Biomechanical factors, chondrocyte viability, and inflammation are important factors in the pathogenesis of arthritis. Nitric oxide (NO) synthesis is increased in arthritis and is a mediator in the response to mechanical compression, chondrocyte apoptosis and in the inflammatory response to the catabolic cytokine IL-1. The most direct effect of NO is the suppression of energy production, which in many cell types is then associated with decreased oxygen (02) consumption, decreased matrix synthesis and the control of cell death. NO and 02 competitively bind to cytochrome oxidase, which is involved in oxidative mitochondrial respiration (OXPHOS). However, articular chondrocytes are highly glycolytic due to their avascular and hence hypoxic environment and OXPHOS only accounts for up to 25% of total steady state ATP production. It is suggested OXPHOS may contribute to more ATP production under conditions of tissue stress, such as inflammation or mechanical stress, or in arthritis where the oxygen tension of the synovial fluid, and hence cartilage, is further decreased. A steady supply of ATP is essential for articular chondrocyte remodeling of the matrix as an adaptation to biomechanical or inflammatory stresses, but also for the high energy requirements of apoptosis. NO is suggested to have both a protective and destructive role in cartilage. Little is known concerning the effect of NO and oxygen on ATP production in articular cartilage under physiological or ipathological conditions. The putative protective effect of NO might be determined by the intracellular redox state since NO and 02 compete for binding to cytochrome oxidase of the mitochondria. Our primary hypothesis is that oxygen tension determines whether NO inhibits ATP production, and if sufficient ATP is available to respond to inflammatory or mechanical stress. We propose to test whether oxygen tension l affects the ability of NO to inhibit the aerobic OXPHOS pathway and hence the source of ATP required to respond to the inflammatory or mechanical stress. We then propose to investigate how these factors affect matrix turnover and cell death. Since mechanical stress is protective to IL-1 induced matrix breakdown we shall investigate if this phenomenon is influenced by oxygen tension.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR049790-01A1
Application #
6730815
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Tyree, Bernadette
Project Start
2004-08-01
Project End
2009-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
1
Fiscal Year
2004
Total Cost
$259,160
Indirect Cost
Name
Duke University
Department
Surgery
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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Davies, C M; Guilak, F; Weinberg, J B et al. (2008) Reactive nitrogen and oxygen species in interleukin-1-mediated DNA damage associated with osteoarthritis. Osteoarthritis Cartilage 16:624-30
Hennerbichler, Alfred; Fermor, Beverley; Hennerbichler, Diana et al. (2007) Regional differences in prostaglandin E2 and nitric oxide production in the knee meniscus in response to dynamic compression. Biochem Biophys Res Commun 358:1047-53
Fermor, B; Christensen, S E; Youn, I et al. (2007) Oxygen, nitric oxide and articular cartilage. Eur Cell Mater 13:56-65;discussion 65
Cernanec, Julie M; Weinberg, J Brice; Batinic-Haberle, Ines et al. (2007) Influence of oxygen tension on interleukin 1-induced peroxynitrite formation and matrix turnover in articular cartilage. J Rheumatol 34:401-7
Weinberg, J Brice; Fermor, Beverley; Guilak, Farshid (2007) Nitric oxide synthase and cyclooxygenase interactions in cartilage and meniscus: relationships to joint physiology, arthritis, and tissue repair. Subcell Biochem 42:31-62
Guilak, Farshid; Lott, Kristen E; Awad, Hani A et al. (2006) Clonal analysis of the differentiation potential of human adipose-derived adult stem cells. J Cell Physiol 206:229-37
Betre, Helawe; Ong, Shin R; Guilak, Farshid et al. (2006) Chondrocytic differentiation of human adipose-derived adult stem cells in elastin-like polypeptide. Biomaterials 27:91-9

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