КУЛЬТУРА ФИБРОБЛАСТОПОДОБНЫХ СИНОВИАЛЬНЫХ КЛЕТОК БОЛЬНЫХ РЕВМАТОИДНЫМ АРТРИТОМ: СВОЙСТВА И ВОЗМОЖНОСТИ

В обзоре представлены данные литературы о структуре синовиальной оболочки у здоровых людей и больных ревматоидным артритом in vivo, рассмотрены особенности фибробластоподобных синовиальных клеток больных ревматоидным артритом (РА) в культуре in vitro, включая морфологию, фенотип, функциональные свойства клеток культуры. Описан стандартный протокол культивирования ФСК in vitro. Подчеркивается, что ФСК характеризуются автономностью функционирования, способностью к инвазивному росту, способностью к миграции в различные, в том числе интактные, суставы, лежащей в основе полиартикулярного поражения при ревматоидном артрите (РА). Особое внимание посвящено характеристике стабильного фенотипа фибробластоподобных синовиальных клеток как результату эпигенетических нарушений: изменениям метилирования ДНК, ацетилирования гистонов, функции микроРНК. ФСК больных РА характеризуются стабильным, возникающим in vivo и сохраняющимся после неоднократных пассажей in vitro тотальным гипометилированием ДНК. При РА ряд промоторов специфических генов (в частности CXCL12, IL-6), играющих существенную роль в патогенезе РА, находится в состоянии гипометилирования. В то же время в ФСК выявляются и гиперметилированные промоторы некоторых генов (гена рецептора смерти 3). Важным механизмом персистенции воспаления при РА является повышение ацетилирования гистонов в промоторах генов, ответственных за продукцию провоспалительных белков, в частности ММP1. Изменения в ацетилировании гистонов в ФСК связаны с высоким уровнем убиквитин-подобного белка SUMO-1 и параллельным снижением уровня специфической протеазы SENP1. Роль ацетилирования гистонов в патогенезе РА подтверждается эффективностью ингибитора деацетилазы гистонов трихостатина A при коллаген-индуцированном артрите у мышей. Содержание микроРНК-155 и микроРНК-146а стабильно повышено в культуре ФСК, так же как и в синовиальной ткани, синовиальной жидкости и МНК ПК пациентов с РА. Экспрессия микроРНК-124а снижена в ФСК от больных РА по сравнению с ОФСК. Экспрессия микроРНК-203 в ФСК также постоянно повышена. Уровень микроРНК-203 повышен в ФСК не только пациентов с многолетним РА по сравнению с остеоартритом и нормальными ФСК, а также у пациентов с ранним РА.

Заключается, что фибробластоподобные синовиальные клетки являются ключевыми клеточными элементами, участвующими в патогенезе ревматоидного артрита, и исследования, посвященные нарушениям их эпигенетической регуляции, находятся в самом начале своего пути. Ферменты и молекулярные комплексы, участвующие в этих процессах, являются потенциальными терапевтическими мишенями.

1. Павлова В.Н. Синовиальная среда суставов. М.: Медицина, 1980. 294 с. [Pavlova V. N. Synovial fluid of joints]. Мoscow: Meditsina, 1980. 294 p.

2. Раденска-Лоповок С.Г. Биопсия синовиальной оболочки как метод оценки эффективности терапии ревматоидного артрита: подход к стандартизации клинических испытаний // Современная ревматология, 2011. №4. С. 31-34. [Radenska-Lopovok S.G. Synovial membrane biopsy as a method for evaluating the efficiency of therapy for rheumatoid arthritis: approach to standardizing clinical trials. Sovremennaya revmatologiya = Modern Rheumatology, 2011, no. 4, pp. 31-34. (In Russ.)]

3. Чумаков П.М. Белок р53 и его универсальные функции в многоклеточном организме // Успехи биологической химии, 2007. Т. 47. С. 3-52. [Chumakov P. M. Versatile Functions of p53 protein in multicellular Organisms. Uspekhi biologicheskoy khimii = Advances Biological Chemistry, 2007, Vol. 47, pp. 3-52. (In Russ.)]

