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

Hdl Handle:
http://hdl.handle.net/10147/143191
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
Citation:
Arthritis Research & Therapy. 2011 Jul 25;13(4):R121
Issue Date:
25-Jul-2011
URI:
http://hdl.handle.net/10147/143191
Abstract:
Abstract Introduction To examine the effects of tumour necrosis factor (TNF) blocking therapy on the levels of early mitochondrial genome alterations and oxidative stress. Methods Eighteen inflammatory arthritis patients underwent synovial tissue oxygen (tpO2) 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. Results 4-HNE levels pre/post anti TNF-α therapy were inversely correlated with in vivo tpO2 (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 tpO2 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. Conclusions 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.
Item Type:
Journal Article

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.accessioned2011-09-26T10:01:02Z-
dc.date.available2011-09-26T10:01:02Z-
dc.date.issued2011-07-25-
dc.identifierhttp://dx.doi.org/10.1186/ar3424-
dc.identifier.citationArthritis Research & Therapy. 2011 Jul 25;13(4):R121-
dc.identifier.urihttp://hdl.handle.net/10147/143191-
dc.description.abstractAbstract Introduction To examine the effects of tumour necrosis factor (TNF) blocking therapy on the levels of early mitochondrial genome alterations and oxidative stress. Methods Eighteen inflammatory arthritis patients underwent synovial tissue oxygen (tpO2) 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. Results 4-HNE levels pre/post anti TNF-α therapy were inversely correlated with in vivo tpO2 (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 tpO2 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. Conclusions 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.-
dc.titleSuccessful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxia-induced mitochondrial mutagenesis in inflammatory arthritis-
dc.typeJournal Article-
dc.language.rfc3066en-
dc.rights.holderBiniecka et al.; licensee BioMed Central Ltd.-
dc.description.statusPeer Reviewed-
dc.date.updated2011-09-23T17:09:23Z-
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