Oxidative Stress and the Development of Osteoarthritis

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Project Summary The long-term objective of this project is to determine the basic mechanisms by which oxidative stress conditions contribute to the pathogenesis of osteoarthritis (OA), with a focus on age-related OA. Oxidative stress occurs when the production of reactive oxygen species (ROS) overwhelms the cellular antioxidant capacity, resulting in disturbances in the control of redox signaling. Peroxiredoxins are a family of antioxidant proteins that control the local levels of H2O2 in the cell and serve to regulate redox signaling events. Work in this project during the current funding period, using human cells, innovative redox biology tools, and unique mouse models, has shown that oxidative stress disrupts homeostatic signaling in chondrocytes by oxidative inactivation of the peroxiredoxins to favor p38 signaling and activation of NFκB over JNK and AKT signaling. It was found that, unlike physiologic levels of H2O2 that activate JNK, pathologic levels inactivate JNK through oxidation of specific cysteine thiols. The loss of JNK signaling alters the function of joint tissues. Deletion of JNK in mice promoted cell senescence and increased the severity of age-related OA, while transgenic mice engineered to overexpress peroxiredoxin-3 in chondrocytes developed less severe age-related OA. A central mechanism by which cell senescence promotes age-related diseases is through the production of inflammatory cytokines and matrix degrading enzymes by senescent cells, referred to as the senescence-associated secretory phenotype (SASP). The overall hypothesis for this renewal is that oxidative stress contributes to the development of OA by activating signaling events in senescent joint tissue cells that promote and maintain the SASP. Aims are: 1) Determine the mechanism by which redox signaling under oxidative stress conditions promotes the development of the SASP. Hypothesis: Oxidative stress creates an imbalance in JNK and p38 activity, favoring p38, to promote the SASP. 2) Identify the role of the endogenous antioxidant systems in regulating the development of the SASP. Hypothesis: Inactivation of one or more of the peroxiredoxins, due to hyperoxidation or NADPH depletion, contributes to the altered redox signaling controlling the SASP. These studies will define a novel mechanism by which disturbed redox signaling, due to oxidative stress in joint tissues, promotes development of OA through the SASP. The results will support the future development of novel therapeutics for OA that control the SASP by targeting specific proteins within redox signaling pathways that promote and maintain the SASP. This “senomorphic” approach of altering the secretory phenotype of senescent cells will provide an important alternative to a “senolytic” strategy of targeted cell death.