Skip to main content

Advertisement

SpringerLink
Log in

Protection Against Titanium Particle-Induced Inflammatory Osteolysis by the Proteasome Inhibitor Bortezomib In Vivo

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Wear particle-induced vascularized granulomatous inflammation and subsequent inflammatory osteolysis is the most common cause of aseptic loosening after total joint replacement (TJR); however, the precise mechanism by which this occurs is unclear. This study investigates the effects of the proteasome inhibitor bortezomib (Bzb) on the expression of key biochemical markers of bone metabolism and vascularised granulomatous tissues, such as receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin (OPG), vascular endothelial growth factor (VEGF) and tumor necrosis factor receptor-associated factor 6 (TRAF6). In addition, the effect of Bzb on apoptosis of CD68+ cells was examined. A total of 32 female BALB/C mice were randomly divided into four groups. After implantation of calvaria bone from syngeneic littermates, titanium (Ti) particles were injected into established air pouches for all mice (excluding negative controls) to provoke inflammatory osteolysis. Subsequently, Bzb was administered at a ratio of 0, 0.1, or 0.5 mg/kg on day 1, 4, 8, and 11 post-surgery to alleviate this response. All of the air pouches were harvested 14 days after the surgical procedure and were processed for molecular and histological analysis. The results demonstrated that Ti injection elevated the expression of RANKL, OPG, VEGF, and TRAF6 at both the gene and protein levels, increased counts of infiltrated cells and thickness of air pouch membranes, and elevated the apoptosis index (AI) of CD68+ cells. Bzb treatment significantly improved Ti particle-induced implanted bone osteolysis, attenuated vascularised granulomatous tissues and elevated AI of CD68+ cells. Therefore, the proteasome pathway may represent an effective therapeutic target for the prevention and treatment of aseptic loosening.

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
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Ingham, E., and J. Fisher. 2005. The role of macrophages in osteolysis of total joint replacement. Biomaterials 26(11): 1271–1286.

    Article  PubMed  CAS  Google Scholar 

  2. Wang, M., P. Sharkey, and R. Tuan. 2004. Particle bioreactivity and wear-mediated osteolysis. The Journal of Arthroplasty 19(8): 1028–1038.

    Article  PubMed  Google Scholar 

  3. Ren, W.P., D.C. Markel, R. Zhang, X. Peng, B. Wu, H. Monica, and P.H. Wooley. 2006. Association between UHMWPE particle-induced inflammatory osteoclastogenesis and expression of RANKL, VEGF, and Flt-1 in vivo. Biomaterials 27(30): 5161–5169.

    Article  PubMed  CAS  Google Scholar 

  4. Al-Saffar, N., J. Mah, Y. Kadoya, and P.A. Revell. 1995. Neovascularisation and the induction of cell adhesion molecules in response to degradation products from orthopaedic implants. Annals of the Rheumatic Diseases 54(3): 201–208.

    Article  PubMed  CAS  Google Scholar 

  5. Ren, W., R. Zhang, D.C. Markel, B. Wu, X. Peng, M. Hawkins, and P.H. Wooley. 2007. Blockade of vascular endothelial growth factor activity suppresses wear debris-induced inflammatory osteolysis. Journal of Rheumatology 34(1): 27–35.

    PubMed  CAS  Google Scholar 

  6. Markel, D.C., R. Zhang, T. Shi, M. Hawkins, and W. Ren. 2009. Inhibitory effects of erythromycin on wear debris-induced VEGF/Flt-1 gene production and osteolysis. Inflammation Research 58(7): 413–421.

    Article  CAS  Google Scholar 

  7. Zhang, W., Peng, X., Cheng, T., and Zhang, X. 2011. Vascular endothelial growth factor gene silencing suppresses wear debris-induced inflammation. Int Orthop. Available from URL: http://www.springerlink.com/content/86m1431q8035755q/ (doi:10.1007/s00264-011-1252-4).

  8. Anandarajah, A.P. 2009. Role of RANKL in bone diseases. Trends in Endocrinology and Metabolism 20(2): 88–94.

    Article  PubMed  CAS  Google Scholar 

  9. Bord, S., D. Ireland, S. Beavan, and J. Compston. 2003. The effects of estrogen on osteoprotegerin, RANKL, and estrogen receptor expression in human osteoblasts. Bone 32(2): 136–141.

    Article  PubMed  CAS  Google Scholar 

  10. Ye, H., J.R. Arron, B. Lamothe, M. Cirilli, T. Kobayashi, N.K. Shevde, D. Segal, O.K. Dzivenu, M. Vologodskaia, and M. Yim. 2002. Distinct molecular mechanism for initiating TRAF6 signalling. Nature 418(6896): 443–447.

    Article  PubMed  CAS  Google Scholar 

  11. Armstrong, A.P., M.E. Tometsko, M. Glaccum, C.L. Sutherland, D. Cosman, and W.C. Dougall. 2002. A RANK/TRAF6-dependent signal transduction pathway is essential for osteoclast cytoskeletal organization and resorptive function. Journal of Biological Chemistry 277(46): 44347–44356.

    Article  PubMed  CAS  Google Scholar 

  12. Boyle, W.J., W.S. Simonet, and D.L. Lacey. 2003. Osteoclast differentiation and activation. Nature 423(6937): 337–342.

    Article  PubMed  CAS  Google Scholar 

  13. Kobayashi, N., Y. Kadono, A. Naito, K. Matsumoto, T. Yamamoto, S. Tanaka, and J. Inoue. 2001. Segregation of TRAF6-mediated signaling pathways clarifies its role in osteoclastogenesis. EMBO Journal 20(6): 1271–1280.

    Article  PubMed  CAS  Google Scholar 

  14. Elliott, P.J., and J.S. Ross. 2001. The proteasome. American Journal of Clinical Pathology 116(5): 637–646.

    Article  PubMed  CAS  Google Scholar 

  15. Wickner, S., M.R. Maurizi, and S. Gottesman. 1999. Posttranslational quality control: folding, refolding, and degrading proteins. Science 286(5446): 1888–1893.

    Article  PubMed  CAS  Google Scholar 

  16. 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.

    Article  PubMed  CAS  Google Scholar 

  17. von Metzler, I., H. Krebbel, M. Hecht, R.A. Manz, C. Fleissner, M. Mieth, M. Kaiser, C. Jakob, J. Sterz, L. Kleeberg, U. Heider, and O. Sezer. 2007. Bortezomib inhibits human osteoclastogenesis. Leukemia 21(9): 2025–2034.

    Article  Google Scholar 

  18. Heider, U., M. Kaiser, C. Müller, C. Jakob, I. Zavrski, C.O. Schulz, C. Fleissner, M. Hecht, and O. Sezer. 2006. Bortezomib increases osteoblast activity in myeloma patients irrespective of response to treatment. European Journal of Haematology 77(3): 233–238.

    Article  PubMed  CAS  Google Scholar 

  19. Arpinati, M., G. Chirumbolo, B. Nicolini, C. Agostinelli, and D. Rondelli. 2008. Selective apoptosis of monocytes and monocyte-derived DCs induced by bortezomib (Velcade). Bone Marrow Transplantation 43(3): 253–259.

    Article  PubMed  Google Scholar 

  20. Rakshit, D.S., K. Ly, T.K. Sengupta, B.J. Nestor, T.P. Sculco, L.B. Ivashkiv, and P.E. Purdue. 2006. Wear debris inhibition of anti-osteoclastogenic signaling by interleukin-6 and interferon- gamma mechanistic insights and implications for periprosthetic osteolysis. The Journal of Bone and Joint Surgery American 88(4): 788–799.

    Article  Google Scholar 

  21. 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.

    Article  PubMed  CAS  Google Scholar 

  22. Livak, K.J., and T.D. Schmittgen. 2001. Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods 25(4): 402–408.

    Article  PubMed  CAS  Google Scholar 

  23. Ren, W., D.C. Markel, R. Schwendener, Y. Ding, B. Wu, and P.H. 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.

    Article  PubMed  Google Scholar 

  24. 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.

    Article  PubMed  Google Scholar 

  25. 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.

    Article  PubMed  Google Scholar 

  26. 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.

    Article  PubMed  CAS  Google Scholar 

  27. Miyanishi, K., M.C.D. Trindade, T. Ma, S.B. Goodman, D.J. Schurman, and R.L. Smith. 2003. Periprosthetic osteolysis: induction of vascular endothelial growth factor from human monocyte/macrophages by orthopaedic biomaterial particles. Journal of Bone and Mineral Research 18(9): 1573–1583.

    Article  PubMed  CAS  Google Scholar 

  28. Senger, D.R., S.J. Galli, A.M. Dvorak, C.A. Perruzzi, V.S. Harvey, and H.F. Dvorak. 1983. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science 219(4587): 983–985.

    Article  PubMed  CAS  Google Scholar 

  29. Ferrara, N., and W.J. Henzel. 1989. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochemical and Biophysical Research Communications 161(2): 851–858.

    Article  PubMed  CAS  Google Scholar 

  30. Leung, D.W., G. Cachianes, W.J. Kuang, D.V. Goeddel, and N. Ferrara. 1989. Vascular endothelial growth factor is a secreted angiogenic mitogen. Science 246(4935): 1306–1309.

    Article  PubMed  CAS  Google Scholar 

  31. Min, J., Y. Kim, E. Kim, Y. Gho, I. Kang, S. Lee, Y. Kong, and Y. Kwon. 2003. Vascular endothelial growth factor up-regulates expression of receptor activator of NF-kappa B (RANK) in endothelial cells. Concomitant increase of angiogenic responses to RANK ligand. Journal of Biological Chemistry 278(41): 39548–39557.

    Article  PubMed  CAS  Google Scholar 

  32. Wong, B., R. Josien, S. Lee, B. Sauter, H. Li, R. Steinman, and Y. Choi. 1997. TRANCE (tumor necrosis factor [TNF]-related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor. The Journal of Experimental Medicine 186(12): 2075–2080.

    Article  PubMed  CAS  Google Scholar 

  33. Leibbrandt, A., and J.M. Penninger. 2008. RANK/RANKL: regulators of immune responses and bone physiology. Annals of the New York Academy of Sciences 1143(1): 123–150.

    Article  PubMed  CAS  Google Scholar 

  34. Mandelin, J., T.F. Li, M. Liljestrom, M. Kroon, R. Hanemaaijer, S. Santavirta, and Y.T. Konttinen. 2003. Imbalance of RANKL/RANK/OPG system in interface tissue in loosening of total hip replacement. The Journal of Bone and Joint Surgery British 85(8): 1196–1201.

    Article  CAS  Google Scholar 

  35. Haynes, D.R., T. Crotti, A. Potter, M. Loric, G.J. Atkins, D.W. Howie, and D.M. Findlay. 2001. The osteoclastogenic molecules RANKL and RANK are associated with periprosthetic osteolysis. The Journal of Bone and Joint Surgery. British Volume 83(6): 902–911.

    Article  PubMed  CAS  Google Scholar 

  36. Ren, W., R. Blasier, X. Peng, T. Shi, P.H. Wooley, and D. Markel. 2009. Effect of oral erythromycin therapy in patients with aseptic loosening of joint prostheses. Bone 44(4): 671–677.

    Article  PubMed  CAS  Google Scholar 

  37. Bylski, D., C. Wedemeyer, J. Xu, T. Sterner, F. Löer, and M. von Knoch. 2009. Alumina ceramic particles, in comparison with titanium particles, hardly affect the expression of RANK-, TNF-α-, and OPG-mRNA in the THP-1 human monocytic cell line. Journal of Biomedical Materials Research. Part A 89(3): 707–716.

    Article  PubMed  Google Scholar 

  38. Granchi, D., G. Ciapetti, I. Amato, S. Pagani, E. Cenni, L. Savarino, S. Avnet, J. Peris, A. Pellacani, and N. Baldini. 2004. The influence of alumina and ultra-high molecular weight polyethylene particles on osteoblast–osteoclast cooperation. Biomaterials 25(18): 4037–4045.

    Article  PubMed  CAS  Google Scholar 

  39. Baumann, B., C. Rader, J. Seufert, U. Nöth, O. Rolf, J. Eulert, and F. Jakob. 2004. Effects of polyethylene and TiAIV wear particles on expression of RANK, RANKL and OPG mRNA. Acta Orthopaedica 75(3): 295–302.

    Article  Google Scholar 

  40. Masui, T., S. Sakano, Y. Hasegawa, H. Warashina, and N. Ishiguro. 2005. Expression of inflammatory cytokines, RANKL and OPG induced by titanium, cobalt-chromium and polyethylene particles. Biomaterials 26(14): 1695–1702.

    Article  PubMed  CAS  Google Scholar 

  41. Inoue, J., T. Ishida, N. Tsukamoto, N. Kobayashi, A. Naito, S. Azuma, and T. Yamamoto. 2000. Tumor necrosis factor receptor-associated factor (TRAF) family: adapter proteins that mediate cytokine signaling. Experimental Cell Research 254(1): 14.

    Article  PubMed  CAS  Google Scholar 

  42. Rauner, M., W. Sipos, and P. Pietschmann. 2006. Osteoimmunology. International Archives of Allergy and Immunology 143(1): 31–48.

    Article  PubMed  Google Scholar 

  43. Hongming, H., and H. Jian. 2009. Bortezomib inhibits maturation and function of osteoclasts from PBMCs of patients with multiple myeloma by downregulating TRAF6. Leukemia Research 33(1): 115–122.

    Article  PubMed  Google Scholar 

  44. Ang, E., N.J. Pavlos, S.L. Rea, M. Qi, T. Chai, J.P. Walsh, T. Ratajczak, M.H. Zheng, and J. Xu. 2009. Proteasome inhibitors impair RANKL-induced NF-κB activity in osteoclast-like cells via disruption of p62, TRAF6, CYLD, and IκBα signaling cascades. Journal of Cellular Physiology 220(2): 450–459.

    Article  PubMed  CAS  Google Scholar 

  45. Baldwin, L., B. Flanagan, P. McLaughlin, R. Parkinson, J. Hunt, and D. Williams. 2002. A study of tissue interface membranes from revision accord knee arthroplasty: the role of T lymphocytes. Biomaterials 23(14): 3007–3014.

    Article  PubMed  CAS  Google Scholar 

  46. Micklem, K., E. Rigney, J. Cordell, D. Simmons, P. Stross, H. Turley, B. Seed, and D. Mason. 1989. A human macrophage-associated antigen (CD68) detected by six different monoclonal antibodies. British Journal of Haematology 73(1): 6–11.

    Article  PubMed  CAS  Google Scholar 

  47. Anan, A., E.S. Baskin-Bey, H. Isomoto, J.L. Mott, S.F. Bronk, J.H. Albrecht, and G.J. Gores. 2006. Proteasome inhibition attenuates hepatic injury in the bile duct-ligated mouse. American Journal of Physiology - Gastrointestinal and Liver Physiology 291(4): G709–G716.

    Article  PubMed  CAS  Google Scholar 

  48. Pagliari, L.J., H. Perlman, H. Liu, and R.M. Pope. 2000. Macrophages require constitutive NF-kappa B activation to maintain A1 expression and mitochondrial homeostasis. Molecular and Cellular Biology 20(23): 8855–8865.

    Article  PubMed  CAS  Google Scholar 

  49. Landgraeber, S., M. von Knoch, F. Loer, A. Wegner, M. Tsokos, and M. Totsch. 2008. Extrinsic and intrinsic pathways of apoptosis in aseptic loosening after total hip replacement. Biomaterials 29(24–25): 3444–3450.

    Article  PubMed  CAS  Google Scholar 

  50. Mao, X., Pan, X., Cheng, T., and Zhang, X. 2011. Therapeutic potential of the proteasome inhibitor bortezomib on titanium particle-induced inflammation in a murine model. Inflammation. Available from URL: http://www.springerlink.com/content/u5516224u6501835/ (doi:10.1007/s10753-011-9392-7).

  51. 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.

    Article  PubMed  CAS  Google Scholar 

  52. 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.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

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

Author information

Authors and Affiliations

  1. Department of Orthopaedics, The Sixth Affiliated People’s Hospital, Shanghai Jiaotong University School of Medicine, 600 Yishan Road, Shanghai, 200233, China

    Xin Mao, Xiaoyun Pan, Song Zhao, Xiaochun Peng, Tao Cheng & Xianlong Zhang

Authors
  1. Xin Mao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoyun Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Song Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiaochun Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tao Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xianlong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xianlong Zhang.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Mao, X., Pan, X., Zhao, S. et al. Protection Against Titanium Particle-Induced Inflammatory Osteolysis by the Proteasome Inhibitor Bortezomib In Vivo . Inflammation 35, 1378–1391 (2012). https://doi.org/10.1007/s10753-012-9451-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-012-9451-8

KEY WORDS

Search

Navigation