Successful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxiainduced mitochondrial mutagenesis in inflammatory arthritis
Citation:
Biniecka M, Kennedy A, Ng CT, Chang TC, Balogh E, Fox E, Veale DJ, Fearon U, O'Sullivan JN., Successful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxiainduced mitochondrial mutagenesis in inflammatory arthritis, Arthritis Research & Therapy, 13, 4, 2011, R121Download Item:
Successful tumour necrosis factor (TNF) blocking therapy suppresses oxidative stress and hypoxiainduced mitochondrial mutagenesis in inflammatory arthritis.pdf (Published (publisher's copy) - Peer Reviewed) 935.0Kb
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-? 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-? treatment.
Sponsor
Grant Number
Health Research Board (HRB)
R10238
Health Research Board (HRB)
JRFC-05-01
Author's Homepage:
http://people.tcd.ie/osullij4Description:
PUBLISHED
Author: O'SULLIVAN, JACINTHA
Type of material:
Journal ArticleCollections:
Series/Report no:
Arthritis Research & Therapy13
4
Availability:
Full text availableKeywords:
Rheumatology, tumour necrosis factor (TNF), arthritisSubject (TCD):
Immunology, Inflammation & InfectionDOI:
http://dx.doi.org/10.1186/ar3424Licences: