Although the pathogenesis of post-traumatic OA remains unknown, clinical studies show that patient age is among the strongest predictive factors for OA following severe knee joint injuries. The basis for this observation is believed to involved age-related changes in articular chondrocytes that decrease the ability of the cells to maintain or restore the tissue. These changes have been described in detain in phenotypic terms, but the underlying cellular and molecular mechanisms that drive aging are less understood. Recent work in our laboratory with human chondrocytes demonstrated a strong positive correlation (P<.01) between donor age and the expression of senescence markers. Together with evidence from other system, these findings strongly suggest that aging, and OA, are linked to the accumulation of dysfunctional, senescent chondrocytes in articular cartilage. The rate of senescent cell accumulation is affected by environmental conditions. Analyses, done in our laboratory showed that chondrocyte senescence in vitro can be accelerated by adverse environmental conditions, including low-level oxidative stress. Joint inquiry creates the potential for increased oxidative stress in vivo. Bleeding and inflammation during the acute phase of injury increase the production of reactive oxygen species (ROS) in the joint. Moreover, joint fractures often result in chronic increases in mechanical shear stress, and preliminary data from our laboratory indicate that shear stress stimulates ROS release by chondrocytes. These observations suggest that trauma-related stresses speed up the accumulation of senescent chondrocytes. Furthermore, the data imply that ROS release by chondrocytes could be prevented by joint distraction which is expected to reduce shear stress by preventing contact between cartilage surfaces. Based on these observations we propose studies to determine the roles of oxidative and mechanical stress in post-traumatic OA. We hypothesize that age-dependent senescence accounts for the greater susceptibility of older individuals to post-traumatic OA. Furthermore, we hypothesize that injury itself, and chronic excessive mechanical stress caused by injury, combine to accelerate the onset of chondrocyte senescence.
The specific aims are: 1) determine the combined effects of aging and oxidative stress on chondrocyte senescence, 2) determine the effects of anti-oxidant defenses on chondrocyte senescence, 3) define mechanical stress conditions that induce ROS production in cartilage, 4) determine if oxidative damage detected in synovial fluid increases with post-traumatic OA and decreases with ankle distraction. Together, these studies will help to define the mechanisms responsible for post-traumatic OA.
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