Total joint replacement using metal and polymeric materials has provided dramatic relief of pain and improvement of function for millions of patients with end-stage arthritis. More than 600,000 total hip and knee replacements are performed annually worldwide at an enormous economic impact. Despite the success of joint replacements, aseptic loosening, frequently associated with periprosthetic osteolysis, and focal osteolysis in the absence of loosening, jeopardizes the long-term function of both cemented and cementless total joint replacements. This proposal will study biomaterial-induced responses of osteoblasts. Our hypothesis is that phagocytosed but non-degradable particulate biomaterials (prosthetic wear debris) launch a catastrophic process in vivo by activating a number of cells (macrophages, fibroblasts, osteoclasts and osteoblasts), and these activated cells together create a unique pathological condition at the interface of bone and prothesis. We propose to investigate this hypothesis by studying altered cellular functions at the molecular level which may trigger, maintain and/or contribute to osteolysis. In particular, we will focus on particulate biomaterial-induced cellular responses in osteoblasts, since these cells, in addition to osteoclasts, may play direct and central roles in periprosthetic osteolysis and aseptic loosening of total joint arthroplasties. Phagocytosis is a natural cell function and it seems to be an attractive hypothesis that there is a common and early intracellular signaling pathway, which triggers the """"""""ultimate"""""""" cell response to non-degradable phagocytosed particulates. The long term goal of this proposal is to define the signal transduction mechanisms by which phagocytosed particulates alter gene expressed in osteoblasts. To address this goal we will (i) identify the specific transcription factors induced by Titianium (Ti) particles, a prototype of particulate wear debris, (ii) define the signaling events that activate these transcription factors, and (iii) identify the genes affected by these transcription factors. In preliminary data, we demonstrate that phagocytosed Ti particulates activate the transcription factor NF-kappa B in an osteoblast cell line (MG-63). NF-kappa B is a key transcription factor in activating gene expression in immune and non-immune cells. We hypothesize that Ti particulate activation of NF-kappa B leads to the induction of proinflammatory cytokines, such as TNFalpha, IL-beta, and IL-6, which in turn contribute to osteolysis. There is currently no information on the regulation and function of NF-kappa B in human osteoblasts. To gain a better understanding of the mechanisms by which phagocytosed particulates activate gene expression in these cells, we will focus on the mechanisms by with TI particles activate the transcription factor NF-kappa B and the NF-kappa B dependent gene expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR045835-03
Application #
6171695
Study Section
Special Emphasis Panel (ZAR1-JRL-A (O1))
Program Officer
Panagis, James S
Project Start
1998-09-30
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2002-08-31
Support Year
3
Fiscal Year
2000
Total Cost
$71,500
Indirect Cost
Name
Rush University Medical Center
Department
Type
DUNS #
068610245
City
Chicago
State
IL
Country
United States
Zip Code
60612
Fritz, Elizabeth A; Glant, Tibor T; Vermes, Csaba et al. (2006) Chemokine gene activation in human bone marrow-derived osteoblasts following exposure to particulate wear debris. J Biomed Mater Res A 77:192-201
Fritz, Elizabeth A; Glant, Tibor T; Vermes, Csaba et al. (2002) Titanium particles induce the immediate early stress responsive chemokines IL-8 and MCP-1 in osteoblasts. J Orthop Res 20:490-8
Carpenter, Laura R; Moy, James N; Roebuck, Kenneth A (2002) Respiratory syncytial virus and TNF alpha induction of chemokine gene expression involves differential activation of Rel A and NF-kappa B1. BMC Infect Dis 2:5
Lum, H; Roebuck, K A (2001) Oxidant stress and endothelial cell dysfunction. Am J Physiol Cell Physiol 280:C719-41
Vermes, C; Glant, T T; Hallab, N J et al. (2001) The potential role of the osteoblast in the development of periprosthetic osteolysis: review of in vitro osteoblast responses to wear debris, corrosion products, and cytokines and growth factors. J Arthroplasty 16:95-100
Jacobs, J J; Roebuck, K A; Archibeck, M et al. (2001) Osteolysis: basic science. Clin Orthop Relat Res :71-7
Roebuck, K A; Carpenter, L R; Lakshminarayanan, V et al. (1999) Stimulus-specific regulation of chemokine expression involves differential activation of the redox-responsive transcription factors AP-1 and NF-kappaB. J Leukoc Biol 65:291-8
Roebuck, K A (1999) Regulation of interleukin-8 gene expression. J Interferon Cytokine Res 19:429-38
Roebuck, K A; Finnegan, A (1999) Regulation of intercellular adhesion molecule-1 (CD54) gene expression. J Leukoc Biol 66:876-88
Roebuck, K A (1999) Oxidant stress regulation of IL-8 and ICAM-1 gene expression: differential activation and binding of the transcription factors AP-1 and NF-kappaB (Review). Int J Mol Med 4:223-30

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