The Korean journal of internal medicine

The Korean Association of Internal Medicine (대한내과학회)
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Tocotrienol regulates osteoclastogenesis in rheumatoid arthritis

  • Kim, Kyoung-Woon (Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Kim, Bo-Mi (Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Won, Ji-Yeon (Convergent Research Consortium for Immunologic Disease, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea) ;
  • Min, Hong Ki (Division of Rheumatology, Department of Internal Medicine, Research Institute of Medical Science, Konkuk University School of Medicine) ;
  • Lee, Seoung Joon (Department of Orthopedic Surgery, Konkuk University School of Medicine) ;
  • Lee, Sang-Heon (Division of Rheumatology, Department of Internal Medicine, Research Institute of Medical Science, Konkuk University School of Medicine) ;
  • Kim, Hae-Rim (Division of Rheumatology, Department of Internal Medicine, Research Institute of Medical Science, Konkuk University School of Medicine)
  • Received : 2019.11.05
  • Accepted : 2019.12.30
  • Published : 2021.03.01
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Abstract

Background/Aims: The present study aimed to investigate whether tocotrienol regulates interleukin 17 (IL-17)-induced osteoclastogenesis in rheumatoid arthritis (RA). Methods: We evaluated the effect of tocotrienol on IL-17-induced receptor activator of nuclear factor kappa B ligand (RANKL) production using RA fibroblast-like synoviocyte (FLS), together with real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Osteoclast differentiation was confirmed after culturing IL-17-treated RA FLS and Th17 cells with tocotrienol and monocytes. We analyzed the suppressive effect of tocotrienol on Th17 cells percentage or Th17-cytokine levels among peripheral blood mononuclear cells using flow cytometry. Results: We found that IL-17 stimulated FLS to produce RANKL and tocotrienol decreased this IL-17-induced RANKL production. Tocotrienol decreased the IL-17-induced activation of mammalian target of rapamycin, extracellular signal-regulated kinase, and inhibitor of kappa B-alpha. When monocytes were incubated with IL-17, RANKL, IL-17-treated FLS or Th17 cells, osteoclasts were differentiated and tocotrienol decreased this osteoclast differentiation. Tocotrienol reduced Th17 cell differentiation and the production of IL-17 and sRANKL; however, tocotrienol did not affect Treg cell differentiation. Conclusions: Tocotrienol inhibited IL-17- activated RANKL production in RA FLS and IL-17-activated osteoclast formation. In addition, tocotrienol reduced Th17 differentiation. Therefore, tocotrienol could be a new therapeutic choice to treat bone destructive processes in RA.

Keywords

Acknowledgement

This research was supported by a grant of the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology, Republic of Korea (NRF-2018R1D1A1A02050982) and the Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science, ICT & Future Planning (NRF-2018R1A2B2006820).