4. Alvaro-Gracia J.M., Zvaifler N.J., Brown C.B., Kaushansky K., Firestein G.S. Cytokines in chronic inflammatory arthritis. VI. Analysis of the synovial cells involved in granulocyte-macrophage colony-stimulating factor production and gene expression in rheumatoid arthritis and its regulation by IL-1 and tumor necrosis factoralpha. J. Immunol., 1991, Vol. 146, no. 10, pp. 3365-3371.

5. Alvaro-Gracia J.M., Zvaifler N.J., Firestein G.S. Cytokines in chronic inflammatory arthritis. V. Mutual antagonism between interferon-gamma and tumor necrosis factor-alpha on HLA-DR expression, proliferation, collagenase production, and granulocyte macrophage colony-stimulating factor production by rheumatoid arthritis synoviocytes. J. Clin. Invest., 1990, Vol. 86, no. 6, pp. 1790-1798.

6. Arend W.P., Dayer J.M. Cytokines and cytokine inhibitors or antagonists in rheumatoid arthritis. Arthritis Rheum., 1990, Vol. 33, pp. 305-315.

7. Bartok B., Firestein G.S. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol. Rev., 2010, Vol. 233, no. 1, pp. 233-255.

8. Boyle W.J., Simonet W.S., Lacey D.L. Osteoclast differentiation and activation. Nature, 2003, Vol. 423, pp. 337-342.

9. Brackertz D., Hagmann J., Kueppers F. Proteinase inhibitors in rheumatoid arthtritis. Ann. Rheum. Dis., 1975, Vol. 34, pp. 225-230.

10. Bromley M., Woolley D.E. Chondrocytes and osteoclasts at subchondral sites of erosions in the rheumatoid joint. Arthitis Rheum., 1984, Vol. 27, pp. 968-975.

11. Burmester G.R., Jahn B., Rohwer P., Zacher J., Winchester R.J., Kalden J.R. Differential expression of Ia antigens by rheumatoid synovial lining cells. J. Clin. Invest., 1987, Vol. 80, pp. 595-604.

12. Close D.R. Matrix metalloproteinase inhibitors in rheumatic diseases. Ann. Rheum. Dis., 2001, Vol. 60, pp. iii62-iii67.

13. Collin-Osdoby P., Rothe L., Anderson F., Nelson M., Maloney W., Osdoby P. Receptor activator of NF-κB and osteoprotegerin expression by human microvascular endothelial cells, regulation by inflammatory cytokines, and role in human osteoclastogenesis. J. Biol. Chem., 2001, Vol. 276, pp. 20659-20672.

14. Dayer J.M., Beutler B., Cerami A. Cachectin/tumor necrosis factor stimulates collagenase and prostaglandin E2 production by human synovial cells and dermal fibroblasts. J. Exp. Med., 1985, Vol. 162, pp. 2163-2168.

15. Dolhain R.J., van der Heiden A.N., ter Haar N.T., Breedveld F.C., Miltenburg A.M. Shift toward T lymphocytes with a T helper 1 cytokine-secretion profile in the joints of patients with rheumatoid arthritis. Arthritis Rheum., 1996, Vol. 39, no. 12, pp. 1961-1969.

16. Edwards J.C., Willoughby D.A. Demonstration of bone marrow derived cells in synovial lining by means of giant intracellular granules as genetic markers. Ann. Rheum. Dis., 1982, Vol. 41, pp. 177-182.

17. Feldges Stanczyk J., Karouzakis E., Jungel A., Ospelt C., Kolling C., Michel Beat A., Gay R.E. Mir-203 Regulates the Expression of IL-6 and Matrix Metalloproteinase(MMP)-1 in RA Synovial Fibroblasts [abstract]. Arthritis Rheum., 2009, Vol. 60, 1893 p.

18. Feldmann M., Brennan F.M., Maini R.N. Role of cytokines in rheumatoid arthritis. Annu. Rev. Immunol., 1996, Vol. 14, pp. 397-440.

19. Firestein G.S. Etiology and pathogenesis of rheumatoid arthritis. In: Firestein G.S., Budd R.C., Harris T., McInnes I.B., Ruddy S., Sergent J.S., editors. Kelly’s Textbook of Rheumatology. 8. Philadelphia, PA: Saunders Elsevier, 2009, pp. 1035-1086.

20. Firestein G.S., Gary S. Invasive fibroblast-like synoviocytes in rheumatoid arthritis. Passive responders or transformed aggressors? Arthritis Rheum., 1996, Vol. 39, pp. 1781-1790.

