Abstract
IntroductionTo examine the effects of tumour necrosis factor (TNF) blocking therapy on the levels of early mitochondrial genome alterations and oxidative stress.MethodsEighteen 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.Results4-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.ConclusionsHigh 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.
Highlights
To examine the effects of tumour necrosis factor (TNF) blocking therapy on the levels of early mitochondrial genome alterations and oxidative stress
We have shown that biologic anti-TNF-a therapy significantly increased the synovial in vivo tissue oxygen partial pressure (tpO2) levels only in those patients who respond to anti-TNF-a therapy [17]
In this study we examine the effect of TNF-blocking therapy on mitochondrial mutagenesis and synovial oxidative stress profiles
Summary
To examine the effects of tumour necrosis factor (TNF) blocking therapy on the levels of early mitochondrial genome alterations and oxidative stress. Free oxygen radicals are highly active molecules and increased mitochondrial ROS generation promotes cellular oxidative stress resulting in oxidative mitochondrial DNA (mtDNA) damage and lipid peroxidation. Mutations and deletions of the mitochondrial genome in genes encoding proteins for subunits of mitochondrial respiratory chain complexes I-V, rRNA and tRNA have been linked to a variety of degenerative human diseases and high levels of mtDNA mutations have been found in many tumours and cancer cells [5,6]. 4-HNE is an endogenously generated a,b unsaturated aldehyde, which is a marker of extensive oxidative stress and can modulate cellular metabolism, inflammatory responses and apoptosis via its effects on transcriptional regulation and protein modification [9]. 4-HNE can form adducts on DNA bases and modifies mtDNA measurement of such modifications may reflect the level of mitochondrial alterations [11]
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