title: Oxidative Stress Promotes Peroxiredoxin Hyperoxidation and Attenuates Pro-survival Signaling in Aging Chondrocytes.
abstract: 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 observedin situin 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.
authors.affiliation: From the Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
authors.forename: John A
authors.initials: JA
authors.lastname: Collins
authors.affiliation: From the Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599.
authors.forename: Scott T
authors.initials: ST
authors.lastname: Wood
authors.affiliation: the Departments of Biochemistry and.
authors.forename: Kimberly J
authors.initials: KJ
authors.lastname: Nelson
authors.affiliation: From the Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Rowe
authors.affiliation: the Department of Veterinary Population Medicine, University of Minnesota College of Veterinary Medicine, St. Paul, Minnesota 55108, and.
authors.forename: Cathy S
authors.initials: CS
authors.lastname: Carlson
authors.affiliation: the Department of Pediatrics, Rush University Medical Center, Chicago, Illinois 60612.
authors.forename: Susan
authors.initials: S
authors.lastname: Chubinskaya
authors.affiliation: the Departments of Biochemistry and.
authors.forename: Leslie B
authors.initials: LB
authors.lastname: Poole
authors.affiliation: Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina 27157.
authors.forename: Cristina M
authors.initials: CM
authors.lastname: Furdui
authors.affiliation: From the Division of Rheumatology, Allergy and Immunology and the Thurston Arthritis Research Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, Richard_loeser@med.unc.edu.
authors.forename: Richard F
authors.initials: RF
authors.lastname: Loeser
mesh_terms: D000328:Adult; D000375:Aging / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D002356:Cartilage / Q000378:metabolism / Q000473:pathology; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D016922:Cellular Senescence / Q000235:genetics; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D061251:Primary Cell Culture; D011499:Protein Processing, Post-Translational; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D046509:Tissue Culture Techniques; D019076:Transgenes; D024483:Vitamin K 3 / Q000494:pharmacology
chemical_list: D018398:Homeodomain Proteins; C115469:Prrx2 protein, mouse; D017382:Reactive Oxygen Species; C484663:Shox2 protein, mouse; D024483:Vitamin K 3; D002374:Catalase; D051057:Proto-Oncogene Proteins c-akt
keywords: aging; cell signaling; osteoarthritis; oxidative stress; peroxiredoxin; redox signaling