Skip to main content

Advertisement

SpringerLink
Log in

Low-Molecular-Weight Fucoidan Inhibits the Viability and Invasiveness and Triggers Apoptosis in IL-1β-Treated Human Rheumatoid Arthritis Fibroblast Synoviocytes

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Fucoidan is a sulfated polysaccharide found mainly in various species of brown algae and brown seaweed. Here, we investigated the effects of low-molecular-weight (LMW) fucoidan (4 kDa) on interleukin-1beta (IL-1β)-stimulated rheumatoid arthritis fibroblast-like synoviocyte (RAFLS). 3-[4,5-Dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay and annexin V/propidium iodide assay were used to assess cell viability and apoptosis, respectively. Transwell assay was performed to evaluate cell invasion. Reverse transcription polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay analysis was done to measure gene expression and secretion. Nuclear factor-kappa B (NF-κB) DNA binding activity was determined by electrophoretic mobility shift assay. LMW fucoidan dose-dependently inhibited the viability and induced apoptosis of IL-1β-treated RAFLS. Fucoidan attenuated IL-1β-induced invasion of RAFLS and decreased the expression and secretion of metalloproteinase (MMP)-1, MMP-3, and MMP-9. Fucoidan suppressed NF-κB binding activity, p65 nuclear translocation, and IκB-α degradation in IL-1β-stimulated RAFLS. Additionally, IL-1β-induced phosphorylation of p38 but not ERK or JNK was significantly impaired by fucoidan treatment. LMW fucoidan reduces the viability, survival, and invasiveness of IL-1β-treated RAFLS, which is associated with inhibition of NF-κB and p38 activation. LMW fucoidan may have therapeutic potential in the treatment of rheumatoid arthritis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Li, H., and A. Wan. 2013. Apoptosis of rheumatoid arthritis fibroblast-like synoviocytes: possible roles of nitric oxide and the thioredoxin 1. Mediators of Inflammation 2013: 953462.

    PubMed Central  PubMed  Google Scholar 

  2. Firestein, G.S. 2003. Evolving concepts of rheumatoid arthritis. Nature 423: 356–361.

    Article  CAS  PubMed  Google Scholar 

  3. Noss, E.H., and M.B. Brenner. 2008. The role and therapeutic implications of fibroblast-like synoviocytes in inflammation and cartilage erosion in rheumatoid arthritis. Immunology Reviews 223: 252–270.

    Article  CAS  Google Scholar 

  4. Karouzakis, E., R.E. Gay, S. Gay, and M. Neidhart. 2009. Epigenetic control in rheumatoid arthritis synovial fibroblasts. Nature Reviews. Rheumatology 5: 266–272.

    Article  CAS  PubMed  Google Scholar 

  5. Bartok, B., and G.S. Firestein. 2010. Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunology Reviews 233: 233–255.

    Article  CAS  Google Scholar 

  6. Huber, L.C., O. Distler, I. Tarner, R.E. Gay, S. Gay, and T. Pap. 2006. Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology (Oxford) 45: 669–675.

    Article  CAS  Google Scholar 

  7. Lefèvre, S., A. Knedla, C. Tennie, A. Kampmann, C. Wunrau, R. Dinser, A. Korb, E.M. Schnäker, I.H. Tarner, P.D. Robbins, C.H. Evans, H. Stürz, J. Steinmeyer, S. Gay, J. Schölmerich, T. Pap, U. Müller-Ladner, and E. Neumann. 2009. Synovial fibroblasts spread rheumatoid arthritis to unaffected joints. Nature Medicine 15: 1414–1420.

    Article  PubMed Central  PubMed  Google Scholar 

  8. Smolen, J.S., D. Aletaha, M. Koeller, M.H. Weisman, and P. Emery. 2007. New therapies for treatment of rheumatoid arthritis. Lancet 370: 1861–1874.

    Article  CAS  PubMed  Google Scholar 

  9. Smolen, J.S., and G. Steiner. 2003. Therapeutic strategies for rheumatoid arthritis. Nature Reviews Drug Discovery 2: 473–488.

    Article  CAS  PubMed  Google Scholar 

  10. Berteau, O., and B. Mulloy. 2003. Sulfated fucans, fresh perspectives: structures, functions, and biological properties of sulfated fucans and an overview of enzymes active toward this class of polysaccharide. Glycobiology 13: 29R–40R.

    Article  CAS  PubMed  Google Scholar 

  11. O’Leary, R., M. Rerek, and E.J. Wood. 2004. Fucoidan modulates the effect of transforming growth factor (TGF)-beta1 on fibroblast proliferation and wound repopulation in in vitro models of dermal wound repair. Biological and Pharmaceutical Bulletin 27: 266–270.

    Article  PubMed  Google Scholar 

  12. Cumashi, A., N.A. Ushakova, M.E. Preobrazhenskaya, A. D’Incecco, A. Piccoli, L. Totani, N. Tinari, G.E. Morozevich, A.E. Berman, M.I. Bilan, A.I. Usov, N.E. Ustyuzhanina, A.A. Grachev, C.J. Sanderson, M. Kelly, G.A. Rabinovich, S. Iacobelli, N.E. Nifantiev, and Consorzio Interuniversitario Nazionale per la Bio-Oncologia, Italy. 2007. A comparative study of the anti-inflammatory, anticoagulant, antiangiogenic, and antiadhesive activities of nine different fucoidans from brown seaweeds. Glycobiology 17: 541–552.

    Article  CAS  PubMed  Google Scholar 

  13. Chabut, D., A.M. Fischer, S. Colliec-Jouault, I. Laurendeau, S. Matou, B. Le Bonniec, and D. Helley. 2003. Low molecular weight fucoidan and heparin enhance the basic fibroblast growth factor-induced tube formation of endothelial cells through heparan sulfate-dependent alpha6 overexpression. Molecular Pharmacology 64: 696–702.

    Article  CAS  PubMed  Google Scholar 

  14. Park, S.B., K.R. Chun, J.K. Kim, K. Suk, Y.M. Jung, and W.H. Lee. 2010. The differential effect of high and low molecular weight fucoidans on the severity of collagen-induced arthritis in mice. Phytotherapy Research 24: 1384–1391.

    Article  CAS  PubMed  Google Scholar 

  15. Nardella, A., F. Chaubet, C. Boisson-Vidal, C. Blondin, P. Durand, and J. Jozefonvicz. 1996. Anticoagulant low molecular weight fucans produced by radical process and ion exchange chromatography of high molecular weight fucans extracted from the brown seaweed Ascophyllum nodosum. Carbohydrate Research 289: 201–208.

    Article  CAS  PubMed  Google Scholar 

  16. Cho, M.L., B.Y. Lee, and S.G. You. 2010. Relationship between oversulfation and conformation of low and high molecular weight fucoidans and evaluation of their in vitro anticancer activity. Molecules 16: 291–297.

    Article  PubMed  Google Scholar 

  17. Arnett, F.C., S.M. Edworthy, D.A. Bloch, D.J. McShane, J.F. Fries, N.S. Cooper, L.A. Healey, S.R. Kaplan, M.H. Liang, H.S. Luthra, et al. 1988. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis and Rheumatism 31: 315–324.

    Article  CAS  PubMed  Google Scholar 

  18. Xue, M., Y. Ge, J. Zhang, Q. Wang, L. Hou, Y. Liu, L. Sun, and Q. Li. 2012. Anticancer properties and mechanisms of fucoidan on mouse breast cancer in vitro and in vivo. PLoS One 7: e43483.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Lee, H.E., E.S. Choi, J.A. Shin, S.O. Lee, K.S. Park, N.P. Cho, and S.D. Cho. 2014. Fucoidan induces caspase-dependent apoptosis in MC3 human mucoepidermoid carcinoma cells. Experimental and Therapeutic Medicine 7: 228–232.

  20. Zhu, C., R. Cao, S.X. Zhang, Y.N. Man, and X.Z. Wu. 2013. Fucoidan inhibits the growth of hepatocellular carcinoma independent of angiogenesis. Evid. Based Complement. Evidence-based Complementary and Alternative Medicine 2013: 692549.

  21. Xue, M., Y. Ge, J. Zhang, Y. Liu, Q. Wang, L. Hou, and Z. Zheng. 2013. Fucoidan inhibited 4T1 mouse breast cancer cell growth in vivo and in vitro via downregulation of Wnt/β-catenin signaling. Nutrition and Cancer 65: 460–468.

    Article  CAS  PubMed  Google Scholar 

  22. Ale, M.T., H. Maruyama, H. Tamauchi, J.D. Mikkelsen, and A.S. Meyer. 2011. Fucose-containing sulfated polysaccharides from brown seaweeds inhibit proliferation of melanoma cells and induce apoptosis by activation of caspase-3 in vitro. Marine Drugs 9: 2605–2621.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Banafa, A.M., S. Roshan, Y.Y. Liu, H.J. Chen, M.J. Chen, G.X. Yang, and G.Y. He. 2013. Fucoidan induces G1 phase arrest and apoptosis through caspases-dependent pathway and ROS induction in human breast cancer MCF-7 cells. Journal of Huazhong University of Science and Technology. Medical Sciences 33: 717–724.

    Article  CAS  Google Scholar 

  24. Kim, E.J., S.Y. Park, J.Y. Lee, and J.H. Park. 2010. Fucoidan present in brown algae induces apoptosis of human colon cancer cells. B.M.C. Gastroenterology 10: 96.

    Article  Google Scholar 

  25. Yamasaki-Miyamoto, Y., M. Yamasaki, H. Tachibana, and K. Yamada. 2009. Fucoidan induces apoptosis through activation of caspase-8 on human breast cancer MCF-7 cells. Journal of Agricultural and Food Chemistry 57: 8677–8682.

    Article  CAS  PubMed  Google Scholar 

  26. Tolboom, T.C., A.H. van der Helm-Van Mil, R.G. Nelissen, F.C. Breedveld, R.E. Toes, and T.W. Huizinga. 2005. Invasiveness of fibroblast-like synoviocytes is an individual patient characteristic associated with the rate of joint destruction in patients with rheumatoid arthritis. Arthritis and Rheumatism 52: 1999–2002.

    Article  PubMed  Google Scholar 

  27. 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: 975–980.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Fan, W., Z.Y. Zhou, X.F. Huang, C.D. Bao, and F. Du. 2013. Deoxycytidine kinase promotes the migration and invasion of fibroblast-like synoviocytes from rheumatoid arthritis patients. International Journal of Clinical and Experimental Pathology 6: 2733–2744.

    PubMed Central  PubMed  Google Scholar 

  29. MacNaul, K.L., N. Chartrain, M. Lark, M.J. Tocci, and N.I. Hutchinson. 1990. Discoordinate expression of stromelysin, collagenase, and tissue inhibitor of metalloproteinases-1 in rheumatoid human synovial fibroblasts. Synergistic effects of interleukin- 1 and tumor necrosis factor-alpha on stromelysin expression. Journal of Biological Chemistry 265: 17238–17245.

    CAS  PubMed  Google Scholar 

  30. Tchetverikov, I., H.K. Ronday, B. Van El, G.H. Kiers, N. Verzijl, J.M. TeKoppele, T.W. Huizinga, J. DeGroot, and R. Hanemaaijer. 2004. MMP profile in paired serum and synovial fluid samples of patients with rheumatoid arthritis. Annals of the Rheumatic Diseases 63: 881–883.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Westhoff, C.S., D. Freudiger, P. Petrow, C. Seyfert, J. Zacher, J. Kriegsmann, T. Pap, S. Gay, P. Stiehl, E. Gromnica-Ihle, and D. Wernicke. 1999. Characterization of collagenase 3 (matrix metalloproteinase 13) messenger RNA expression in the synovial membrane and synovial fibroblasts of patients with rheumatoid arthritis. Arthritis and Rheumatism 42: 1517–1527.

    Article  CAS  PubMed  Google Scholar 

  32. Posthumus, M.D., P.C. Limburg, J. Westra, M.A. van Leeuwen, and M.H. van Rijswijk. 2000. Serum matrix metalloproteinase 3 in early rheumatoid arthritis is correlated with disease activity and radiological progression. Journal of Rheumatology 27: 2761–2768.

    CAS  PubMed  Google Scholar 

  33. Ou, Y., W. Li, X. Li, Z. Lin, and M. Li. 2011. Sinomenine reduces invasion and migration ability in fibroblast-like synoviocytes cells co-cultured with activated human monocytic THP-1 cells by inhibiting the expression of MMP-2, MMP-9, CD147. Rheumatology International 31: 1479–1485.

    Article  CAS  PubMed  Google Scholar 

  34. Makarov, S.S. 2001. NF-kappa B in rheumatoid arthritis: a pivotal regulator of inflammation, hyperplasia, and tissue destruction. Arthritis Research 3: 200–206.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Xiao, Y., M. Sun, Z. Zhan, Y. Ye, M. Huang, Y. Zou, L. Liang, X. Yang, and H. Xu. 2014. Increased phosphorylation of ezrin is associated with the migration and invasion of fibroblast-like synoviocytes from patients with rheumatoid arthritis. Rheumatology (Oxford) 53: 1291–1300.

    Article  CAS  Google Scholar 

  36. Ying, X., X. Chen, S. Cheng, Z. Zhao, X. Guo, H. Chen, J. Hong, L. Peng, and H. Xu. 2013. SeMet inhibits IL-1β-induced rheumatoid fibroblast-like synoviocytes proliferation and the production of inflammatory mediators. Biological Trace Element Research 153: 437–445.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Medical Affairs, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, China

    Zunhua Shu

  2. Department of Ophthalmology, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, China

    Xiaozhe Shi

  3. Department of Rheumatology, Affiliated Hospital of Changchun University of Traditional Chinese Medicine, Changchun, China

    Daqing Nie

  4. The Second Department of Orthopedics (Spine Surgery), Xining First People’s Hospital, #3 Huzhu Xiang, Chengzhong District, Xining, 810000, China

    Bingyu Guan

Authors
  1. Zunhua Shu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaozhe Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daqing Nie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bingyu Guan
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bingyu Guan.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shu, Z., Shi, X., Nie, D. et al. Low-Molecular-Weight Fucoidan Inhibits the Viability and Invasiveness and Triggers Apoptosis in IL-1β-Treated Human Rheumatoid Arthritis Fibroblast Synoviocytes. Inflammation 38, 1777–1786 (2015). https://doi.org/10.1007/s10753-015-0155-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-015-0155-8

KEY WORDS

Search

Navigation