Abstract

Aseptic loosening of joint implants is one of the major problems in clinical orthopaedics. We and others have recently provided evidence that adherent endotoxin is involved in the stimulation by wear particles of both cytokine production and osteoclast differentiation. However, the importance of endotoxin in vivo is less well studied. Our proposed studies are, therefore, designed to more conclusively test the over-all hypothesis that adherent endotoxin is an important stimulator of wear particle- induced osteolysis. This hypothesis does not suggest that adherent endotoxin is the only stimulator of osteolysis, only that endotoxin is an important stimulator. The following specific aims are proposed:
Aim 1. To determine the mechanism of action of adherent endotoxin in vitro.
This aim will test three alternative, but not mutually-exclusive, hypotheses The first hypothesis is that the wear particles deliver endotoxin to the responding cells. The second hypothesis is that adherent endotoxin on the wear particles increases attachment to, and/or phagocytosis by, the responding cells. The third hypotheses is that adherent endotoxin alters the nature of the cellular response to the wear particles.
Aim 2. To determine whether adherent endotoxin is an important stimulator of particle-induce osteolysis in vivo.
This aim will two complementary hypothesis The first hypothesis is that adherent endotoxin is an important stimulator of wear particle-induced osteolysis in mice. The second hypothesis is that wear particles retrieved from patients with aseptic loosening contain substantial amounts of adherent endotoxin.
Aim 3. To determine whether adherent endotoxin is an important inhibitor of bone formation on orthopaedic implant materials in vitro.
This aim will test two complementary hypotheses. The first hypothesis is that removal of adherent endotoxin will increase attachment, proliferation, and/or osteoblastic differentiation of mesenchymal precursor cells cultured on titanium discs. The second hypothesis is that endotoxin hyporesponsiveness will increase attachment, proliferation, and/or osteoblastic differentiation of mesenchymal precursor cells cultured on titanium discs.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR043769-08
Application #
6651195
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Panagis, James S
Project Start
1996-09-27
Project End
2005-08-31
Budget Start
2003-09-01
Budget End
2005-08-31
Support Year
8
Fiscal Year
2003
Total Cost
$267,750
Indirect Cost

  Institution

Name
Case Western Reserve University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106

  Publications

Islam, Andrew S; Beidelschies, Michelle A; Huml, Anne et al. (2011) Titanium particles activate toll-like receptor 4 independently of lipid rafts in RAW264.7 murine macrophages. J Orthop Res 29:211-7
Beidelschies, Michelle A; Huang, Honglian; McMullen, Megan R et al. (2008) Stimulation of macrophage TNFalpha production by orthopaedic wear particles requires activation of the ERK1/2/Egr-1 and NF-kappaB pathways but is independent of p38 and JNK. J Cell Physiol 217:652-66
Taki, Naoya; Tatro, Joscelyn M; Lowe, Robert et al. (2007) Comparison of the roles of IL-1, IL-6, and TNFalpha in cell culture and murine models of aseptic loosening. Bone 40:1276-83
Tatro, Joscelyn M; Taki, Naoya; Islam, Andrew S et al. (2007) The balance between endotoxin accumulation and clearance during particle-induced osteolysis in murine calvaria. J Orthop Res 25:361-9
Smith, Matthew V; Lee, Michael J; Islam, Andrew S et al. (2007) 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 89:1019-27
Taki, Naoya; Tatro, Joscelyn M; Nalepka, Jennifer L et al. (2005) Polyethylene and titanium particles induce osteolysis by similar, lymphocyte-independent, mechanisms. J Orthop Res 23:376-83
Greenfield, Edward M; Bi, Yanming; Ragab, Ashraf A et al. (2005) Does endotoxin contribute to aseptic loosening of orthopedic implants? J Biomed Mater Res B Appl Biomater 72:179-85
Nalepka, Jennifer L; Greenfield, Edward M (2004) Detection of bacterial endotoxin in human tissues. Biotechniques 37:413-7
Ragab, Ashraf A; Nalepka, Jennifer L; Bi, Yanming et al. (2002) Cytokines synergistically induce osteoclast differentiation: support by immortalized or normal calvarial cells. Am J Physiol Cell Physiol 283:C679-87
Greenfield, Edward M; Bi, Yamming; Ragab, Ashraf A et al. (2002) The role of osteoclast differentiation in aseptic loosening. J Orthop Res 20:1-8

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