This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Obesity increases the risk of osteoarthritis (OA) in both weight-bearing (e.g., knee and hip) and non-weight bearing (e.g., hand) joints, suggesting that a systemic factor mediates the onset of the disease. Soluble mediators released from adipose tissue may be this critical link. Once considered simply an energy storage depot, adipose tissue is now understood to be a dynamic endocrine-like organ, increasing the release of proinflammatory cytokines with the development of obesity. Chronic production of inflammatory mediators, such as interleukin-1? and nitric oxide, may stimulate catabolic processes in articular cartilage by impairing mitochondrial electron transport chain function and producing reactive oxygen species. We hypothesize that mild, chronic inflammation that accrues with aging and is accelerated by obesity impairs mitochondrial-mediated redox regulatory systems in chondrocytes thereby increasing their susceptibility to acute inflammatory-induced oxidative damage, cell death, and matrix catabolism. In preliminary studies, dietinduced obese mice developed knee OA in proportion to body fat gain. To be able to make direct measurements of chondrocyte mitochondrial function and redox regulation, we propose to study the development of knee OA in F344BN rats. We will investigate the effect of age and diet-induced obesity on systemic and local (i.e., joint) levels of adipose tissue and inflammatory mediators, and we will determine how age and a high-fat diet modify chondrocyte electron transport chain function, cellular redox potentials, and protein oxidation. We then propose to determine how these mechanisms regulate the development of knee OA following a local cytokine challenge in aged rats fed normal and high-fat chow.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Exploratory Grants (P20)
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Special Emphasis Panel (ZRR1-CR-B (01))
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Oklahoma Medical Research Foundation
Oklahoma City
United States
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