21. Firestein G.S., Alvaro-Garcia J.S., Maki R. Quantitative analysis of cytokine gene expression in rheumatoid arthritis. J. Immunol., 1990, Vol. 144, pp. 3347-3353.

22. Firestein G.S., Nguyen K., Aupperle K.R., Yeo M., Boyle D.L., Zvaifler N.J. Apoptosis in rheumatoid arthritis: p53 overexpression in rheumatoid arthritis synovium. Am. J. Pathol., 1996, Vol. 149, pp. 2143-2151.

23. Fu L.H., Ma C.L., Cong B., Li S.J., Chen H.Y., Zhang J.G. Hypomethylation of proximal CpG motif of interleukin-10 promoter regulates its expression in human rheumatoid arthritis. Acta. Pharmacol. Sin., 2011, Vol. 32, pp. 1373-1380.

24. Grabiec A.M., Krausz S., de Jager W., Burakowski T., Groot D., Sanders M.E., Prakken B.J., Maslinski W., Eldering E., Tak P.P., Reedquist K.A. Histone deacetylase inhibitors suppress inflammatory activation of rheumatoid arthritis patient synovial macrophages and tissue. J. Immunol., 2010, Vol. 184, pp. 2718-2728.

25. Grabiec A.M., Tak P.P., Reedquist K.A. Targeting histone deacetylase activity in rheumatoid arthritis and asthma as prototypes of inflammatory disease: should we keep our HATs on? Arthritis Res. Ther., 2008, Vol. 10, p. 226.

26. Gravallese E.M., Manning C., Tsay A., Naito A., Pan C., Amento E., Goldring S.R. Synovial tissue in rheumatoid arthritis is a source of osteoclast differentiation factor. Arthritis Rheum., 2000, Vol. 43, pp. 250-258.

27. Green D.R., Knight R.A., Melino G., Finazzi-Agro A., Orrenius S. Ten years of publication in cell death. Cell Death Differ., 2004, Vol. 11, pp. 2-3.

28. Hadler N.M., Johnson A.M., Spitznagel J.K., Quinet R.J. Protease inhibitors in inflammatory synovial effusions. Ann. Rheum. Dis., 1981, Vol. 40, pp. 55-59.

29. Hamann J., Wishaupt J.O., van Lier R.A., Smeets T.J., Breedveld F.C., Tak P.P. Expression of the activation antigen CD97 and its ligand CD55 in rheumatoid synovial tissue. Arthritis Rheum., 1999, Vol. 42, pp. 650-658.

30. Hitchon C.A., El-Gabalawy H.S. The synovium in rheumatoid arthritis. Open Rheumatol. J., 2011, Vol. 5, pp. 107-114.

31. Huber L.C., Brock M., Hemmatazad H., Giger O.T., Moritz F., Trenkmann M., Distler J.H. W., Gay R.E., Kolling C., Moch H., Michel B.A., Gay S., Distler O., Jungel A. Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients. Arthritis Rheum., 2007, Vol. 56, pp. 1087-1093.

32. Huber L.C., Distler O., Tarner I., Gay R.E., Gay S., Pap T. Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology. Oxford, 2006, Vol. 45, pp. 669-675.

33. Ishida K., Kobayashi T., Ito S., Komatsu Y., Yokoyama T., Okada M., Abe A., Murasawa A., Yoshie H. Interleukin-6 gene promoter methylation in rheumatoid arthritis and chronic periodontitis. J. Periodontol, 2012, Vol. 83, pp. 917-925.

34. Isomaki P., Punnonen J. Pro- and anti-inflammatory cytokines in rheumatoid arthritis. Ann. Med., 1997, Vol. 29, pp. 499-507.

35. Iwanaga T., Shikichi M., Kitamura H., Yanase H., Nozawa-Inoue K. Morphology and functional roles of synoviocytes in the joint. Arch. Histol. Cytol., 2000, Vol. 63, no. 1, pp. 17-31.

36. Jungel A., Baresova V., Ospelt C., Simmen B.R., Michel B.A., Gay R.E., Gay S., Seemayer C.A., Neidhart M. Trichostatin A sensitises rheumatoid arthritis synovial fibroblasts for TRAIL-induced apoptosis. Ann. Rheum. Dis., 2006, Vol. 65, pp. 910-912.

