This Article
Right arrow Full Text Free
Right arrow Full Text (PDF) Free
Right arrow Letters to the Editor: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when Letters to the Editor are posted
Right arrow Alert me if a correction is posted
Services
Right arrow E-mail this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My File Cabinet
Right arrow Download to citation manager
Right arrow Rights and Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by BLAINE, T. A.
Right arrow Articles by O'KEEFE, R. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by BLAINE, T. A.
Right arrow Articles by O'KEEFE, R. J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us   Add to Facebook   Add to Technorati   Add to Twitter  
What's this?
The Journal of Bone and Joint Surgery 78:1181-92 (1996)
© 1996 The Journal of Bone and Joint Surgery, Inc.

Increased Levels of Tumor Necrosis Factor-{alpha} and Interleukin-6 Protein and Messenger RNA in Human Peripheral Blood Monocytes due to Titanium Particles*

THEODORE A. BLAINE, M.D.{dagger}, RANDY N. ROSIER, M.D., PH.D.{dagger}, J. EDWARD PUZAS, PH.D.{dagger}, R. JOHN LOONEY, M.D.{dagger}, PAUL R. REYNOLDS, PH.D.{dagger}, SUSAN D. REYNOLDS, PH.D.{dagger} and REGIS J. O'KEEFE, M.D.{dagger}, ROCHESTER, NEW YORK

Investigation performed at the Departments of Orthopaedics and Immunology, University of Rochester School of Medicine and Dentistry, Rochester

Cytokines produced by macrophages in the periprosthetic membranes surrounding joint replacements have been implicated as causal agents in osteolysis and prosthetic loosening. The present study characterizes the response of human peripheral blood monocytes to titanium particles. Monocytes were obtained from volunteers and blood that had been donated to the American Red Cross and were cultured in the presence of titanium particles (one to three micrometers in diameter). There were consistent dose-dependent increases in the production of TNF-{alpha} (tumor necrosis factor-{alpha}) and IL-6 (interleukin-6) protein, with the greatest stimulation generally observed with a concentration of 6 x 105 to 6 x 106 particles of titanium per milliliter. The level of TNF-{alpha} was the greatest (fifty to 1000 times greater than the control level) after eight hours of exposure to titanium particles; the level of IL-6 was two to five times greater than the control level after sixteen hours of exposure. These increases were similar to those observed after stimulation with lipopolysaccharide and depended on de novo synthesis rather than on release from intracellular stores. The production of TNF-{alpha} was inhibited in a dose-dependent manner by the translational inhibitor cycloheximide and the transcriptional inhibitor actinomycin D, indicating the requirement for both mRNA (messenger RNA) and protein synthesis for the induction of cytokine synthesis by titanium particles. Although the increase in the levels of cytokine mRNA in response to titanium was rapid (thirty to ninety minutes), the increase in the level of TNF-{alpha} mRNA preceded that of IL-6 mRNA. The level of TNF-{alpha} mRNA was the greatest at ninety minutes and the level of IL-6 mRNA was the greatest at three hours. After stimulation with titanium particles, the level of TNF-{alpha} mRNA was increased as much as fivefold and the level of IL-6 mRNA, as much as twelvefold. CLINICAL RELEVANCE: Awareness of the importance of wear debris particles in cytokine-induced bone resorption has resulted in improvements in the designs of implants and in operative techniques to reduce wear of components. The present study further elucidates the biological mechanisms involved in periprosthetic osteolysis. Titanium-stimulated biosynthesis of the cytokines TNF-{alpha} and IL-6, which are both potent stimulators of bone resorption, requires increases in the synthesis of both mRNA and protein by monocytes. An understanding of the complex mechanisms of the induction of cytokine synthesis by particles of wear debris will facilitate the design of pharmacological agents to control periprosthetic bone resorption. These agents, in combination with other efforts to reduce the generation of wear debris, may improve the longevity of orthopaedic implants.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us   Add to Facebook Facebook   Add to Technorati Technorati   Add to Twitter Twitter    What's this?


