Advertisement

Inflammation

, Volume 40, Issue 6, pp 1825–1835 | Cite as

Suppressive Effects of TSAHC in an Experimental Mouse Model and Fibroblast-Like Synoviocytes of Rheumatoid Arthritis

  • Min-Gyu Jeon
  • Yun-Hong Cheon
  • Hye-Song Lim
  • Sang Mi Yi
  • Young Sun Suh
  • Hyun-Ok Kim
  • Young-Sool Hah
  • Ki-Hun Park
  • Hae Sook NohEmail author
  • Sang-Il LeeEmail author
ORIGINAL ARTICLE
  • 238 Downloads

Abstract

The purpose of this study is to investigate the effect of TSAHC [4′-(p-toluenesulfonylamido)-4-hydroxychalcone] in K/BxN serum transfer arthritis model and fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLS). In in vivo experiments, TSAHC attenuated the incidence and severity of arthritis in comparison with the vehicle group. Histological findings showed that TSAHC decreased the inflammation, bone erosion, cartilage damage, and osteoclasts activity in the ankle. Furthermore, we confirmed by biochemical analysis that the observations were associated with the decreased expression of proinflammatory cytokines, matrix metalloproteinases (MMPs), and RANKL in serum and ankle. In in vitro experiments, TSAHC induced apoptosis, while it significantly suppressed tumor necrosis factor-α (TNF-α)-induced cell proliferation in RA-FLS. Moreover, TSAHC inhibited mRNA expression of TNF-α-induced interleukin (IL)-6, MMP-1, MMP-3, and MMP-13. Evaluation of signaling events showed that TSAHC inhibited the translocation and transcriptional activity of nuclear factor-kappa B (NF-κB) by regulating phosphorylated-IκB-α (p-IκB-α) and IκB-α in TNF-α-induced RA-FLS. Our results suggest that TSAHC inhibits experimental arthritis in mice and suppresses TNF-α-induced RA-FLS activities via NF-κB pathway. Therefore, TSAHC may have therapeutic potential for the treatment of RA.

KEY WORDS

rheumatoid arthritis TSAHC fibroblast-like synoviocytes inflammation 

Notes

Acknowledgments

This work was supported by grants (NRF-2015R1A5A2008833) from the Basic Science Research Program through the National Research Foundation (NRF) of Korea funded by the Ministry of Science, ICT and Future Planning and 2012 clinical research grant from Gyeongsang National University Hospital.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights

All experiments involving mice and human tissues in this study were approved by the Institutional Animal Care and Use Committee of Gyeongsang National University and Hospital (GNU-121018-M0043). The employed procedures were also consistent with the Ethical Guidelines of the International Association for the Study of Gyeongsang National University and Hospital.

