Skip to main content

Advertisement

SpringerLink
Log in

SUMO-Conjugating Enzyme UBC9 Promotes Proliferation and Migration of Fibroblast-like Synoviocytes in Rheumatoid Arthritis

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease with high morbidity and mortality. Fibroblast-like synoviocytes (FLS) in the synovial tissues play critical roles in joint destruction. Recent studies implicate the sumoylation in the regulation of the inflammation and arthritis. Thus, we explored whether SUMO-conjugating enzyme UBC9 is involved in the progression of RA using a mouse collagen-induced arthritis (CIA) model. The effects of UBC9 siRNA on cell invasion and migration in human RA-FLS were also assessed in vitro. Treatment with siRNA against UBC9 for 3 weeks reduced the arthritis score and joint destruction. The expression of SUMO-1 and UBC9 protein in CIA joints was inhibited by UBC9 knockdown. Serum levels of anti-collagen (CII) antibodies, vascular endothelial growth factor A (VEGF-A), matrix metalloproteinases (MMP)-3, and MMP-9 were also decreased in CIA mice. In vitro, UBC9 silencing inhibited the secretion of VEGF-A, MMP-3, and MMP-9 from TNF-α-stimulated human RA-FLS. TNF-α-induced RA-FLS proliferation and migration were significantly attenuated by UBC9 knockdown. These findings indicate that SUMO-conjugating enzyme UBC9 promotes proliferation and migration of fibroblast-like synoviocytes in rheumatoid arthritis. Inhibition of UBC9 activity may be a viable therapeutic target in amelioration of disease progression in RA by attenuating FLS proliferation, migration, and invasion.

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
Figure 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Choy, E.H., and G.S. Panayi. 2001. Cytokine pathways and joint inflammation in rheumatoid arthritis. New England Journal of Medicine 344: 907–916.

    Article  CAS  PubMed  Google Scholar 

  2. Bottini, N., and G.S. Firestein. 2013. Duality of fibroblast-like synoviocytes in RA: passive responders and imprinted aggressors. Nature Reviews. Rheumatology 9: 24–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Ma, Y., and R.M. Pope. 2005. The role of macrophages in rheumatoid arthritis. Current Pharmaceutical Design 11: 569–580.

    Article  CAS  PubMed  Google Scholar 

  4. Firestein, G.S., F. Echeverri, M. Yeo, N.J. Zvaifler, and D.R. Green. 1997. Somatic mutations in the p53 tumor suppressor gene in rheumatoid arthritis synovium. Proceedings of the National Academy of Sciences of the United States of America 94: 10895–10900.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Muller-Ladner, U., T. Pap, R.E. Gay, M. Neidhart, and S. Gay. 2005. Mechanisms of disease: the molecular and cellular basis of joint destruction in rheumatoid arthritis. Nature Clinical Practice Rheumatology 1: 102–110.

    Article  PubMed  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. Muller-Ladner, U., J. Kriegsmann, B.N. Franklin, S. Matsumoto, T. Geiler, R.E. Gay, et al. 1996. Synovial fibroblasts of patients with rheumatoid arthritis attach to and invade normal human cartilage when engrafted into SCID mice. American Journal of Pathology 149: 1607–1615.

    CAS  PubMed Central  PubMed  Google Scholar 

  8. Tsai, C., L.A. Diaz Jr., N.G. Singer, L.L. Li, A.H. Kirsch, R. Mitra, et al. 1996. Responsiveness of human T lymphocytes to bacterial superantigens presented by cultured rheumatoid arthritis synoviocytes. Arthritis and Rheumatism 39: 125–136.

    Article  CAS  PubMed  Google Scholar 

  9. Tran, C.N., M.J. Davis, L.A. Tesmer, J.L. Endres, C.D. Motyl, C. Smuda, et al. 2007. Presentation of arthritogenic peptide to antigen-specific T cells by fibroblast-like synoviocytes. Arthritis and Rheumatism 56: 1497–1506.

    Article  CAS  PubMed  Google Scholar 

  10. Huber, L.C., J. Stanczyk, A. Jüngel, and S. Gay. 2007. Epigenetics in inflammatory rheumatic diseases. Arthritis and Rheumatism 56: 3523–3531.

    Article  CAS  PubMed  Google Scholar 

  11. Wilkinson, K.A., and J.M. Henley. 2010. Mechanisms, regulation and consequences of protein SUMOylation. Biochemistry Journal 428: 133–145.

    Article  CAS  Google Scholar 

  12. Wang, Y., and M. Dasso. 2009. SUMOylation and deSUMOylation at a glance. Journal of Cell Science 122: 4249–4252.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Huber, L.C., J.H. Distler, F. Moritz, H. Hemmatazad, T. Hauser, B.A. Michel, et al. 2007. Trichostatin A prevents the accumulation of extracellular matrix in a mouse model of bleomycin-induced skin fibrosis. Arthritis and Rheumatism 56: 2755–2764.

    Article  CAS  PubMed  Google Scholar 

  14. Wooley, P.H., H.S. Luthra, J.M. Stuart, and C.S. David. 1981. Type II collagen-induced arthritis in mice. I. Major histocompatibility complex (I region) linkage and antibody correlates. Journal of Experimental Medicine 154: 688–700.

    Article  CAS  PubMed  Google Scholar 

  15. Minakuchi, Y., F. Takeshita, N. Kosaka, H. Sasaki, Y. Yamamoto, M. Kouno, et al. 2004. Atelocollagen-mediated synthetic small interfering RNA delivery for effective gene silencing in vitro and in vivo. Nucleic Acids Research 32: e109.

    Article  PubMed Central  PubMed  Google Scholar 

  16. Tarrant, T.K., P. Liu, R.R. Rampersad, D. Esserman, L.R. Rothlein, R.G. Timoshchenko, et al. 2012. Decreased Th17 and antigen-specific humoral responses in CX3 CR1-deficient mice in the collagen- induced arthritis model. Arthritis and Rheumatism 64: 1379–1387.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Nishikawa, M., A. Myoui, T. Tomita, K. Takahi, A. Nampei, and H. Yoshikawa. 2003. Prevention of the onset and progression of collagen-induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653. Arthritis and Rheumatism 48: 2670–2681.

    Article  CAS  PubMed  Google Scholar 

  18. Aletaha, D., T. Neogi, A.J. Silman, J. Funovits, D.T. Felson, C.O. Bingham 3rd, et al. 2010. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis and Rheumatism 62: 2569–2581.

    Article  PubMed  Google Scholar 

  19. Yoshioka, Y., E. Kozawa, H. Urakawa, E. Arai, N. Futamura, L. Zhuo, et al. 2013. Suppression of hyaluronan synthesis alleviates inflammatory responses in murine arthritis and in human rheumatoid synovial fibroblasts. Arthritis and Rheumatism 65: 1160–1170.

    Article  CAS  PubMed  Google Scholar 

  20. Cha, H.S., S. Rosengren, D.L. Boyle, and G.S. Firestein. 2010. PUMA regulation and proapoptotic effects in fibroblast-like synoviocytes.Arthritis Rheum. 2006;54:587–92.

    Google Scholar 

  21. Dinatale BC, Perdew GH. Protein function analysis: rapid, cell-based siRNA-mediated ablation of endogenous expression with simultaneous ectopic replacement. Cytotechnology 62: 95–100.

  22. Lee, M.S., S.A. Yoo, C.S. Cho, P.G. Suh, W.U. Kim, and S.H. Ryu. 2006. Serum amyloid A binding to formyl peptide receptor-like 1 induces synovial hyperplasia and angiogenesis. Journal of Immunology 177: 5585–5594.

    Article  CAS  Google Scholar 

  23. Chang, S.K., Z. Gu, and M.B. Brenner. 2010. Fibroblast-like synoviocytes in inflammatory arthritis pathology: the emerging role of cadherin-11. Immunology Reviews 233: 256–266.

    Article  CAS  Google Scholar 

  24. Afuwape, A.O., S. Kiriakidis, and E.M. Paleolog. 2002. The role of the angiogenic molecule VEGF in the pathogenesis of rheumatoid arthritis. Histology and Histopathology 17: 961–972.

    CAS  PubMed  Google Scholar 

  25. Franz, J.K., T. Pap, K.M. Hummel, M. Nawrath, W.K. Aicher, Y. Shigeyama, et al. 2000. Expression of sentrin, a novel antiapoptotic molecule, at sites of synovial invasion in rheumatoid arthritis. Arthritis and Rheumatism 43: 599–607.

    Article  CAS  PubMed  Google Scholar 

  26. Liacini, A., J. Sylvester, W.Q. Li, and M. Zafarullah. 2002. Inhibition of interleukin-1-stimulated MAP kinases, activating protein-1 (AP-1) and nuclear factor kappa B (NF-kappa B) transcription factors down-regulates matrix metalloproteinase gene expression in articular chondrocytes. Matrix Biology 21: 251–262.

    Article  CAS  PubMed  Google Scholar 

  27. Liacini, A., J. Sylvester, W.Q. Li, W. Huang, F. Dehnade, M. Ahmad, et al. 2003. Induction of matrix metalloproteinase-13 gene expression by TNF-alpha is mediated by MAP kinases, AP-1, and NF-kappaB transcription factors in articular chondrocytes. Experimental Cell Research 288: 208–217.

    Article  CAS  PubMed  Google Scholar 

  28. Desterro, J.M., M.S. Rodriguez, and R.T. Hay. 1998. SUMO-1 modification of IkappaBalpha inhibits NF-kappaB activation. Molecular Cell 2: 233–239.

    Article  CAS  PubMed  Google Scholar 

  29. Huang, T.T., S.M. Wuerzberger-Davis, Z.H. Wu, and S. Miyamoto. 2003. Sequential modification of NEMO/IKKgamma by SUMO-1 and ubiquitin mediates NF-kappaB activation by genotoxic stress. Cell 115: 565–576.

    Article  CAS  PubMed  Google Scholar 

  30. Saltzman, A., G. Searfoss, C. Marcireau, M. Stone, R. Ressner, R. Munro, et al. 1998. hUBC9 associates with MEKK1 and type I TNF-alpha receptor and stimulates NFkappaB activity. FEBS Letters 425: 431–435.

    Article  CAS  PubMed  Google Scholar 

  31. Navarro-Millán, I., and J.R. Curtis. 2013. Newest clinical trial results with antitumor necrosis factor and nonantitumor necrosis factor biologics for rheumatoid arthritis. Current Opinion in Rheumatology 25: 384–390.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Conflict of Interest

None.

Author information

Authors and Affiliations

  1. Department of Rheumatology, Jinan Central Hospital Affiliated to Shandong University, No. 105 Jiefang Road, Lixia District, Jinan, 250013, China

    Faxin Li, Xueyan Li, Fanhua Meng & Fang Ma

  2. Department of Radiology, Jinan Central Hospital Affiliated to Shandong University, Jinan, China

    Liqing Kou

  3. Department of Pharmacy, Jinan Central Hospital Affiliated to Shandong University, Jinan, China

    Yi Li

Authors
  1. Faxin Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xueyan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Liqing Kou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yi Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fanhua Meng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fang Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Faxin Li.

Additional information

Faxin Li and Xueyan Li contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, F., Li, X., Kou, L. et al. SUMO-Conjugating Enzyme UBC9 Promotes Proliferation and Migration of Fibroblast-like Synoviocytes in Rheumatoid Arthritis. Inflammation 37, 1134–1141 (2014). https://doi.org/10.1007/s10753-014-9837-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-014-9837-x

KEY WORDS

Search

Navigation