Oxidative Stress and the Development of Osteoarthritis

项目总结:

Project Summary: The long-term objective of this project is to determine the basic mechanisms by which oxidative stress conditions specifically and directly contribute to the pathogenesis of osteoarthritis (OA) with a particular focus on age-related OA. Mitochondrial dysfunction, a hallmark of aging found in OA, contributes to age-related conditions through promoting cellular oxidative stress. Rather than simply causing random oxidative damage to cells and tissues, the modern definition of oxidative stress emphasizes that an imbalance in favor of oxidants leads to disruption of normal redox signaling. The present project has provided evidence in human cells and tissues and in aging mice that oxidative stress originating in the mitochondria disrupts chondrocyte signaling to contribute to OA through excessive protein thiol oxidation. This resulted in inhibition of pro-survival and pro-anabolic Akt and Smad signaling and promotion of pro-death and pro-catabolic p38 signaling. Consistent with a mitochondrial source of H2O2, transgenic mice that overexpress human catalase targeted to the mitochondria developed less age-related OA. We also found that pathologic levels of H2O2 inhibit JNK2 signaling and JNK2 knockout mice develop more severe age-related OA. Peroxiredoxins (Prxs) are major regulators of redox signaling due to their abundance in the cell and high reaction rates with H2O2. We found evidence linking inactivation of Prxs through hyperoxidation, including the mitochondrial Prx3, to disrupted chondrocyte signaling including Akt and JNK2 inhibition with p38 activation resulting in cell death. These findings support our overall hypothesis that in OA, pathological levels of ROS, including mitochondrial H2O2, inhibit anabolic and promote catabolic and cell death signaling through excessive protein thiol oxidation. To test this hypothesis our aims are: 1) Determine the mechanism by which mitochondrial peroxiredoxin-3 (Prx3) hyperoxidation disrupts chondrocyte signaling under oxidative stress conditions. We will test the hypothesis that Prx3 hyperoxidation results in oxidation of protein thiols in specific signaling proteins to favor catabolic and cell death pathways over anabolic and cell survival pathways. 2) Determine the effects of transgenic overexpression of Prx3 on the development of OA in mice. This aim will test the hypothesis that overexpression of Prx3 will reduce age-related OA. These studies will shift the field from a focus on random oxidative damage as the mechanism by which aging and oxidative stress promote OA to an understanding of the role of disturbed redox signaling. This mechanism is important to understand because therapeutic targeting of specific proteins that regulate redox signaling is feasible, is an active area of investigation, and promises to be much more effective than targeting random oxidative damage using non-specific anti-oxidants.