References

  1. 1.
    Hah, Y.S., Y.R. Lee, J.S. Jun, H.S. Lim, H.O. Kim, Y.G. Jeong, G.M. Hur, et al. 2010. A20 suppresses inflammatory responses and bone destruction in human fibroblast-like synoviocytes and in mice with collagen-induced arthritis. Arthritis and Rheumatism 62 (8): 2313–2321. doi: 10.1002/art.27545.CrossRefPubMedGoogle Scholar
  2. 2.
    Park, Y.J., S.A. Yoo, and W.U. Kim. 2014. Role of endoplasmic reticulum stress in rheumatoid arthritis pathogenesis. Journal of Korean Medical Science 29 (1): 2–11. doi: 10.3346/jkms.2014.29.1.2.CrossRefPubMedGoogle Scholar
  3. 3.
    Kong, J.S., S.A. Yoo, H.S. Kim, H.A. Kim, K. Yea, S.H. Ryu, Y.J. Chung, C.S. Cho, and W.U. Kim. 2010. Inhibition of synovial hyperplasia, rheumatoid T cell activation, and experimental arthritis in mice by sulforaphane, a naturally occurring isothiocyanate. Arthritis and Rheumatism 62 (1): 159–170. doi: 10.1002/art.25017.CrossRefPubMedGoogle Scholar
  4. 4.
    Doody, K.M., S.M. Stanford, C. Sacchetti, M.N. Svensson, C.H. Coles, N. Mitakidis, W.B. Kiosses, et al. 2015. Targeting phosphatase-dependent proteoglycan switch for rheumatoid arthritis therapy. Science Translational Medicine 7 (288):288ra276). doi: 10.1126/scitranslmed.aaa4616.
  5. 5.
    Tian, J., J.W. Chen, J.S. Gao, L. Li, and X. Xie. 2013. Resveratrol inhibits TNF-alpha-induced IL-1beta, MMP-3 production in human rheumatoid arthritis fibroblast-like synoviocytes via modulation of PI3kinase/Akt pathway. Rheumatology International 33 (7): 1829–1835. doi: 10.1007/s00296-012-2657-0.CrossRefPubMedGoogle Scholar
  6. 6.
    Keffer, J., L. Probert, H. Cazlaris, S. Georgopoulos, E. Kaslaris, D. Kioussis, and G. Kollias. 1991. Transgenic mice expressing human tumour necrosis factor: a predictive genetic model of arthritis. The EMBO Journal 10 (13): 4025–4031.PubMedPubMedCentralGoogle Scholar
  7. 7.
    Lee, Y.R., J.K. Hwang, H.S. Lee, Y.J. Cheon, J.H. Ryu, S.I. Lee, H.B. Kwak, et al. 2011. SPA0355, a thiourea analogue, inhibits inflammatory responses and joint destruction in fibroblast-like synoviocytes and mice with collagen-induced arthritis. British Journal of Pharmacology 164 (2b): 794–806. doi: 10.1111/j.1476-5381.2011.01441.x.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Taylor, G.A., E. Carballo, D.M. Lee, W.S. Lai, M.J. Thompson, D.D. Patel, D.I. Schenkman, et al. 1996. A pathogenetic role for TNF alpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity 4 (5): 445–454.CrossRefPubMedGoogle Scholar
  9. 9.
    Brennan, F.M., and I.B. McInnes. 2008. Evidence that cytokines play a role in rheumatoid arthritis. The Journal of Clinical Investigation 118 (11): 3537–3545. doi: 10.1172/JCI36389.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Umar, S., O. Hedaya, A.K. Singh, and S. Ahmed. 2015. Thymoquinone inhibits TNF-alpha-induced inflammation and cell adhesion in rheumatoid arthritis synovial fibroblasts by ASK1 regulation. Toxicology and Applied Pharmacology 287 (3): 299–305. doi: 10.1016/j.taap.2015.06.017.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Baldwin, A.S., Jr. 1996. The NF-kappa B and I kappa B proteins: new discoveries and insights. Annual Review of Immunology 14: 649–683. doi: 10.1146/annurev.immunol.14.1.649.CrossRefPubMedGoogle Scholar
  12. 12.
    Ghosh, S., M.J. May, and E.B. Kopp. 1998. NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses. Annual Review of Immunology 16: 225–260. doi: 10.1146/annurev.immunol.16.1.225.CrossRefPubMedGoogle Scholar
  13. 13.
