 1: factorization approach. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2017;27(1):16-28.

6. Torshin IYu, Rudakov KV. Combinatorial analysis of the solvability properties of the problems of recognition and completeness of algorithmic models. Part 2: metric approach within the framework of the theory of classification of feature values. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2017;27(2):184-99.

7. Torshin IYu. Optimal dictionaries of the final information on the basis of the solvability criterion and their applications in bioinformatics. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2013;23(2):319-27.

8. Torshin IYu, Rudakov KV. On the theoretical basis of the metric analysis of poorly formalized problems of recognition and classification. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2015;25(4):577-87.

9. Torshin IYu, Rudakov KV. On the Procedures of Generation of Numerical Features Over Partitions of Sets of Objects in the Problem of Predicting Numerical Target Variables. Pattern Recognition and Image Analysis (Advances in Mathematical Theory and Applications). 2019;29(4):654-67. doi: 10.1134/S105466181904017

10. Zitnik M, Sosivc R, Maheshwari S, Leskovec J. BioSNAP Datasets: Stanford Biomedical Network Dataset Collection, Aug 2018. Available from: http://snap.stanford.edu/biodata

11. The Gene Ontology Consortium. The Gene Ontology Resource: 20 years and still GOing strong. Nucleic Acids Res. Jan 2019;47(D1):D330-D338.

12. Nie F, Ding F, Chen B, et al. Dendritic cells aggregate inflammation in experimental osteoarthritis through a toll-like receptor (TLR)-dependent machinery response to challenges. Life Sci. 2019 Dec 1;238:116920. doi: 10.1016/j.lfs.2019.116920. Epub 2019 Oct 11.

13. Huang ZY, Perry E, Huebner JL, et al. Biomarkers of inflammation — LBP and TLR-predict progression of knee osteoarthritis in the DOXY clinical trial. Osteoarthritis Cartilage. 2018 Dec;26(12):1658-65. doi: 10.1016/j.joca.2018.08.005. Epub 2018 Aug 23.

14. Won Y, Yang JI, Park S, Chun JS. LBP and CD14, cofactors of toll-like receptors, are essential for low-grade inflammation-induced exacerbation of post-traumatic osteoarthritis. Arthritis Rheum. 2021 Feb 8. doi: 10.1002/art.41679

15. Clanchy FIL, Borghese F, Bystrom J, et al. TLR expression profiles are a function of disease status in rheumatoid arthritis and experimental arthritis. J Autoimmun. 2021 Mar;118:102597. doi: 10.1016/j.jaut.2021.102597. Epub 2021 Jan 22.

16. Hwang HS, Lee MH, Kim HA. The TLR-2/TonEBP signaling pathway regulates 29-kDa fibronectin fragment-dependent expression of matrix metalloproteinases. Sci Rep. 2021 Apr 26;11(1):8891. doi: 10.1038/s41598-021-87813-8

17. Miller RE, Ishihara S, Tran PB, et al. An aggrecan fragment drives osteoarthritis pain through Toll-like receptor 2. JCI Insight. 2018 Mar 22;3(6):e95704. doi: 10.1172/jci.insight.95704

18. Liu YX, Wang GD, Wang X, et al. Effects of TLR-2/NF-kB signaling pathway on the occurrence of degenerative knee osteoarthritis: an in vivo and in vitro study. Oncotarget. 2017 Jun 13;8(24):38602-17. doi: 10.18632/oncotar-get.16199

19. Liu X, Cai HX, Cao PY, et al. TLR4 contributes to the damage of cartilage and subchondral bone in discectomy-induced TMJOA mice. J Cell Mol Med. 2020 Oct;24(19):11489-99. doi: 10.1111/jcmm.15763. Epub 2020 Sep 11.

20. Kalaitzoglou E, Lopes EBP, Fu Y, et al. TLR4 Promotes and DAP12 Limits Obesity-Induced Osteoarthritis in Aged Female Mice. JBMR Plus. 2018 Oct 4;3(4):e10079. doi: 10.1002/jbm4.10079. eCollection 2019 Apr.

21. Barreto G, Senturk B, Colombo L, et al. Lumican is upregulated in osteoarthritis and contributes to TLR4-induced pro-inflammatory activation of cartilage degradation and macrophage polarization. Osteoarthritis Cartilage. 2020 Jan;28(1):92-101. doi: 10.1016/j.joca.2019.10.011. Epub 2019 Nov 9.

22. Murata K, Uchida K, Takano S, et al. Osteoarthritis patients with high haemoglobin A1c have increased Toll-like receptor 4 and matrix metalloprotease-13 expression in the synovium. Diabetes Metab Syndr Obes. 2019 Jul 16;12:1151-9. doi: 10.2147/DMSO.S209677. eCollection 2019.

23. Liang H, Wang H, Luo L, et al. Toll-like receptor 4 promotes high glucose-induced catabolic and inflammatory responses in chondrocytes in an NF-kB-dependent manner. Life Sci. 2019 Jul 1;228:258-65. doi: 10.1016/j.lfs.2019.04.011. Epub 2019 Apr 4.

24. Wang B, Li J, Tian F. Downregulation of lncRNA SNHG14 attenuates osteoarthritis by inhibiting FSTL-1 mediated NLRP3 and TLR4/NF-kB pathway through miR-124-3p. Life Sci. 2021 Apr 1;270:119143. doi: 10.1016/j.lfs.2021.119143. Epub 2021 Feb 1.

25. Elmazoglu Z, Aydin Bek Z, Saribas SG, et al. S-Allylcysteine Inhibits Chondrocyte Inflammation to Reduce Human Osteoarthritis via Targeting RAGE, TLR4, JNK and Nrf2 Signaling: Comparison with Colchicine. Biochem Cell Biol. 2021 Apr 30. doi: 10.1139/bcb-2021-0004

26. Qi W, Chen Y, Sun S, et al. Inhibiting TLR4 signaling by linarin for preventing inflammatory response in osteoarthritis. Aging (Albany NY). 2021 Feb 1;13(4):5369-82. doi: 10.18632/aging.202469. Epub 2021 Feb 1.

27. Wang Q, Zhuang D, Feng W, et al. Fraxetin inhibits interleukin-1 в-induced apoptosis, inflammation, and matrix degradation in chondrocytes and protects rat cartilage in vivo. Saudi Pharm J.2020 Dec;28(12):1499-506. doi: 10.1016/j.jsps.2020.09.016. Epub 2020 Sep 25.

28. Tsuno H, Arito M, Suematsu N, et al. A proteomic analysis of serum-derived exosomes in rheumatoid arthritis. BMC Rheumatol. 2018 Nov 27;2:35. doi: 10.1186/s41927-018-0041-8. eCollection 2018.

29. Han W, Chen X, Wang X, et al. TLR-4, TLR-5 and IRF4 are diagnostic markers of knee osteoarthritis in the middle-aged and elderly patients and related to disease activity and inflammatory factors. Exp Ther Med. 2020 Aug;20(2):1291-8. doi: 10.3892/etm.2020.8825. Epub 2020 May 30.

30. Qiu B, Xu X, Yi P, Hao Y. Curcumin reinforces MSC-derived exosomes in attenuating osteoarthritis via modulating the miR-124/NF-kB and miR-143/ROCK1/TLR9 signalling pathways. J Cell Mol Med. 2020 Sep;24(18):10855-65. doi: 10.1111/jcmm.15714. Epub 2020 Aug 9.

31. Hamasaki M, Terkawi MA, Onodera T, et al. Transcriptional profiling of murine macrophages stimulated with cartilage fragments revealed a strategy for treatment of progressive osteoarthritis. Sci Rep. 2020 May 5;10(1):7558. doi: 10.1038/s41598-020-64515-1

32. Hu S, Wang J, Xu Y, et al. Anti-inflammation effects of fucosylated chondroitin sulphate from Acaudina molpadioides by altering gut microbiota in obese mice. Food Funct. 2019 Mar 20;10(3):1736-46. doi: 10.1039/c8fo02364f

33. Korotkyi O, Huet A, Dvorshchenko K, et al. Probiotic Composition and Chondroitin Sulfate Regulate TLR-2/4-Mediated NF-kB Inflammatory Pathway and Cartilage Metabolism in Experimental Osteoarthritis. Probiotics Antimicrob Proteins. 2021 Jan 18. doi: 10.1007/s12602-020-09735-7

34. Jin M, Iwamoto T, Yamada K, et al. Effects of chondroitin sulfate and its oligosaccharides on toll-like receptor-mediated IL-6 secretion by macrophage-like J774.1 cells. Biosci Biotechnol Biochem. 2011;75(7):1283-9. doi: 10.1271/bbb.110055. Epub 2011 Jul 7.

35. Jin M, Iwamoto T, Yamada K, et al. Disaccharide derived from chondroitin sulfate A suppressed CpG-induced IL-6 secretion in macrophage-like J774.1 cells. Cytokine. 2010 Jul;51(1):53-9. doi: 10.1016/j.cyto.2010.03.002. Epub 2010 Mar 29.

36. Facchini FA, Zaffaroni L, Minotti A, et al. Structure-Activity Relationship in Monosaccharide-Based Toll-Like Receptor 4 (TLR4) Antagonists. J Med Chem. 2018 Apr 12;61(7):2895-909. doi: 10.1021/acs.jmed-chem.7b01803. Epub 2018 Mar 12.

37. Iannotta M, Belardo C, Trotta MC, et al. N-palmitoyl-D-glucosamine, a Natural Monosaccharide-Based Glycolipid, Inhibits TLR4 and Prevents LPS-Induced Inflammation and Neuropathic Pain in Mice. Int J Mol Sci. 2021 Feb 2;22(3):1491. doi: 10.3390/ijms22031491

38. Громова ОА, Торшин ИЮ, Зайчик БЦ и др. О различиях в стандартизации лекарственных препаратов на основе экстрактов хондроитина сульфата. ФАРМАКОЭКОНОМИКА. Современная фармакоэкономика и фармакоэпидемиология. 2021;14(1):40-52. doi: 10.17749/2070-4909/farmakoekonomika.2021.083.

39. Торшин ИЮ, Лила АМ, Наумов АВ и др. Метаанализ клинических исследований эффективности лечения остеоартита препаратом Хондрогард. ФАРМАКОЭКОНОМИКА. Современная фармакоэкономика и фармакоэпидемиология. 2020;13(4):18-29. doi: 10.17749/2070-4909/farmakoekonomika.2020.066.