, Volume 35, Issue 3, pp 905–912 | Cite as

Therapeutic Potential of the Proteasome Inhibitor Bortezomib on Titanium Particle-Induced Inflammation in a Murine Model

  • Xin Mao
  • Xiaoyun Pan
  • Tao Cheng
  • Xianlong Zhang


Wear particle-induced aseptic loosening has been recognized as a harmful inflammatory process that jeopardizes the longevity of total joint replacement. The proteasome controls the activation of NF-κB and subsequent inflammatory mediators, such as TNF-α and IL-1β; thus, we investigated whether proteasome inhibition can ameliorate wear particle-induced inflammation in a murine model. A total of 48 BALB/C mice were divided into four groups. Titanium (Ti) particles were injected into the established air pouches of all mice (except negative controls) to provoke inflammation, and then 0.1 or 0.5 mg/kg of Bortezomib (Bzb, a proteasome inhibitor) was administered to ameliorate the inflammation response, while air pouches without Bzb administration were used as loading controls. The air pouches were harvested 2 or 7 days after Bzb injection for molecular and histological analyses. Inflammation responses in the air pouch tissues of Bzb treatment groups are lower than those in the Ti-stimulated group, and this occurs in a dose-dependent manner. Bzb can significantly attenuate the severity of Ti-induced inflammation in air pouches.


particle aseptic loosening air pouch Bortezomib NF-κB 



This work was supported by the Integration of Medicine and Engineering Foundation of Shanghai Jiaotong University (YG2010MS33).


  1. 1.
    Daniel, J., P. Pynsent, and D. McMinn. 2004. Metal-on-metal resurfacing of the hip in patients under the age of 55 years with osteoarthritis. Journal of Bone and Joint Surgery. British Volume 86(2): 177–184.CrossRefGoogle Scholar
  2. 2.
    Sundfeldt, M., L.V. Carlsson, C.B. Johansson, P. Thomsen, and C. Gretzer. 2006. Aseptic loosening, not only a question of wear: A review of different theories. Acta Orthopaedica 77(2): 177–197.PubMedCrossRefGoogle Scholar
  3. 3.
    Mabilleau, G., Y.M. Kwon, H. Pandit, D.W. Murray, and A. Sabokbar. 2008. Metal-on-metal hip resurfacing arthroplasty: A review of periprosthetic biological reactions. Acta Orthopaedica 79(6): 734–747.PubMedCrossRefGoogle Scholar
  4. 4.
    Purdue, P.E., P. Koulouvaris, B.J. Nestor, and T.P. Sculco. 2006. The central role of wear debris in periprosthetic osteolysis. HSS Journal 2(2): 102–113.PubMedCrossRefGoogle Scholar
  5. 5.
    Ingham, E., and J. Fisher. 2005. The role of macrophages in osteolysis of total joint replacement. Biomaterials 26(11): 1271–1286.PubMedCrossRefGoogle Scholar
  6. 6.
    Ren, W., X.H. Li, B.D. Chen, and P.H. Wooley. 2004. Erythromycin inhibits wear debris-induced osteoclastogenesis by modulation of murine macrophage NF-κB activity. Journal of Orthopaedic Research 22(1): 21–29.PubMedCrossRefGoogle Scholar
  7. 7.
    Goodman, S.B., M. Trindade, T. Ma, M. Genovese, and R.L. Smith. 2005. Pharmacologic modulation of periprosthetic osteolysis. Clinical Orthopaedics and Related Research 430: 39–45.PubMedCrossRefGoogle Scholar
  8. 8.
    Paramore, A., and S. Frantz. 2003. Bortezomib. Nature Reviews. Drug Discovery 2(8): 611–612.PubMedCrossRefGoogle Scholar
  9. 9.
    Diptendu, S., L. Khanh, K. Tapas, J. Bryan, P. Thomas, B. Lionel, and P. Edward. 2006. Wear debris inhibition of anti-osteoclastogenic signaling by interleukin-6 and interferon-γ mechanistic insights and implications for periprosthetic osteolysis. Journal of Bone and Joint Surgery. American Volume 88(4): 788–799.CrossRefGoogle Scholar
  10. 10.
    Wooley, P.H., R. Morren, J. Andary, S. Sud, S.Y. Yang, L. Mayton, D. Markel, A. Sieving, and S. Nasser. 2002. Inflammatory responses to orthopaedic biomaterials in the murine air pouch. Biomaterials 23(2): 517–526.PubMedCrossRefGoogle Scholar
  11. 11.
    Ren, W., D. Markel, R. Schwendener, Y. Ding, B. Wu, and P. Wooley. 2008. Macrophage depletion diminishes implant-wear-induced inflammatory osteolysis in a mouse model. Journal of Biomedical Materials Research. Part A 85(4): 1043–1051.PubMedCrossRefGoogle Scholar
  12. 12.
    Edwards, J., A. Sedgwick, and D. Willoughby. 1981. The formation of a structure with the features of synovial lining by subcutaneous injection of air: An in vivo tissue culture system. The Journal of Pathology 134(2): 147–156.PubMedCrossRefGoogle Scholar
  13. 13.
    Ciechanover, A. 1994. The ubiquitin–proteasome proteolytic pathway. Cell 79(1): 13–21.PubMedCrossRefGoogle Scholar
  14. 14.
    Goldberg, A.L. 2003. Protein degradation and protection against misfolded or damaged proteins. Nature 426(6968): 895–899.PubMedCrossRefGoogle Scholar
  15. 15.
    Richardson, P.G., B. Barlogie, J. Berenson, S. Singhal, S. Jagannath, D. Irwin, S.V. Rajkumar, G. Srkalovic, M. Alsina, and R. Alexanian. 2003. A phase 2 study of bortezomib in relapsed, refractory myeloma. The New England Journal of Medicine 348(26): 2609–2617.PubMedCrossRefGoogle Scholar
  16. 16.
    Lee, S.W., J.H. Kim, Y.B. Park, and S.K. Lee. 2009. Bortezomib attenuates murine collagen-induced arthritis. Annals of the Rheumatic Diseases 68(11): 1761–1767.PubMedCrossRefGoogle Scholar
  17. 17.
    Yannaki, E., A. Papadopoulou, E. Athanasiou, P. Kaloyannidis, A. Paraskeva, D. Bougiouklis, P. Palladas, M. Yiangou, and A. Anagnostopoulos. 2010. The proteasome inhibitor bortezomib drastically affects inflammation and bone disease in adjuvant-induced arthritis in rats. Arthritis and Rheumatism 62(11): 3277–3288.PubMedCrossRefGoogle Scholar
  18. 18.
    Lawrence, T. 2009. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harbor Perspectives in Biology 1(6): a001651.PubMedCrossRefGoogle Scholar
  19. 19.
    Mankan, A.K., M.W. Lawless, S.G. Gray, D. Kelleher, and R. McManus. 2009. NF-κB regulation: The nuclear response. Journal of Cellular and Molecular Medicine 13(4): 631–643.PubMedCrossRefGoogle Scholar
  20. 20.
    Karin, M., Y. Yamamoto, and Q.M. Wang. 2004. The IKK NF-κB system: A treasure trove for drug development. Nature Reviews. Drug Discovery 3(1): 17–26.PubMedCrossRefGoogle Scholar
  21. 21.
    Jimi, E., K. Aoki, H. Saito, F. D’Acquisto, M.J. May, I. Nakamura, T. Sudo, T. Kojima, F. Okamoto, and H. Fukushima. 2004. Selective inhibition of NF-kappaB blocks osteoclastogenesis and prevents inflammatory bone destruction in vivo. Nature Medicine 10(6): 617–624.PubMedCrossRefGoogle Scholar
  22. 22.
    Xu, J., H.F. Wu, E.S.M. Ang, K. Yip, M. Woloszyn, M.H. Zheng, and R.X. Tan. 2009. NF-κB modulators in osteolytic bone diseases. Cytokine & Growth Factor Reviews 20(1): 7–17.CrossRefGoogle Scholar
  23. 23.
    Jones, L.C., C. Frondoza, and D.S. Hungerford. 1999. Immunohistochemical evaluation of interface membranes from failed cemented and uncemented acetabular components. Journal of Biomedical Materials Research 48(6): 889–898.PubMedCrossRefGoogle Scholar
  24. 24.
    Stea, S., M. Visentin, D. Granchi, G. Ciapetti, M. Donati, A. Sudanese, C. Zanotti, and A. Toni. 2000. Cytokines and osteolysis around total hip prostheses. Cytokine 12(10): 1575–1579.PubMedCrossRefGoogle Scholar
  25. 25.
    Epstein, F.H., P.J. Barnes, and M. Karin. 1997. Nuclear factor-кB-a pivotal transcription factor in chronic inflammatory disease. The New England Journal of Medicine 336(15): 1066–1071.CrossRefGoogle Scholar
  26. 26.
    Baumann, H., and J. Gauldie. 1994. The acute phase response. Immunology Today 15(2): 74–80.PubMedCrossRefGoogle Scholar
  27. 27.
    Lin, E., S.E. Calvano, and S.F. Lowry. 2000. Inflammatory cytokines and cell response in surgery. Surgery 127(2): 117–126.PubMedCrossRefGoogle Scholar
  28. 28.
    Cheng, T., G.Y. Zhang, C.J. Guo, and X. Zhang. 2010. Effects of NF-κB inhibitor on titanium particulate-induced inflammation in a murine model. Journal of Surgical Research 162(2): 225–230.PubMedCrossRefGoogle Scholar
  29. 29.
    Zhou, F., X. Zhu, H. Mao, H. Yang, D. Geng, and Y. Xu. 2010. Effects of a cannabinoid receptor 2 selective antagonist on the inflammatory reaction to titanium particles in vivo and in vitro. The Journal of International Medical Research 38(6): 2023–2032.PubMedGoogle Scholar
  30. 30.
    Hofbauer, L., D. Lacey, C. Dunstan, T. Spelsberg, B. Riggs, and S. Khosla. 1999. Interleukin-1 [beta] and tumor necrosis factor-[alpha], but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 25(3): 255–259.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Xin Mao
    • 1
  • Xiaoyun Pan
    • 1
  • Tao Cheng
    • 1
  • Xianlong Zhang
    • 1
  1. 1.Department of Orthopedics, The Sixth Affiliated People’s HospitalShanghai Jiaotong University School of MedicineShanghaiChina

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