Successful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxia-induced mitochondrial mutagenesis in inflammatory arthritis.

Hdl Handle:
http://hdl.handle.net/10147/217171
Title:
Successful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxia-induced mitochondrial mutagenesis in inflammatory arthritis.
Authors:
Biniecka, Monika; Kennedy, Aisling; Ng, Chin T; Chang, Ting C; Balogh, Emese; Fox, Edward; Veale, Douglas J; Fearon, Ursula; O'Sullivan, Jacintha N
Affiliation:
Translation Rheumatology Research Group, Dublin Academic Medical Centre, The Conway Institute of Biomolecular and Biomedical Research, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland.
Citation:
Successful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxia-induced mitochondrial mutagenesis in inflammatory arthritis. 2011, 13 (4):R121 Arthritis Res. Ther.
Journal:
Arthritis research & therapy
Issue Date:
2011
URI:
http://hdl.handle.net/10147/217171
DOI:
10.1186/ar3424
PubMed ID:
21787418
Abstract:
To examine the effects of tumour necrosis factor (TNF) blocking therapy on the levels of early mitochondrial genome alterations and oxidative stress.; Eighteen inflammatory arthritis patients underwent synovial tissue oxygen (tpO(2)) measurements and clinical assessment of disease activity (DAS28-CRP) at baseline (T0) and three months (T3) after starting biologic therapy. Synovial tissue lipid peroxidation (4-HNE), T and B cell specific markers and synovial vascular endothelial growth factor (VEGF) were quantified by immunohistochemistry. Synovial levels of random mitochondrial DNA (mtDNA) mutations were assessed using Random Mutation Capture (RMC) assay.; 4-HNE levels pre/post anti TNF-α therapy were inversely correlated with in vivo tpO(2) (P < 0.008; r = -0.60). Biologic therapy responders showed a significantly reduced 4-HNE expression (P < 0.05). High 4-HNE expression correlated with high DAS28-CRP (P = 0.02; r = 0.53), tender joint count for 28 joints (TJC-28) (P = 0.03; r = 0.49), swollen joint count for 28 joints (SJC-28) (P = 0.03; r = 0.50) and visual analogue scale (VAS) (P = 0.04; r = 0.48). Strong positive association was found between the number of 4-HNE positive cells and CD4+ cells (P = 0.04; r = 0.60), CD8+ cells (P = 0.001; r = 0.70), CD20+ cells (P = 0.04; r = 0.68), CD68+ cells (P = 0.04; r = 0.47) and synovial VEGF expression (P = 0.01; r = 063). In patients whose in vivo tpO(2) levels improved post treatment, significant reduction in mtDNA mutations and DAS28-CRP was observed (P < 0.05). In contrast in those patients whose tpO2 levels remained the same or reduced at T3, no significant changes for mtDNA mutations and DAS28-CRP were found.; High levels of synovial oxidative stress and mitochondrial mutation burden are strongly associated with low in vivo oxygen tension and synovial inflammation. Furthermore these significant mitochondrial genome alterations are rescued following successful anti TNF-α treatment.
Language:
en
MeSH:
Arthritis, Rheumatoid; Biological Agents; Cell Hypoxia; DNA, Mitochondrial; Humans; Immunohistochemistry; Mitochondria; Mutagenesis; Mutation; Oxidative Stress; Oxygen; Reverse Transcriptase Polymerase Chain Reaction; Synovial Membrane; Tumor Necrosis Factor-alpha
ISSN:
1478-6362
Ethical Approval:
N/A

