title: Proapoptotic activity of a monomeric smac mimetic on human fibroblast-like synoviocytes from patients with rheumatoid arthritis.
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.
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, University of Study, Milan, Italy, donatella.lattuada@unimi.it.
authors.forename: D
authors.initials: D
authors.lastname: Lattuada
authors.forename: C
authors.initials: C
authors.lastname: Casnici
authors.forename: K
authors.initials: K
authors.lastname: Crotta
authors.forename: P F
authors.initials: PF
authors.lastname: Seneci
authors.forename: C
authors.initials: C
authors.lastname: Corradini
authors.forename: M
authors.initials: M
authors.lastname: Truzzi
authors.forename: F
authors.initials: F
authors.lastname: Ingegnoli
authors.forename: O
authors.initials: O
authors.lastname: Marelli
mesh_terms: D018501:Antirheumatic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D001172:Arthritis, Rheumatoid / Q000473:pathology*; D040761:Biomimetic Materials / Q000494:pharmacology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D024101:Mitochondrial Proteins / Q000494:pharmacology*; D013582:Synovial Fluid / Q000166:cytology / Q000187:drug effects*
chemical_list: D018501:Antirheumatic Agents; D051017:Apoptosis Regulatory Proteins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins