ACTIVITY OF MONOMERIC SECOND MITOCHONDRIAL ACTIVATOR OF CASPASES (SMAC) MIMETIC COMPOUNDS ON HUMAN FIBROBLAST-LIKE SYNOVIOCYTES FROM RHEUMATOID ARTHRITIS PATIENTS

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterised by systemic and intrarticular inflammation. Fibroblast-like synoviocytes (FLSs) in RA have an activated phenotype with increased expression of pro-inflammatory cytokines and matrix metalloproteiases, which sustain chronic inflammation and damage bone and cartilage. RA-FLSs also display resistance to apoptosis, which accounts for the synovial membrane hyperplasia. SMAC-mimetic compounds antagonise the activity of inhibitors of apoptosis proteins (IAPs), which regulate apoptotic and inflammatory pathways. We investigated whether SMAC127 had pro-apoptotic and anti-inflammatory effects on RA-FLSs. To better recreate an optimal in vitro model of the intrrticular environment, we also studied the effects of the addition of synovial fluid (SF) to cultures. We found that SMAC 127 could down-regulate IAPs levels and could effectively induce apoptosis - as demonstrated by apoptosis assays with Annexin V in different culture conditions and caspase-3 cleavage. Furthermore, SMAC 127 could down-regulate pro-inflammatory cytokines (TNF-alpha, IL-15 and IL-6) and induce an up-regulation of the anti-inflammatory cytokine IL-10. The levels of marix metalloproteinase-1 (MMP-1) where also reduced, whereas we did not observe any significant effects on RANKL/OPG axis. Based on these results, SMAC mimetic compounds could be a very useful treatment in patients with RA since the very early stage of the disease.