(Taken from the application): Total joint replacement implant survival is limited by aseptic loosening of the prosthesis. Implant loosening results from periprosthetic bone resorption which is mediated by a chronic inflammatory response to implant-derived particulate debris. Understanding the basic cellular and molecular events involved in this osteolytic process will introduce potential molecular targets for therapeutic intervention. Previous experiments with genetic blockade of the TNF signaling pathway, prevents experimental, particle-induced osteolysis. Thus, we focus on the nuclear transcription factor kappa B (NF-kB) which is essential for osteoclast formation and is a known mediator of TNF-induced gene transcription. We show in osteoclast precursor cells, that implant particles induce TNF expression and are potent activators of NF-kB. TNF activates NF-kB in these cells via a novel, cell-specific mechanism involving the tyrosine kinase c-src and the NF-kB inhibitory protein (IkB). This suggests that particles may exert their effect via a similar signaling pathway. We hypothesize that in osteoclast precursor cells polymethylmethacrylate (PMMA) particles activate NF-kB via a TNF signaling pathway involving c-src phosphorylation of IkB and that blocking particle-induced NF-kB activation will inhibit osteoclastogenesis in vitro.
Our aims are: 1) to determine the mechanism(s) by which PMMA particles induce NF-kB activation in osteoclast precursor cells and 2) to determine the effect of blocking NF-kB activation on PMMA-induced osteoclastogenesis in vitro.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR047096-02
Application #
6375342
Study Section
Special Emphasis Panel (ZAR1-AAA-B (M1))
Program Officer
Panagis, James S
Project Start
2000-09-01
Project End
2003-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
2
Fiscal Year
2001
Total Cost
$77,000
Indirect Cost
Name
Washington University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Abu-Amer, Yousef; Darwech, Isra; Clohisy, John C (2007) Aseptic loosening of total joint replacements: mechanisms underlying osteolysis and potential therapies. Arthritis Res Ther 9 Suppl 1:S6
Clohisy, John C; Hirayama, Teruhisa; Frazier, Elfaridah et al. (2004) NF-kB signaling blockade abolishes implant particle-induced osteoclastogenesis. J Orthop Res 22:13-20
Clohisy, John C; Frazier, Elfaridah; Hirayama, Teruhisa et al. (2003) RANKL is an essential cytokine mediator of polymethylmethacrylate particle-induced osteoclastogenesis. J Orthop Res 21:202-12
Abbas, S; Clohisy, J C; Abu-Amer, Y (2003) Mitogen-activated protein (MAP) kinases mediate PMMA-induction of osteoclasts. J Orthop Res 21:1041-8
Clohisy, John C; Teitelbaum, Steven; Chen, Shaoping et al. (2002) Tumor necrosis factor-alpha mediates polymethylmethacrylate particle-induced NF-kappaB activation in osteoclast precursor cells. J Orthop Res 20:174-81
Abu-Amer, Y; Dowdy, S F; Ross, F P et al. (2001) TAT fusion proteins containing tyrosine 42-deleted IkappaBalpha arrest osteoclastogenesis. J Biol Chem 276:30499-503