Oxidative stress-mediated post-translational modifications of redox-sensitive proteins are postulated as a key mechanism underlying age-related cellular dysfunction and disease progression. Peroxiredoxins (PRX) are critical intracellular antioxidants that also regulate redox signaling events. Age-related osteoarthritis is a common form of arthritis that has been associated with mitochondrial dysfunction and oxidative stress. The objective of this study was to determine the effect of aging and oxidative stress on chondrocyte intracellular signaling, with a specific focus on oxidation of cytosolic PRX2 and mitochondrial PRX3. Menadione was used as a model to induce cellular oxidative stress. Compared with chondrocytes isolated from young adult humans, chondrocytes from older adults exhibited higher levels of PRX1-3 hyperoxidation basally and under conditions of oxidative stress. Peroxiredoxin hyperoxidation was associated with inhibition of pro-survival Akt signaling and stimulation of pro-death p38 signaling. These changes were prevented in cultured human chondrocytes by adenoviral expression of catalase targeted to the mitochondria (MCAT) and in cartilage explants from MCAT transgenic mice. Peroxiredoxin hyperoxidation was observed in situ in human cartilage sections from older adults and in osteoarthritic cartilage. MCAT transgenic mice exhibited less age-related osteoarthritis. These findings demonstrate that age-related oxidative stress can disrupt normal physiological signaling and contribute to osteoarthritis and suggest peroxiredoxin hyperoxidation as a potential mechanism.Aging is characterized by an inability to maintain homeostasis resulting in a progressive loss of function and is associated with many chronic conditions including cancer, type II diabetes, neurodegenerative disease, cardiovascular disease, and osteoarthritis (1, 2). Although several theories aimed at explaining the aging phenotype have been suggested, an age-related imbalance between the production of reactive oxygen species (ROS) 2 and the antioxidant capacity of the cell has been identified as a contributing factor (3-5). Although the original free radical theory of aging focused on accumulation of cellular damage from excessive ROS as a cause for aging and age-related conditions, more recent studies suggest that disturbances in redox signaling that result from age-related oxidative stress are likely to play a key role (5-7). Increased levels of ROS caused by mitochondrial dysfunction, one of the hallmarks of aging, have been proposed to contribute to age-related oxidative stress, but the underlying mechanisms for how this increase causes a disruption in cell signaling leading to cell and tissue dysfunction is poorly understood (1, 4, 8).Recent advances in redox signaling recognize that reversible post-translational oxidative modifications of reactive protein cysteine thiols mediated by controlled production of H 2 O 2 regulate key signal transduction events (9, 10). The cysteine-dependent peroxiredoxins (PRXs), which display high rea...

Objective Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is elevated in the serum and synovial fluid of osteoarthritic (OA) patients. In this study, the potential role of MIF in OA was studied using human joint tissues and in vivo in mice with age-related and surgically induced OA. Methods MIF in conditioned media from human chondrocytes and meniscal cells and from cartilage explants was measured by ELISA. Severity of OA was analyzed histologically in male wild-type and Mif−/− mice at 12- and 22-months of age and following destabilization of the medial meniscus (DMM) surgery in 12-week old Mif−/− mice as well as in wild-type mice treated with a neutralizing MIF antibody. Synovial hyperplasia was graded in S100A8 immunostained histologic sections. Bone morphometric parameters were measured by microCT analysis. Results Human OA chondrocytes secreted 3-fold higher levels of MIF than normal chondrocytes, while normal and OA meniscal cells produced equivalent amounts. Compared to age- and strain-matched controls, the cartilage, bone, and synovium in older adult mice with Mif deletion were protected from changes of naturally occurring age-related OA. No protection from DMM-induced OA was seen in young adult Mif−/− mice or in wild-type mice treated with anti-MIF. Increased bone density in 8 week-old mice with Mif deletion was not maintained at 12-months. Conclusions These results demonstrate a differential mechanism in the pathogenesis of naturally occurring age-related OA compared to injury-induced OA. The inhibition of MIF may represent a novel therapeutic target in the reduction of age-related OA.

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