Mitochondrial mutagenesis correlates with the local inflammatory environment in XXXX .

@entity1 @entity650 @entity32 @entity625 @entity1356 @entity310 @entity469 @entity26 @entity603 @entity12662 @entity309
BACKGROUND: To examine the association between mitochondrial mutagenesis and the proinflammatory microenvironment in @entity1 with @entity625 . METHODS: Fifty @entity1 with @entity625 underwent arthroscopy and synovial tissue biopsies, synovial fluid and clinical assessment were obtained. Fifteen @entity1 pre/post-TNFi therapy were also recruited. Normal synovial biopsies were obtained from 10 subjects undergoing interventional arthroscopy. Macroscopic @entity603 /vascularity was measured by visual analogue scale. Cell-specific markers CD3 (T cells) and @entity469 (macrophages) were quantified by immunohistology. @entity310 , @entity650 , IFNy and @entity1356 were measured in synovial fluids by MSD multiplex assays. Synovial tissue mitochondrial mutagenesis was quantified using a mitochondrial random mutation capture assay (RMCA). The direct effect of @entity310 on oxidative stress and mitochondrial function was assessed in primary cultures of @entity309 synovial fibroblast cells (RASFCs). Mitochondrial mutagenesis, reactive @entity26 species (ROS), mitochondrial membrane potential (MMP) and mitochondrial mass (MM) were quantified using the RMCA and specific cell fluorescent probes. RESULTS: A significant increase in mtDNA mutation frequency was demonstrated in inflamed synovial tissue compared with control (p<0.05), an effect that was independent of age. mtDNA mutations positively correlated with macroscopic @entity603 (r=0.52, p<0.016), vascularity (r=0.54, p<0.01) and with synovial fluid cytokine levels of @entity310 (r=0.74, p<0.024) and IFNy (r=0.72, p<0.039). mtDNA mutation frequency post-TNFi therapy was significantly lower in @entity1 with a DAS<3.2 (p<0.05) and associated with clinical and microscopic measures of disease (p<0.05). In vitro @entity310 significantly induced mtDNA mutations, ROS, MM and @entity12662 in RASFCs (all p<0.05). CONCLUSION: High mitochondrial mutations are strongly associated with @entity32 showing a direct link between mitochondrial mutations and key proinflammatory pathways.
