Differential peroxiredoxin hyperoxidation regulates MAP kinase signaling in human articular chondrocytes

These results suggest that hyperoxidation of specific Prx isoforms is associated with distinct cell signaling events and identify Prx3 redox status as an important regulator of anabolic and catabolic signal transduction

John A. Collins; Scott T. Wood; Jesalyn A. Bolduc; N.P. Dewi Nurmalasari; Susan Chubinskaya; Leslie B. Poole; Cristina M. Furdui; Kimberly J. Nelson; Richard F. Loeser


Scholarcy highlights

  • Through its controlled release, H2O2 acts as a key second messenger in specific signaling pathways that are important for cellular homeostasis
  • We found that menadione and DMNQ could be used as H2O2-producing tools that resulted in differential hyperoxidation profiles of Prx1-Prx3 as well as phosphorylation of Prx1 that were associated with changes in specific redoxregulated signaling pathways
  • DMNQ led to oxidation of Prx3, we found no evidence that DMNQ treatment led to Prx3 hyperoxidation
  • Because Prx3 is located in the mitochondria, these findings suggested menadione generated higher levels of mitochondrial H2O2 than DMNQ, which was supported by the findings using the mitochondrial-targeted Orp-1-roGFP
  • The menadione-induced hyperoxidation of Prx2 and Prx3 and phosphorylation of Prx1 was associated with increased phosphorylation of p38 and inhibition of insulin-like growth factor-1-induced Akt activity while DMNQ-induced hyperoxidation of Prx1 and Prx2 was associated with phosphorylation of p38 and Jun N-terminal kinase activation without inhibition of IGF-1 stimulated Akt activity
  • No significant differences in Prx2 hyperoxidized monomer formation were observed between menadione and DMNQ
  • These findings suggested that Prx3 hyperoxidation in the presence of menadione was responsible for the loss of Akt activity in response to IGF-1
  • The findings from the current study suggest that targeted therapeutic approaches aimed at maintaining mitochondrial Prx3 activity may represent a novel strategy to restore homeostatic cell signaling events in chondrocytes under conditions of mitochondrial-mediated oxidative stress

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