37. Kanbe K., Takemura T., Takeuchi K., Chen Q., Takagishi K., Inoue K. Synovectomy reduces stromal-cellderived factor-1 (SDF-1) which is involved in the destruction of cartilage in osteoarthritis and rheumatoid arthritis. J. Bone Joint. Surg. Br., 2004, Vol. 86, pp. 296-300.

38. Karouzakis E., Gay R.E., Michel B.A., Gay S., Neidhart M. DNA hypomethylation in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum., 2009, Vol. 60, pp. 3613-3622.

39. Karouzakis E., Rengel Y., Jungel A., Kolling C., Gay R.E., Michel B.A., Tak P.P., Gay S., Neidhart M., Ospelt C. DNA methylation regulates the expression of CXCL12 in rheumatoid arthritis synovial fibroblasts. Genes Immun., 2011, Vol. 12, pp. 643-652.

40. Kawabata T., Nishida K., Takasugi K., Ogawa H., Sada K., Kadota Y., Inagaki J., Hirohata S., Ninomiya Y., Makino H. Increased activity and expression of histone deacetylase 1 in relation to tumor necrosis factor-alpha in synovial tissue of rheumatoid arthritis. Arthritis Res. Ther., 2010, Vol. 12, R133.

41. Kobayashi I., Ziff M. Electron microscopic studies of lymphoid cells in the rheumatoid synovial membrane. Arthritis Rheum., 1973, Vol. 16, pp. 471-486.

42. Korb A., Pavenstädt H., Pap T. Cell death in rheumatoid arthritis. Apoptosis, 2009, Vol. 14, no. 4, pp. 447-454.

43. Kurowska M., Rudnicka W., Kontny E., Janicka I., Chorazy M., Kowalczewski J., Ziółkowska M., FerrariLacraz S., Strom T.B., Maśliński W. Fibroblast-like synoviocytes from rheumatoid arthritis patients express functional IL-15 receptor complex: endogenous IL-15 in autocrine fashion enhances cell proliferation and expression of Bclx(L) and Bcl-2. J. Immunol,. 2002, Vol. 169, pp. 1760-1767.

44. Lacey D.L., Timms E., Tan H-L., Kelley M.J., Dunstan C.R., Burgess T., Elliot R., Colombero A., Elliot G., Scully S., Hsu H., Sullivan J., Hawkins N., Davy E., Capparelli C., Eli A., Qian Y.X., Kaufman S., Sarosi I., Shalhoub V., Senaldi G., Guo J., Delaney J., Boyle W.J. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell, 1998, Vol. 93, pp. 165-176.

45. Lee D.M., Kiener H.P., Agarwal S.K., Noss E.H., Watts G.F., Chisaka O., Takeichi M., Brenner M.B. Cadherin-11 in synovial lining formation and pathology in arthritis. Science, 2007, Vol. 315, pp. 1006-1010.

46. Lefèvre S., Knedla A., Tennie C., Kampmann A., Wunrau C., Dinser R., Korb A., Schnäker E.M., Tarner I.H., Robbins P.D., Evans C.H., Stürz H., Steinmeyer J., Gay S., Schölmerich J., Pap T., Müller-Ladner U., Neumann E. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nat. Med., 2009, Vol. 15, no. 12, pp. 1414-1420.

47. Lewis B.P., Shih I.H., Jones-Rhoades M.W., Bartel D.P., Burge C.B. Prediction of mammalian microRNA targets. Cell, 2003, Vol. 115, pp. 787-798.

48. Lin H.S., Hu C.Y., Chan H.Y., Liew Y.Y., Huang H.P., Lepescheux L., Bastianelli E., Baron R., Rawadi G., Clément-Lacroix P. Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents. Br. J. Pharmacol., 2007, Vol. 150, pp. 862-872.

49. Lin S.Y., Hsieh S.C., Lin Y.C., Lee C.N., Tsai M.H., Lai L.C., Chuang E.Y., Chen P.C., Hung C.C., Chen L.Y., Hsieh W.S., Niu D.M., Su Y.N., Ho H.N. A whole genome methylation analysis of systemic lupus erythematosus: hypomethylation of the IL10 and IL1R2 promoters is associated with disease activity. Genes Immun., 2012, Vol. 13, pp. 214-220.

50. Liu H., Pope R.M. Apoptosis in rheumatoid arthritis: friend or foe. Rheum. Dis. Clin. North Am., 2004, Vol. 30, pp. 603-625.

51. Maciejewska-Rodrigues H., Karouzakis E., Strietholt S., Hemmatazad H., Neidhart M., Ospelt C., Gay R.E., Michel B.A., Pap T., Gay S., Jüngel A. Epigenetics and rheumatoid arthritis: the role of SENP1 in the regulation of MMP-1 expression. J. Autoimmun., 2010, Vol. 35, pp. 15-22.

52. Mapp P.I., Revell P.A. Ultrastructural characterisation of macrophages (type A cells) in the synovial lining. Rheumatol. Int., 1988, Vol. 8, no. 4, pp. 171-176.

53. Martel-Pelletier J., Pelletier J.P., Fahmi H. Cyclooxygenase-2 and prostaglandins in articular tissues. Seminars in Arthritis and Rheumatism, 2003, Vol. 33, no. 3, pp. 155-167.

54. Matsumoto S., Müller-Ladner U., Gay R.E., Nishioka K., Gay S. Ultrastructural demonstration of apoptosis, Fas and Bcl-2 expression of rheumatoid synovial fibroblasts. J. Rheumatol., 1996, Vol. 23, pp. 1345-1352.

55. Mitsiades C.S., Mitsiades N.S, McMullan C.J., Poulaki V., Shringarpure R., Hideshima T., Akiyama M., Chauhan D., Munshi N., Gu X., Bailey C., Joseph M., Libermann T.A., Richon V.M., Marks P.A., Anderson K.C. Transcriptional signature of histone deacetylase inhibition in multiple myeloma: biological and clinical implications. Proc. Natl. Acad. Sci. U S A, 2004, Vol. 101, pp. 540-545.

56. Morales-Ducret J., Wayner E., Elices M.J., Alvaro-Gracia J.M., Zvaifler N.J., Firestein G.S. Alpha 4/beta 1 integrin (VLA-4) ligands in arthritis. Vascular cell adhesion molecule-1 expression in synovium and on fibroblastlike synoviocytes. J. Immunol., 1992, Vol. 149, no. 4, pp. 1424-1431.

57. Müller-Ladner U., Kriegsmann J., Franklin B.N., Matsumoto S., Geiler T., Gay R.E., Gay S. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. Am. J. Pathol., 1996, Vol. 149, pp. 1607-1615.

58. Murata K., Yoshitomi H., Tanida S., Ishikawa M., Nishitani K., Ito H., Nakamura T. Plasma and synovial fluid microRNAs as potential biomarkers of rheumatoid arthritis and osteoarthritis. Arthritis Res. Ther., 2010, Vol. 12, R86.

59. Nakamachi Y., Kawano S., Takenokuchi M., Nishimura K., Sakai Y., Chin T., Saura R., Kurosaka M., Kumagai S. MicroRNA-124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum., 2009, Vol. 60, pp. 1294-1304.

60. Nakamura T., Kukita T., Shobuike T., Nagata K., Wu Z., Ogawa K., Hotokebuchi T., Kohashi O., Kukita A. Inhibition of histone deacetylase suppresses osteoclastogenesis and bone destruction by inducing IFN-beta production. J. Immunol., 2005, Vol. 175, pp. 5809-5816.

61. Nakasa T., Miyaki S., Okubo A., Hashimoto M., Nishida K., Ochi M., Asahara H. Expression of microRNA-146 in rheumatoid arthritis synovial tissue. Arthritis Rheum., 2008, Vol. 58, pp. 1284-1292.

62. Nasu Y., Nishida K., Miyazawa S., Komiyama T., Kadota Y., Abe N., Yoshida A., Hirohata S., Ohtsuka A., Ozaki T. Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model. Osteoarthritis and Cartilage, 2008, Vol. 16, pp. 723-732.

63. Neidhart M., Rethage J., Kuchen S., Künzler P., Crowl R.M., Billingham M.E. Retrotransposable L1 elements expressed in rheumatoid arthritis synovial tissue: association with genomic DNA hypomethylation and influence on gene expression. Arthritis Rheum., 2000, Vol. 43, pp. 2634-2647.