This article has been cited by other articles:


Home page
 JBJSHome page
M. V. Smith, M. J. Lee, A. S. Islam, J. L. Rohrer, V. M. Goldberg, M. A. Beidelschies, and E. M. Greenfield
Inhibition of the PI3K-Akt Signaling Pathway Reduces Tumor Necrosis Factor-{alpha} Production in Response to Titanium Particles in Vitro
J. Bone Joint Surg. Am., May 1, 2007; 89(5): 1019 - 1027.
[Abstract] [Full Text] [PDF]

Home page
 JBJSHome page
D. S. Rakshit, K. Ly, T. K. Sengupta, B. J. Nestor, T. P. Sculco, L. B. Ivashkiv, and P. E. Purdue
Wear Debris Inhibition of Anti-Osteoclastogenic Signaling by Interleukin-6 and Interferon-{gamma} Mechanistic Insights and Implications for Periprosthetic Osteolysis
J. Bone Joint Surg. Am., April 1, 2006; 88(4): 788 - 799.
[Abstract] [Full Text] [PDF]

Home page
 JBJSHome page
D. Togawa, T. W. Bauer, I. H. Lieberman, and H. Sakai
Lumbar Intervertebral Body Fusion Cages: Histological Evaluation of Clinically Failed Cages Retrieved from Humans
J. Bone Joint Surg. Am., January 1, 2004; 86(1): 70 - 79.
[Abstract] [Full Text] [PDF]

Home page
 JBJSHome page
L. M. Childs, J. J. Goater, R. J. O'Keefe, and E. M. Schwarz
Effect of Anti-Tumor Necrosis Factor-{alpha} Gene Therapy on Wear Debris-Induced Osteolysis
J. Bone Joint Surg. Am., December 1, 2001; 83(12): 1789 - 1797.
[Abstract] [Full Text] [PDF]

Home page
 JBJSHome page
P. F. Pollice, R. N. Rosier, R. J. Looney, J. E. Puzas, E. M. Schwarz, and R. J. O'Keefe
Oral Pentoxifylline Inhibits Release of Tumor Necrosis Factor-Alpha from Human Peripheral Blood Monocytes : A Potential Treatment for Aseptic Loosening of Total Joint Components
J. Bone Joint Surg. Am., July 1, 2001; 83(7): 1057 - 1061.
[Abstract] [Full Text] [PDF]

Home page
 JBJSHome page
Y. Bi, R. R. VanDeMotter, A. A. Ragab, V. M. Goldberg, J. M. Anderson, and E. M. Greenfield
Titanium Particles Stimulate Bone Resorption by Inducing Differentiation of Murine Osteoclasts
J. Bone Joint Surg. Am., April 1, 2001; 83(4): 501 - 501.
[Abstract] [Full Text]

Home page
 JBJSHome page
C. Vermes, R. Chandrasekaran, J. J. Jacobs, J. O. Galante, K. A. Roebuck, and T. T. Glant
The Effects of Particulate Wear Debris, Cytokines, and Growth Factors on the Functions of MG-63 Osteoblasts
J. Bone Joint Surg. Am., February 1, 2001; 83(2): 201 - 201.
[Abstract] [Full Text]

Home page
 JBJSHome page
K. A ROEBUCK, J. J. JACOBS, and T. T. GLANT
New Horizons in Orthopaedic Research: Elucidation of Cellular Signal Transduction Pathways
J. Bone Joint Surg. Am., May 1, 1999; 81(5): 599 - 602.
[Full Text]

Home page
 JBJSHome page
T. A. BLAINE, P. F. POLLICE, R. N. ROSIER, P. R. REYNOLDS, J. E. PUZAS, and R. J. O'KEEFE
Modulation of the Production of Cytokines in Titanium-Stimulated Human Peripheral Blood Monocytes by Pharmacological Agents. The Role of cAMP-Mediated Signaling Mechanisms*{{dagger}}
J. Bone Joint Surg. Am., October 1, 1997; 79(10): 1519 - 28.
[Abstract] [Full Text]