    Han, Z., D.L. Boyle, A.M. Manning, and G.S. Firestein. 1998. AP-1 and NF-kappaB regulation in rheumatoid arthritis and murine collagen-induced arthritis. Autoimmunity 28 (4): 197–208. doi: 10.3109/08916939808995367.CrossRefPubMedGoogle Scholar
  14. 14.
    Handel, M.L., L.B. McMorrow, and E.M. Gravallese. 1995. Nuclear factor-kappa B in rheumatoid synovium. Localization of p50 and p65. Arthritis and Rheumatism 38 (12): 1762–1770.CrossRefPubMedGoogle Scholar
  15. 15.
    Youn, J., H.Y. Kim, J.H. Park, S.H. Hwang, S.Y. Lee, C.S. Cho, and S.K. Lee. 2002. Regulation of TNF-alpha-mediated hyperplasia through TNF receptors, TRAFs, and NF-kappaB in synoviocytes obtained from patients with rheumatoid arthritis. Immunology Letters 83 (2): 85–93.CrossRefPubMedGoogle Scholar
  16. 16.
    Yadav, V.R., S. Prasad, B. Sung, and B.B. Aggarwal. 2011. The role of chalcones in suppression of NF-kappaB-mediated inflammation and cancer. International Immunopharmacology 11 (3): 295–309. doi: 10.1016/j.intimp.2010.12.006.CrossRefPubMedGoogle Scholar
  17. 17.
    Makita, H., T. Tanaka, H. Fujitsuka, N. Tatematsu, K. Satoh, A. Hara, and H. Mori. 1996. Chemoprevention of 4-nitroquinoline 1-oxide-induced rat oral carcinogenesis by the dietary flavonoids chalcone, 2-hydroxychalcone, and quercetin. Cancer Research 56 (21): 4904–4909.PubMedGoogle Scholar
  18. 18.
    Opletalova, V., and D. Sedivy. 1999. Chalcones and their heterocyclic analogs as potential antifungal chemotherapeutic agents. Ceská a Slovenská Farmacie 48 (6): 252–255.PubMedGoogle Scholar
  19. 19.
    Lopez, S.N., M.V. Castelli, S.A. Zacchino, J.N. Dominguez, G. Lobo, J. Charris-Charris, J.C. Cortes, et al. 2001. In vitro antifungal evaluation and structure-activity relationships of a new series of chalcone derivatives and synthetic analogues, with inhibitory properties against polymers of the fungal cell wall. Bioorganic & Medicinal Chemistry 9 (8): 1999–2013.CrossRefGoogle Scholar
  20. 20.
    Spribille, R., and G. Forkmann. 1982. Chalcone synthesis and hydroxylation of flavonoids in 3′-position with enzyme preparations from flowers of Dianthus caryophyllus L. (carnation). Planta 155 (2): 176–182. doi: 10.1007/BF00392549.CrossRefPubMedGoogle Scholar
  21. 21.
    Hah, Y.S., Y.H. Cheon, H.S. Lim, H.Y. Cho, B.H. Park, S.O. Ka, Y.R. Lee, et al. 2014. Myeloid deletion of SIRT1 aggravates serum transfer arthritis in mice via nuclear factor-kappaB activation. PloS One 9 (2): e87733. doi: 10.1371/journal.pone.0087733.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Lee, S.A., H.W. Ryu, Y.M. Kim, S. Choi, M.J. Lee, T.K. Kwak, H.J. Kim, M. Cho, K.H. Park, and J.W. Lee. 2009. Blockade of four-transmembrane L6 family member 5 (TM4SF5)-mediated tumorigenicity in hepatocytes by a synthetic chalcone derivative. Hepatology 49 (4): 1316–1325. doi: 10.1002/hep.22777.CrossRefPubMedGoogle Scholar
  23. 23.
    Lee, S.I., D.L. Boyle, A. Berdeja, and G.S. Firestein. 2012. Regulation of inflammatory arthritis by the upstream kinase mitogen activated protein kinase kinase 7 in the c-Jun N-terminal kinase pathway. Arthritis Research & Therapy 14 (1): R38. doi: 10.1186/ar3750.CrossRefGoogle Scholar
  24. 24.
    Arnett, F.C., S.M. Edworthy, D.A. Bloch, D.J. McShane, J.F. Fries, N.S. Cooper, L.A. Healey, et al. 1988. The American rheumatism association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis and Rheumatism 31 (3): 315–324.CrossRefPubMedGoogle Scholar
  25. 25.