64. Nile C.J., Read R.C., Akil M., Duff G.W., Wilson A.G. Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum., 2008, Vol. 58, pp. 2686-2693.

65. Nishida K., Komiyama T., Miyazawa S., Shen Z.N., Furumatsu T., Doi H., Yoshida A., Yamana J., Yamamura M., Ninomiya Y., Inoue H., Asahara H. Histone deacetylase inhibitor suppression of autoantibodymediated arthritis in mice via regulation of p16INK4a and p21(WAF1/Cip1) expression. Arthritis Rheum., 2004, Vol. 50, no. 10, pp. 3365-3376.

66. Nishioka K., Hasunuma T., Kato T., Sumida T. ,Kobata T. Apoptosis in rheumatoid arthritis: A novel pathway in the regulation of synovial tissue. Arthritis Rheum., 1998, Vol. 41, pp. 1-9.

67. Ospelt C., Reedquist K.A., Gay S., Tak P.P. Inflammatory memories: is epigenetics the missing link to persistent stromal cell activation in rheumatoid arthritis? Autoimmun. Rev., 2011, Vol. 10, no. 9, pp. 519-524.

68. Pauley K.M., Satoh M., Chan A.L., Bubb M.R., Reeves W.H., Chan E.K. Upregulated miR-146a expression in peripheral blood mononuclear cells from rheumatoid arthritis patients. Arthritis Res. Ther., 2008, Vol. 10, R101.

69. Perlman H., Georganas C., Pagliari L.J., Koch A.E., Haines K., Pope R.M. Bcl-2 expression in synovial fibroblasts is essential for maintaining mitochondrial homeostasis and cell viability. J. Immunol., 2000, Vol. 164, pp. 5227-5235.

70. Pitsillides A.A., Wilkinson L.S., Mehdizadeh S., Bayliss M.T., Edwards J.C. Uridine diphosphoglucose dehydrogenase activity in normal and rheumatoid synovium: the description of a specialized synovial lining cell. Int. J. Exp. Pathol., 1993, Vol. 74, no. 1, pp. 27-34.

71. Redlich K., Hayer S., Ricci R., David J.P., Tohidast-Akrad M., Kollias G., Steiner G., Smolen J.S., Wagner E.F., Schett G. Osteoclasts are essential for TNF-α-mediated joint destruction. J. Clin. Invest., 2002, Vol. 110, pp. 1419-1427.

72. Rosengren S., Boyle D.L., Firestein G.S. Acquisition, culture, and phenotyping of synovial fibroblasts. Methods Mol. Med., 2007, Vol. 135, pp. 365-375.

73. Schett G., Hayer S., Zwerina J., Redlich K., Smolen J.S. Mechanisms of disease: the link between RANKL and arthritic bone disease. Nat. Clin. Pract. Rheumatol., 2005, Vol. 1, pp. 47-54.

74. Schulze-Koops H., Kalden J.R. The balance of Th1/Th2 cytokines in rheumatoid arthritis. Best Pract. Res. Clin. Rheumatol., 2001, Vol. 15, pp. 677-691.

75. Shirinsky I.V., Shirinsky V. S. Cytokines in Rheumatoid Arthritis. In: Preedy V.R., Hunter R.J., editors. Science publishers Jersey, British Isles, Enfield, New Hampshire: Cytokines, 2011, pp. 403-417.

76. Stanczyk J., Ospelt C., Karouzakis E., Filer A., Raza K., Kolling C., Gay R., Buckley C.D., Tak P.P., Gay S., Kyburz D. Altered expression of microRNA-203 in rheumatoid arthritis synovial fibroblasts and its role in fibroblast activation. Arthritis Rheum., 2011, Vol. 63, pp. 373-381.

77. Stanczyk J., Pedrioli D.M., Brentano F., Sanchez-Pernaute O., Kolling C., Gay R.E., Detmar M., Gay S., Kyburz D. Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum., 2008, Vol. 58, pp. 1001-1009.

78. Sterner D.E., Berger S.L. Acetylation of histones and transcription-related factors. Microbiol. Mol. Biol. Rev., 2000, Vol. 64, no. 2, pp. 435-459.

