Differential peroxiredoxin hyperoxidation regulates MAP kinase signaling in human articular chondrocytes

Abstract

The peroxiredoxin (Prx) family of Cys-dependent peroxidases control intracellular levels of H 2 O 2 and can regulate signal transduction. Inhibition of the Prxs, through hyperoxidation amongst other mechanisms, leads to oxidative stress conditions that can alter homeostatic signaling. To determine the effects oxidation of Prx1-Prx3 has on MAP kinase and IGF-1 signaling events in human chondrocytes, this study used 2-methyl-1,4-naphthoquinone (menadione) and 2,3-dimethyl-1,4naphthoquinone (DMNQ) as H 2 O 2 generating tools due to their differential mechanisms of action. Menadione and DMNQ generated similar levels of intracellular H 2 O 2 as determined using the biosensor Orp1-roGFP and by measuring Prx redox status. However, menadione generated higher levels of mitochondrial H 2 O 2 associated with Prx3 hyperoxidation and phosphorylation of Prx1 while DMNQ treatment was associated with hyperoxidation of cytosolic Prx1 and Prx2 but not mitochondrial Prx3. Both menadione and DMNQ induced sustained phosphorylation of p38 but only DMNQ activated JNK. Menadione but not DMNQ inhibited IGF-1induced Akt phosphorylation. Chondrocytes transduced with an adenoviral vector to overexpress Prx3 displayed decreased PrxSO 2/3 formation in response to menadione which was associated with restoration of IGF-1-mediated Akt signaling and inhibition of p38 phosphorylation. Prx1 and Prx2 overexpression had no effects on Prx redox status but Prx1 overexpression enhanced basal Akt

Spaceflight and hind limb unloading induces an arthritic phenotype in knee articular cartilage and menisci of rodents

“…Mitochondrial dysfunction within the menisci after spaceflight is also in agreement with altered mitochondrial dysfunction and stress observed during and after spaceflight from multiple rodent tissues and astronauts 24 These molecular and phenotypic responses in the menisci are similar in nature to the response observed in the knee and hip articular cartilage from female mice after 30 days of HLU 16 . Similar catabolic mechanisms and responses have also been observed in other in vitro and in vivo osteoarthritic models, with increased oxidative stress, reduced anabolic pathways, and evidence of mitochondrial dysfunction 42 – 47 . Clinically, circulating MMP levels that are also associated with collagen degradation with arthritis (e.g., MMP-3) were increased during a 21 day head-down tilt bedrest study as a spaceflight microgravity analogue 48 .…”

Overexpression of Peroxiredoxin 3 in Cartilage Reduces the Severity of Age‐Related Osteoarthritis But Not Surgically Induced Osteoarthritis in Mice

“…The overexpression of catalase targeted to the mitochondria counteracted excessive mitochondrial H 2 O 2 , inhibited p38 activation, and promoted Akt activity and chondrocyte survival in vitro, whereas transgenic mice overexpressing catalase in the mitochondria (mitochondrial catalase [MCAT] mice) developed less severe age‐related OA ( 6 ). Likewise, adenoviral overexpression of mitochondrial Prx3 in chondrocytes was able to inhibit p38 activation and restore Akt signaling under conditions of excessive mitochondrial ROS ( 7 ). These results suggested that inhibition of excessive mitochondrial ROS may be a useful strategy to combat cartilage degradation in OA.…”

Effect of 2-Cys Peroxiredoxins Inhibition on Redox Modifications of Bull Sperm Proteins

“…Inhibition of 2-Cys PRDX activity without oxidative stress caused a decrease in oxPTMs in all detected sperm proteins, which suggests that, under physiological conditions, 2-Cys PRDXs are involved in redox signaling through the use of reversible oxidative modifications of a specific group of redox-sensitive proteins ( Figure 8 B). Such direct redox interactions between 2-Cys PRDXs and redox-sensitive target proteins occur in several signaling pathways, such as apoptosis signaling [ 27 , 28 ], cytokine-induced STAT3 signaling [ 9 ], platelet-derived growth factor signaling [ 29 ], MAP kinase signaling [ 30 ], and replisome activity regulation [ 31 ] of somatic cells. In sperm, the role of 2-Cys PRDXs in homeostatic signaling is poorly understood.…”