    Yokota, K., T. Miyazaki, M. Hirano, Y. Akiyama, and T. Mimura. 2006. Simvastatin inhibits production of interleukin 6 (IL-6) and IL-8 and cell proliferation induced by tumor necrosis factor-alpha in fibroblast-like synoviocytes from patients with rheumatoid arthritis. The Journal of Rheumatology 33 (3): 463–471.PubMedGoogle Scholar
  26. 26.
    Ahrens, D., A.E. Koch, R.M. Pope, M. Stein-Picarella, and M.J. Niedbala. 1996. Expression of matrix metalloproteinase 9 (96-kd gelatinase B) in human rheumatoid arthritis. Arthritis and Rheumatism 39 (9): 1576–1587.CrossRefPubMedGoogle Scholar
  27. 27.
    Lindy, O., Y.T. Konttinen, T. Sorsa, Y. Ding, S. Santavirta, A. Ceponis, and C. Lopez-Otin. 1997. Matrix metalloproteinase 13 (collagenase 3) in human rheumatoid synovium. Arthritis and Rheumatism 40 (8): 1391–1399. doi: 10.1002/1529-0131(199708)40.CrossRefPubMedGoogle Scholar
  28. 28.
    Martel-Pelletier, J., D.J. Welsch, and J.P. Pelletier. 2001. Metalloproteases and inhibitors in arthritic diseases. Best Practice & Research. Clinical Rheumatology 15 (5): 805–829. doi: 10.1053/berh.2001.0195.CrossRefGoogle Scholar
  29. 29.
    Seemayer, C.A., S. Kuchen, P. Kuenzler, V. Rihoskova, J. Rethage, W.K. Aicher, B.A. Michel, et al. 2003. Cartilage destruction mediated by synovial fibroblasts does not depend on proliferation in rheumatoid arthritis. The American Journal of Pathology 162 (5): 1549–1557. doi: 10.1016/S0002-9440(10)64289-7.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Sorsa, T., Y.T. Konttinen, O. Lindy, C. Ritchlin, H. Saari, K. Suomalainen, K.K. Eklund, and S. Santavirta. 1992. Collagenase in synovitis of rheumatoid arthritis. Seminars in Arthritis and Rheumatism 22 (1): 44–53.CrossRefPubMedGoogle Scholar
  31. 31.
    Tolboom, T.C., E. Pieterman, W.H. van der Laan, R.E. Toes, A.L. Huidekoper, R.G. Nelissen, F.C. Breedveld, and T.W. Huizinga. 2002. Invasive properties of fibroblast-like synoviocytes: correlation with growth characteristics and expression of MMP-1, MMP-3, and MMP-10. Annals of the Rheumatic Diseases 61 (11): 975–980.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Lee, Y.R., S.H. Kweon, K.B. Kwon, J.W. Park, T.R. Yoon, and B.H. Park. 2009. Inhibition of IL-1beta-mediated inflammatory responses by the IkappaB alpha super-repressor in human fibroblast-like synoviocytes. Biochemical and Biophysical Research Communications 378 (1): 90–94. doi: 10.1016/j.bbrc.2008.11.002.CrossRefPubMedGoogle Scholar
  33. 33.
    Woo, S.J., K. Lim, S.Y. Park, M.Y. Jung, H.S. Lim, M.G. Jeon, S.I. Lee, and B.H. Park. 2015. Endogenous conversion of n-6 to n-3 polyunsaturated fatty acids attenuates K/BxN serum-transfer arthritis in fat-1 mice. The Journal of Nutritional Biochemistry 26 (7): 713–720. doi: 10.1016/j.jnutbio.2015.01.011.CrossRefPubMedGoogle Scholar
  34. 34.
    Khanna, D., G. Sethi, K.S. Ahn, M.K. Pandey, A.B. Kunnumakkara, B. Sung, A. Aggarwal, and B.B. Aggarwal. 2007. Natural products as a gold mine for arthritis treatment. Current Opinion in Pharmacology 7 (3): 344–351. doi: 10.1016/j.coph.2007.03.002.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Convergence Medical Sciences, Institute of Health SciencesGyeongsang National University School of MedicineJinJuRepublic of Korea
  2. 2.Department of Internal Medicine, Institute of Health ScienceGyeongsang National University Hospital, Gyeongsang National UniversityJinjuRepublic of Korea
  3. 3.Clinical Research InstituteGyeongsang National University HospitalJinjuRepublic of Korea
  4. 4.Division of Applied Life Science (BK21 plus), IALSGraduate School of Gyeongsang National University JinjuJinjuRepublic of Korea

Personalised recommendations