Full metadata record

DC FieldValue Language
dc.contributor.authorBiniecka, Monika-
dc.contributor.authorKennedy, Aisling-
dc.contributor.authorNg, Chin T-
dc.contributor.authorChang, Ting C-
dc.contributor.authorBalogh, Emese-
dc.contributor.authorFox, Edward-
dc.contributor.authorVeale, Douglas J-
dc.contributor.authorFearon, Ursula-
dc.contributor.authorO'Sullivan, Jacintha N-
dc.date.accessioned2012-03-30T11:51:51Z-
dc.date.available2012-03-30T11:51:51Z-
dc.date.issued2011-
dc.identifier.citationSuccessful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxia-induced mitochondrial mutagenesis in inflammatory arthritis. 2011, 13 (4):R121 Arthritis Res. Ther.-
dc.identifier.issn1478-6362-
dc.identifier.pmid21787418-
dc.identifier.doi10.1186/ar3424-
dc.identifier.urihttp://hdl.handle.net/10147/217171-
dc.description.abstractTo examine the effects of tumour necrosis factor (TNF) blocking therapy on the levels of early mitochondrial genome alterations and oxidative stress.-
dc.description.abstractEighteen inflammatory arthritis patients underwent synovial tissue oxygen (tpO(2)) measurements and clinical assessment of disease activity (DAS28-CRP) at baseline (T0) and three months (T3) after starting biologic therapy. Synovial tissue lipid peroxidation (4-HNE), T and B cell specific markers and synovial vascular endothelial growth factor (VEGF) were quantified by immunohistochemistry. Synovial levels of random mitochondrial DNA (mtDNA) mutations were assessed using Random Mutation Capture (RMC) assay.-
dc.description.abstract4-HNE levels pre/post anti TNF-α therapy were inversely correlated with in vivo tpO(2) (P < 0.008; r = -0.60). Biologic therapy responders showed a significantly reduced 4-HNE expression (P < 0.05). High 4-HNE expression correlated with high DAS28-CRP (P = 0.02; r = 0.53), tender joint count for 28 joints (TJC-28) (P = 0.03; r = 0.49), swollen joint count for 28 joints (SJC-28) (P = 0.03; r = 0.50) and visual analogue scale (VAS) (P = 0.04; r = 0.48). Strong positive association was found between the number of 4-HNE positive cells and CD4+ cells (P = 0.04; r = 0.60), CD8+ cells (P = 0.001; r = 0.70), CD20+ cells (P = 0.04; r = 0.68), CD68+ cells (P = 0.04; r = 0.47) and synovial VEGF expression (P = 0.01; r = 063). In patients whose in vivo tpO(2) levels improved post treatment, significant reduction in mtDNA mutations and DAS28-CRP was observed (P < 0.05). In contrast in those patients whose tpO2 levels remained the same or reduced at T3, no significant changes for mtDNA mutations and DAS28-CRP were found.-
dc.description.abstractHigh levels of synovial oxidative stress and mitochondrial mutation burden are strongly associated with low in vivo oxygen tension and synovial inflammation. Furthermore these significant mitochondrial genome alterations are rescued following successful anti TNF-α treatment.-
dc.language.isoen-
dc.rightsArchived with thanks to Arthritis research & therapyen_GB
dc.subject.meshArthritis, Rheumatoid-
dc.subject.meshBiological Agents-
dc.subject.meshCell Hypoxia-
dc.subject.meshDNA, Mitochondrial-
dc.subject.meshHumans-
dc.subject.meshImmunohistochemistry-
dc.subject.meshMitochondria-
dc.subject.meshMutagenesis-
dc.subject.meshMutation-
dc.subject.meshOxidative Stress-
dc.subject.meshOxygen-
dc.subject.meshReverse Transcriptase Polymerase Chain Reaction-
dc.subject.meshSynovial Membrane-
dc.subject.meshTumor Necrosis Factor-alpha-
dc.titleSuccessful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxia-induced mitochondrial mutagenesis in inflammatory arthritis.en_GB
dc.contributor.departmentTranslation Rheumatology Research Group, Dublin Academic Medical Centre, The Conway Institute of Biomolecular and Biomedical Research, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland.-
dc.identifier.journalArthritis research & therapy-
dc.type.qualificationlevelN/Aen
cr.approval.ethicalN/Aen
dc.description.provinceConnachten
dc.description.provinceLeinster-

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