79. Strahl B.D., Allis C.D. The language of covalent histone modifications. Nature, 2000, Vol. 403, pp. 41-45.

80. Sun Y., Cheung H.S. p53, proto-oncogene and rheumatoid arthritis. Semin. Arthr. Rheum., 2002, Vol. 31, no. 5, pp. 299-310.

81. Szyf M. Epigenetics, DNA methylation, and chromatin modifying drugs. Annu. Rev. Pharmacol. Toxicol., 2009, Vol. 49, pp. 243-263.

82. Takami N., Osawa K., Miura Y., Komai K., Taniguchi M., Shiraishi M., Sato K., Iguchi T., Shiozawa K., Hashiramoto A., Shiozawa S. Hypermethylated promoter region of DR3, the death receptor 3 gene, in rheumatoid arthritis synovial cells. Arthritis Rheum., 2006, Vol. 54, pp. 779-787.

83. Takayanagi H., Iizuka H., Juji T., Nakagawa T., Yamamoto A., Miyazaki T., Koshihara Y., Oda H., Nakamura K., Tanaka S. Involvement of receptor activator of nuclear factor kappaB ligand/osteoclast differentiation factor in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Arthritis Rheum., 2000, Vol. 43, pp. 259-269.

84. Takemura S., Braun A., Crowson C., Kurtin P.J., Cofield R.H., O’Fallon W.M., Goronzy J.J., Weyand C.M. Lymphoid neogenesis in rheumatoid synovitis. J. Immunol., 2001, Vol. 167, pp. 1072-1080.

85. Valencia X., Higgins J.M., Kiener H.P., Lee D.M., Podrebarac T.A., Dascher C.C., Watts G.F., Mizoguchi E., Simmons B., Patel D.D., Bhan A.K., Brenner M.B. Cadherin-11 provides specific cellular adhesion between fibroblast-like synoviocytes. J. Exp. Med., 2004, Vol. 200, pp. 1673-1679.

86. van Oosterhout M., Levarht E.W., Sont J.K., Huizinga T.W., Toes R.E., van Laar J.M. Clinical efficacy of infliximab plus methotrexate in DMARD naive and DMARD refractory rheumatoid arthritis is associated with decreased synovial expression of TNF alpha and IL18 but not CXCL12. Ann. Rheum. Dis., 2005, Vol. 64, pp. 537-543.

87. Vervoordeldonk M.J., Tak P.P. Cytokines in rheumatoid arthritis. Curr. Rheumatol. Rep., 2002, Vol. 4, pp. 208-217.

88. Weidauer E., Yasuda Y., Biswal B.K., Cherny M., James M.N., Brömme D. Effects of disease-modifying antirheumatic drugs (DMARDs) on the activities of rheumatoid arthritis-associated cathepsins K and S. Biol. Chem., 2007, Vol. 388, no. 3, pp. 331-336.

89. Yamanishi Y., Boyle D.L., Rosengren S., Green D.R., Zvaifler N.J., Firestein G.S. Regional analysis of p53 mutations in rheumatoid arthritis synovium. Proc. Natl. Acad. Sci. USA., 2002, Vol. 99, no. 15, pp. 10025-10030.

90. Yasuda H., Shima N., Nakagawa N., Yamaguchi K., Kinosaki M., Mochizuki S-I., Tomoyasu A., Yano K., Goto M., Murakami A., Tsuda E., Morinaga T., Higashio K., Udagawa N., Takahashi N., Suda T. Osteoclast differentiation factor is a ligand for osteoprotegerin/ osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl. Acad. Sci. USA., 1998, Vol. 95, pp. 3597-3602.

91. Young C.L., Adamson T.C., Vaughan J.H., Fox R.I. Immunologic characterization of synovial membrane lymphocytes in rheumatoid arthritis. Arthritis Rheum., 1984, Vol. 27, pp. 32-39.

92. Zimmermann T., Kunisch E., Pfeiffer R., Hirth A., Stahl H.D., Sack U., Laube A., Liesaus E., Roth A., Palombo-Kinne E., Emmrich F., Kinne R.W. Isolation and characterization of rheumatoid arthritis synovial fibroblasts from primary culture – primary culture cells markedly differ from fourth-passage cells. Arthritis Res., 2001, Vol. 3, pp. 72-76.