Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Mitochondrial Mutagenesis in Synovial Tissue Is Associated with In Vivo Hypoxia, Inflammation and Oxidative Damage.
Biniecka2, Monika, Fox1, Edward, Ng2, Chin T., Harty2, Len, Fearon2, Ursula, Veale2, Douglas J., O'Sullivan2, Jacintha
Mitochondrial components are highly susceptible to attack by oxygen radicals due to their close proximity to the electron transport chain and the presence of polyunsaturated fatty acid rich membranes. Oxidative damage to mitochondrial DNA (mtDNA) itself can affect genes encoding respiratory chain complexes and transcription, which may lead to further mitochondrial DNA mutations. Moreover, ROS induced oxidative damage could potentially be a major source of mitochondrial genomic instability leading to respiratory chain dysfunction. The aim of this study was to examine the relationship of random mitochondrial DNA point mutations to in vivo synovial tissue oxygen level (tpO2), synovial inflammation and lipid oxidative damage in the inflamed joint of inflammatory arthritis patients.
Oxygen partial pressure in synovial tissue (tpO2) was measured in vivo using a combined oxygen/temperature Licox probe. Synovial membrane biopsies were obtained from the site of the oxygen tension measurement under direct visualization at the time of arthroscopy. The newly validated mitochondrial Random Mutation Capture assay was used to quantitatively evaluate alterations of the mitochondrial genome in synovial tissue biopsies. Expression of inflammatory cell specific markers (CD68 of macrophages and CD3 of T cells) and lipid peroxidation (4-HNE) were quantified by immunohistochemistry.
Twenty subjects were recruited prior to starting therapy with biologic agents (14 patients with RA and 6 patients with PsA). The median synovial tissue pO2 level was profoundly hypoxic at 25.47mmHg, equivalent to an ambient oxygen tension 3.3%. The mutations detected were mainly transitions i.e. AT>GC and CG>TA, characteristic of mutation following oxidative stress. A statistically significant increase in the frequency of point mutations was detected in synovial biopsies in patients with tpO2<20mmHg compared to patients with tpO2>20mmHg (p<0.05). Higher in vivo tpO2 was significantly associated with a decrease in the frequency of mtDNA point mutations (p=0.05; r=-0.38). Significantly greater mitochondrial mutation burden correlated with high expression of CD68 (p=0.026; r=0.44) and CD3 (p=0.047; r=0.29) positive cells in the sublining layer of synovial tissue. Higher frequency of random mitochondrial DNA mutations was also significantly associated with higher synovial 4-HNE cytoplasmic expression in lining and sublining layers of the synovium (p=0.04; r=0.46 and p=0.03; r=0.44 respectively).
Higher frequency of random mitochondrial mutations was significantly associated with reduced in vivo oxygen level, with higher microscopic inflammation and oxidative stress. This data implicates that alterations in the mitochondrial genome may be a consequence of severe hypoxic levels in the inflamed joint.
To cite this abstract, please use the following information:
Biniecka, Monika, Fox, Edward, Ng, Chin T., Harty, Len, Fearon, Ursula, Veale, Douglas J., et al; Mitochondrial Mutagenesis in Synovial Tissue Is Associated with In Vivo Hypoxia, Inflammation and Oxidative Damage. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :360