Oxidative Stress and the Development of Osteoarthritis

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.