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- Title
Proapoptotic Activity of a Monomeric Smac Mimetic on Human Fibroblast-Like Synoviocytes from Patients with Rheumatoid Arthritis.
- Authors
Lattuada, D.; Casnici, C.; Crotta, K.; Seneci, P.F.; Corradini, C.; Truzzi, M.; Ingegnoli, F.; Marelli, O.
- Abstract
Inhibitors of apoptosis proteins (IAPs) block cell death in response to diverse stimuli. The mitochondrial protein, second mitochondria-derived activator of caspase (Smac), negatively regulates IAP inhibition of caspase activity. We investigated the proapoptotic activity of a synthetic Smac (Smac 066) on fibroblast-like synoviocytes (FLS) derived from patients with active rheumatoid arthritis (RA). We found that Smac 066 induced significant apoptosis in all RA-FLS samples. Furthermore, IAPs, which are upregulated in RA-FLS, were downregulated by Smac 066. This suggested that IAPs upregulation was responsible for RA-FLS sensitivity to Smac 066. Next, we analysed caspase activation and found that Smac 066 was associated with caspase 8 and caspase 3 activities. We then investigated the mechanism underlying Smac 066 downregulation of IAPs in RA-FLS with an apoptotic pathway array. Interestingly, Smac 066 significantly upregulated IGFBP-5, a protein involved in differentiation, apoptosis, and osteoblastic activation. Smac 066 may represent a new therapeutic approach to RA treatment.
- Subjects
APOPTOSIS; FIBROBLASTS; MESENCHYMAL stem cells; RHEUMATOID arthritis; CELL death; AVERSIVE stimuli; PATIENTS
- Publication
Inflammation, 2015, Vol 38, Issue 1, p102
- ISSN
0360-3997
- Publication type
Article
- DOI
10.1007/s10753-014-0012-1