Skip to main content

Advertisement

SpringerLink
Log in

Therapeutic effects of lactosyl derivative Gu-4 in a collagen-induced arthritis rat model

  • Published:
Glycoconjugate Journal Aims and scope Submit manuscript

Abstract

Rheumatoid arthritis (RA) is an inflammatory disorder that is characterized by persistent recurrence of joint inflammation leading to cartilage and bone destruction. The present anti-arthritis therapies failed to achieve satisfactory remission in all patients; therefore, it is still necessary to develop novel approaches to fulfill the demand in clinic. Here, we reported the therapeutic effects of lactosyl derivative Gu-4, a synthetic compound that was previously identified as a selective inhibitor against leukocyte integrin CD11b, in a bovine type II collagen induced arthritis (CIA) rat model. First, prophylactic administration of Gu-4 (1.2728 mg/kg) to rats by intraperitoneal injection every 2 days from the first day of collagen immunization significantly decreased the incidence of CIA, diminished the mean paw volume increase, and reduced the number of swollen paws. Second, administration of Gu-4 (1.2728 mg/kg) to rats at early-onset stage of CIA prevented the progression of the pathological process of RA, accelerated the remission of paw edema, and declined the arthritis score; after 5 weeks treatment, X-ray and histological examinations were carried out, the ankle joint of hind limb of Gu-4 treated CIA rats exhibited slighter bone erosion and much less inflammatory cell infiltration compared to those of saline treated animals; furthermore, Gu-4 remarkably attenuated the production of rheumatoid factor (RF) in the serum of CIA rats as determined by ELISA. Moreover, we performed in vitro lymphocyte proliferation assay and found that Gu-4 significantly inhibited the proliferation of splenic lymphocytes isolated from CIA rats in a dose-dependent manner. Our results suggest that Gu-4 can effectively ameliorate CIA and might be an alternative option for the treatment of RA.

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
Fig. 5

Similar content being viewed by others

References

  1. Sweeney, S.E., Firestein, G.S.: Rheumatoid arthritis: regulation of synovial inflammation. Int. J. Biochem. Cell Biol. 36, 372–378 (2004)

    Article  PubMed  CAS  Google Scholar 

  2. Brennan, F.M., Maini, R.N., Feldmann, M.: Role of pro-inflammatory cytokines in rheumatoid arthritis. Springer Semin. Immunopathol. 20, 133–147 (1998)

    Article  PubMed  CAS  Google Scholar 

  3. Raptopoulou, A., Sidiropoulos, P., Katsouraki, M., Boumpas, D.T.: Anti-citrulline antibodies in the diagnosis and prognosis of rheumatoid arthritis: evolving concepts. Crit. Rev. Clin. Lab. Sci. 44, 339–363 (2007)

    Article  PubMed  CAS  Google Scholar 

  4. Joe, B., Griffiths, M.M., Remmers, E.F., Wilder, R.L.: Animal models of rheumatoid arthritis and related inflammation. Curr. Rheumatol. Rep. 1, 139–148 (1999)

    Article  PubMed  CAS  Google Scholar 

  5. Asquith, D.L., Miller, A.M., McInnes, I.B., Liew, F.Y.: Animal models of rheumatoid arthritis. Eur. J. Immunol. 39, 2040–2044 (2009)

    Article  PubMed  CAS  Google Scholar 

  6. Myers, L.K., Rosloniec, E.F., Cremer, M.A., Kang, A.H.: Collagen-induced arthritis, an animal model of autoimmunity. Life Sci. 61, 1861–1878 (1997)

    Article  PubMed  CAS  Google Scholar 

  7. Terato, K., Hasty, K.A., Reife, R.A., Cremer, M.A., Kang, A.H., et al.: Induction of arthritis with monoclonal antibodies to collagen. J. Immunol. 148, 2103–2108 (1992)

    PubMed  CAS  Google Scholar 

  8. Kleinau, S., Martinsson, P., Heyman, B.: Induction and suppression of collagen-induced arthritis is dependent on distinct Fcγ receptors. J. Exp. Med. 191, 1611 (2000)

    Article  PubMed  CAS  Google Scholar 

  9. Fonseca, J.E., Cortez-Dias, N., Francisco, A., Sobral, M., Canhao, H., et al.: Inflammatory cell infiltrate and RANKL/OPG expression in rheumatoid synovium: comparison with other inflammatory arthropathies and correlation with outcome. Clin. Exp. Rheumatol. 23, 185–192 (2005)

    PubMed  CAS  Google Scholar 

  10. Kim, H.J., Krenn, V., Steinhauser, G., Berek, C.: Plasma cell development in synovial germinal centers in patients with rheumatoid and reactive arthritis. J. Immunol. 162, 3053–3062 (1999)

    PubMed  CAS  Google Scholar 

  11. Pillinger, M.H., Abramson, S.B.: The neutrophil in rheumatoid arthritis. Rheum. Dis. Clin. North Am. 21, 691–714 (1995)

    PubMed  CAS  Google Scholar 

  12. Wipke, B.T., Allen, P.M.: Essential role of neutrophils in the initiation and progression of a murine model of rheumatoid arthritis. J. Immunol. 167, 1601–1608 (2001)

    PubMed  CAS  Google Scholar 

  13. McDonald, B., Pittman, K., Menezes, G.B., Hirota, S.A., Slaba, I., et al.: Intravascular danger signals guide neutrophils to sites of sterile inflammation. Sci. STKE 330, 362 (2010)

    CAS  Google Scholar 

  14. Sadik, C.D., Kim, N.D., Luster, A.D.: Neutrophils cascading their way to inflammation. Trends Immunol. 32, 452–460 (2011)

    Article  PubMed  CAS  Google Scholar 

  15. Ley, K., Laudanna, C., Cybulsky, M.I., Nourshargh, S.: Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat. Rev. Immunol. 7, 678–689 (2007)

    Article  PubMed  CAS  Google Scholar 

  16. Williams, M.R., Azcutia, V., Newton, G., Alcaide, P., Luscinskas, F.W.: Emerging mechanisms of neutrophil recruitment across endothelium. Trends Immunol. 32, 461–469 (2011)

    Article  PubMed  CAS  Google Scholar 

  17. Kong, Y.Y., Feige, U., Sarosi, I., Bolon, B., Tafuri, A., et al.: Activated T cells regulate bone loss and joint destruction in adjuvant arthritis through osteoprotegerin ligand. Nature 402, 304–309 (1999)

    Article  PubMed  CAS  Google Scholar 

  18. De Vita, S., Zaja, F., Sacco, S., De Candia, A., Fanin, R., et al.: Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenetic role of B cells. Arthritis Rheum. 46, 2029–2033 (2002)

    Article  PubMed  Google Scholar 

  19. Nakken, B., Munthe, L.A., Konttinen, Y.T., Sandberg, A.K., Szekanecz, Z., et al.: B-cells and their targeting in rheumatoid arthritis–current concepts and future perspectives. Autoimmun. Rev. 11, 28–34 (2011)

    Article  PubMed  CAS  Google Scholar 

  20. Tanaka, Y.: Recent progress in clinical trials for rheumatic diseases. Nihon Rinsho 67, 619–625 (2009)

    PubMed  Google Scholar 

  21. Zhao, Z., Li, Q., Hu, J., Li, Z., Liu, J., et al.: Lactosyl derivatives function in a rat model of severe burn shock by acting as antagonists against CD11b of integrin on leukocytes. Glycoconj. J. 26, 173–188 (2009)

    Article  PubMed  CAS  Google Scholar 

  22. Yan, T., Li, Q., Zhou, H., Zhao, Y., Yu, S., et al.: Gu-4 suppresses affinity and avidity modulation of CD11b and improves the outcome of mice with endotoxemia and sepsis. PLoS One 7, e30110 (2012)

    Article  PubMed  CAS  Google Scholar 

  23. Li, H., Li, Q., Cai, M.S., Li, Z.J.: Synthesis of galactosyl and lactosyl derivatives as potential anti-metastasis compounds. Carbohydr. Res. 328, 611–615 (2000)

    Article  PubMed  CAS  Google Scholar 

  24. Butz, D.E., Li, G., Huebner, S.M., Cook, M.E.: A mechanistic approach to understanding conjugated linoleic acid’s role in inflammation using murine models of rheumatoid arthritis. Am. J. Physiol. Regul. Integr. Comp. Physiol. 293, R669–R676 (2007)

    Article  PubMed  CAS  Google Scholar 

  25. Tomita, T., Kakiuchi, Y., Tsao, P.S.: THR0921, a novel peroxisome proliferator-activated receptor gamma agonist, reduces the severity of collagen-induced arthritis. Arthritis Res. Ther. 8, R7 (2006)

    Article  PubMed  Google Scholar 

  26. Nell, V.P., Machold, K.P., Stamm, T.A., Eberl, G., Heinzl, H., et al.: Autoantibody profiling as early diagnostic and prognostic tool for rheumatoid arthritis. Ann. Rheum. Dis. 64, 1731–1736 (2005)

    Article  PubMed  CAS  Google Scholar 

  27. Gabriel, S.E.: The epidemiology of rheumatoid arthritis. Rheum. Dis. Clin. North Am. 27, 269–281 (2001)

    Article  PubMed  CAS  Google Scholar 

  28. Majithia, V., Geraci, S.A.: Rheumatoid arthritis: diagnosis and management. Am. J. Med. 120, 936–939 (2007)

    Article  PubMed  Google Scholar 

  29. Smolen, J.S., Steiner, G.: Therapeutic strategies for rheumatoid arthritis. Nat. Rev. Drug Discov. 2, 473–488 (2003)

    Article  PubMed  CAS  Google Scholar 

  30. Firth, J.: Rheumatoid arthritis: diagnosis and multidisciplinary management. Br. J. Nurs. 20, 1179–1180, 1182, 1184–1175 (2011)

    Google Scholar 

  31. Cascao, R., Rosario, H.S., Souto-Carneiro, M.M., Fonseca, J.E.: Neutrophils in rheumatoid arthritis: more than simple final effectors. Autoimmun. Rev. 9, 531–535 (2010)

    Article  PubMed  CAS  Google Scholar 

  32. Cascao, R., Rosario, H.S., Fonseca, J.E.: Neutrophils: warriors and commanders in immune mediated inflammatory diseases. Acta Reumatol. Port. 34, 313–326 (2009)

    PubMed  CAS  Google Scholar 

  33. Ponchel, F., Morgan, A.W., Bingham, S.J., Quinn, M., Buch, M., et al.: Dysregulated lymphocyte proliferation and differentiation in patients with rheumatoid arthritis. Blood 100, 4550–4556 (2002)

    Article  PubMed  CAS  Google Scholar 

  34. Svensson, L., Jirholt, J., Holmdahl, R., Jansson, L.: B cell-deficient mice do not develop type II collagen-induced arthritis (CIA). Clin. Exp. Immunol. 111, 521–526 (1998)

    Article  PubMed  CAS  Google Scholar 

  35. Edwards, J.C., Szczepanski, L., Szechinski, J., Filipowicz-Sosnowska, A., Emery, P., et al.: Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N. Engl. J. Med. 350, 2572–2581 (2004)

    Article  PubMed  CAS  Google Scholar 

  36. Wipke, B.T., Wang, Z., Nagengast, W., Reichert, D.E., Allen, P.M.: Staging the initiation of autoantibody-induced arthritis: a critical role for immune complexes. J. Immunol. 172, 7694–7702 (2004)

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was financially supported by the Natural Science Foundation of China (Grant No. 2008104GZ40166), the State New Drug Innovation Plan (Grant No. 2009ZX09103-044), and a project from the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). The authors thank Dr. Lei Lan for her help with the revision of this manuscript.

Author information

Authors and Affiliations

  1. Jiangsu Province Key Laboratory for Molecular and Medical Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, China

    Jie Fan, Huiting Zhou, Shihui Wang, Hailian Wang, Yushun Zhang, Yingtao Guo & Zhihui Zhao

  2. State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, 100083, China

    Qing Li & Zhongjun Li

Authors
  1. Jie Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Huiting Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shihui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hailian Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yushun Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yingtao Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Qing Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zhongjun Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhihui Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zhongjun Li or Zhihui Zhao.

Additional information

Jie Fan, Huiting Zhou and Qing Li contributed equally to this paper.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Fan, J., Zhou, H., Wang, S. et al. Therapeutic effects of lactosyl derivative Gu-4 in a collagen-induced arthritis rat model. Glycoconj J 29, 305–313 (2012). https://doi.org/10.1007/s10719-012-9407-0

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10719-012-9407-0

Keywords

Search

Navigation