References

  1. Harris ED Jr. Rheumatoid arthritis. Pathophysiology and implications for therapy. N Engl J Med 1990;322:1277-1289. https://doi.org/10.1056/NEJM199005033221805
  2. Rosen CJ, Bouxsein ML. Mechanisms of disease: is osteoporosis the obesity of bone? Nat Clin Pract Rheumatol 2006;2:35-43. https://doi.org/10.1038/ncprheum0070
  3. Bartok B, Firestein GS. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev 2010;233:233-255. https://doi.org/10.1111/j.0105-2896.2009.00859.x
  4. Gravallese EM. Bone destruction in arthritis. Ann Rheum Dis 2002;61 Suppl 2:ii84-ii86. https://doi.org/10.1136/ard.61.suppl_2.ii84
  5. Lubberts E, van den Bersselaar L, Oppers-Walgreen B, et al. IL-17 promotes bone erosion in murine collagen-induced arthritis through loss of the receptor activator of NF-kappa B ligand/osteoprotegerin balance. J Immunol 2003;170:2655-2662. https://doi.org/10.4049/jimmunol.170.5.2655
  6. Jovanovic DV, Di Battista JA, Martel-Pelletier J, et al. IL17 stimulates the production and expression of proinflammatory cytokines, IL-beta and TNF-alpha, by human macrophages. J Immunol 1998;160:3513-3521.
  7. Kim KW, Kim HR, Kim BM, Cho ML, Lee SH. Th17 cytokines regulate osteoclastogenesis in rheumatoid arthritis. Am J Pathol 2015;185:3011-3024. https://doi.org/10.1016/j.ajpath.2015.07.017
  8. Genovese MC, Greenwald M, Cho CS, et al. A phase II randomized study of subcutaneous ixekizumab, an anti-interleukin-17 monoclonal antibody, in rheumatoid arthritis patients who were naive to biologic agents or had an inadequate response to tumor necrosis factor inhibitors. Arthritis Rheumatol 2014;66:1693-1704. https://doi.org/10.1002/art.38617
  9. Genovese MC, Durez P, Richards HB, et al. Efficacy and safety of secukinumab in patients with rheumatoid arthritis: a phase II, dose-finding, double-blind, randomised, placebo controlled study. Ann Rheum Dis 2013;72:863-869. https://doi.org/10.1136/annrheumdis-2012-201601
  10. Qureshi AA, Tan X, Reis JC, et al. Inhibition of nitric oxide in LPS-stimulated macrophages of young and senescent mice by δ-tocotrienol and quercetin. Lipids Health Dis 2011;10:239. https://doi.org/10.1186/1476-511X-10-239
  11. Yam ML, Abdul Hafid SR, Cheng HM, Nesaretnam K. Tocotrienols suppress proinflammatory markers and cyclooxygenase-2 expression in RAW264.7 macrophages. Lipids 2009;44:787-797. https://doi.org/10.1007/s11745-009-3326-2
  12. Qureshi AA, Reis JC, Papasian CJ, Morrison DC, Qureshi N. Tocotrienols inhibit lipopolysaccharide-induced pro-inflammatory cytokines in macrophages of female mice. Lipids Health Dis 2010;9:143. https://doi.org/10.1186/1476-511X-9-143
  13. Radhakrishnan A, Tudawe D, Chakravarthi S, Chiew GS, Haleagrahara N. Effect of γ-tocotrienol in counteracting oxidative stress and joint damage in collagen-induced arthritis in rats. Exp Ther Med 2014;7:1408-1414. https://doi.org/10.3892/etm.2014.1592
  14. Haleagrahara N, Swaminathan M, Chakravarthi S, Radhakrishnan A. Therapeutic efficacy of vitamin E δ-tocotrienol in collagen-induced rat model of arthritis. Biomed Res Int 2014;2014:539540. https://doi.org/10.1155/2014/539540
  15. Ha H, Lee JH, Kim HN, Lee ZH. x-Tocotrienol inhibits osteoclastic bone resorption by suppressing RANKL expression and signaling and bone resorbing activity. Biochem Biophys Res Commun 2011;406:546-551. https://doi.org/10.1016/j.bbrc.2011.02.085
  16. Lee JH, Kim HN, Yang D, et al. Trolox prevents osteoclastogenesis by suppressing RANKL expression and signaling. J Biol Chem 2009;284:13725-13734. https://doi.org/10.1074/jbc.M806941200
  17. Brooks R, Kalia P, Ireland DC, Beeton C, Rushton N. Direct inhibition of osteoclast formation and activity by the vitamin E isomer gamma-tocotrienol. Int J Vitam Nutr Res 2011;81:358-367. https://doi.org/10.1024/0300-9831/a000087
  18. Kim HR, Kim KW, Kim BM, Lee KA, Lee SH. N-acetyl-l-cysteine controls osteoclastogenesis through regulating Th17 differentiation and RANKL production in rheumatoid arthritis. Korean J Intern Med 2019;34:210-219. https://doi.org/10.3904/kjim.2016.329
  19. Brentano F, Schorr O, Gay RE, Gay S, Kyburz D. RNA released from necrotic synovial fluid cells activates rheumatoid arthritis synovial fibroblasts via Toll-like receptor 3. Arthritis Rheum 2005;52:2656-2665. https://doi.org/10.1002/art.21273
  20. Kim SJ, Chen Z, Essani AB, et al. Identification of a novel toll-like receptor 7 endogenous ligand in rheumatoid arthritis synovial fluid that can provoke arthritic joint inflammation. Arthritis Rheumatol 2016;68:1099-1110. https://doi.org/10.1002/art.39544
  21. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337-342. https://doi.org/10.1038/nature01658
  22. Qureshi AA, Khan DA, Mushtaq S, Ye SQ, Xiong M, Qureshi N. δ-Tocotrienol feeding modulates gene expression of EIF2, mTOR, protein ubiquitination through multiple-signaling pathways in chronic hepatitis C patients. Lipids Health Dis 2018;17:167. https://doi.org/10.1186/s12944-018-0804-7
  23. Chang PN, Yap WN, Lee DT, Ling MT, Wong YC, Yap YL. Evidence of gamma-tocotrienol as an apoptosis-inducing, invasion-suppressing, and chemotherapy drug-sensitizing agent in human melanoma cells. Nutr Cancer 2009;61:357-366. https://doi.org/10.1080/01635580802567166
  24. Feldmann M, Brennan FM, Foxwell BM, Maini RN. The role of TNF alpha and IL-1 in rheumatoid arthritis. Curr Dir Autoimmun 2001;3:188-199.
  25. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 2007;7:429-442. https://doi.org/10.1038/nri2094
  26. Guo YJ, Chen J, Xiong XG, Wu D, Zhu H, Liang QH. Effect of Bizhongxiao decoction and its dismantled formulae on IL-1 and TNF levels in collagen-induced arthritis in rat synovial joints. Theor Biol Med Model 2012;9:47. https://doi.org/10.1186/1742-4682-9-47
  27. Lee WS, Lee EG, Sung MS, Choi YJ, Yoo WH. Atorvastatin inhibits osteoclast differentiation by suppressing NF-κB and MAPK signaling during IL-1β-induced osteoclastogenesis. Korean J Intern Med 2018;33:397-406. https://doi.org/10.3904/kjim.2015.244
  28. Wu SJ, Liu PL, Ng LT. Tocotrienol-rich fraction of palm oil exhibits anti-inflammatory property by suppressing the expression of inflammatory mediators in human monocytic cells. Mol Nutr Food Res 2008;52:921-929. https://doi.org/10.1002/mnfr.200700418

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