title: Smac127 Has Proapoptotic and Anti-Inflammatory Effects on Rheumatoid Arthritis Fibroblast-Like Synoviocytes.
abstract: Rheumatoid arthritis (RA) is characterized by synovial inflammation and hyperplasia. Fibroblast-like synoviocytes (FLSs) are apoptosis-resistant and contribute to the pathogenesis of RA by producing cytokines and proteolytic enzymes, which degrade the extracellular matrix. We evaluated the proapoptotic and anti-inflammatory activity of the small molecule Smac127 on RA-FLSs cultured in synovial fluid (SF), in order to reproduce the physiopathological environmental characteristic of RA joints. In this context, Smac127 induces apoptosis by inhibiting apoptosis proteins (IAPs). This inhibition activates caspase 3 and restores the apoptotic pathway. In addition, Smac127 induces a significant inhibition of the secretion of IL-15 and IL-6, stimulation of pannus formation, and damage of bone and cartilage in RA. Also the secretion of the anti-inflammatory cytokine IL-10 is dramatically increased in the presence of Smac127. The cartilage destruction in RA patients is partly mediated by metalloproteinases; here we show that the MMP-1 production by fibroblasts cultured in SF is significantly antagonized by Smac127. Conversely, this molecule has no significant effects on RANKL and OPG production. Our observations demonstrate that Smac127 has beneficial regulatory effects on inflammatory state of RA-FLSs and suggest a potential use of Smac127 for the control of inflammation and disease progression in RA.
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, School of Medicine, University of Milan, 20129 Milan, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Lattuada
authors.affiliation: Division of Rheumatology, A.O. Institute of Gaetano Pini, Department of Clinical Sciences & Community Health, University of Milan, 20122 Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Gualtierotti
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, School of Medicine, University of Milan, 20129 Milan, Italy.
authors.forename: K
authors.initials: K
authors.lastname: Crotta
authors.affiliation: Department of Chemistry, University of Milan, 20129 Milan, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Seneci
authors.affiliation: Division of Rheumatology, A.O. Institute of Gaetano Pini, Department of Clinical Sciences & Community Health, University of Milan, 20122 Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Ingegnoli
authors.affiliation: Department of Biomedical, Surgical and Dental Sciences, University of Milan c/o Ist Division of Orthopaedy and Traumatology, A.O. Institute of Gaetano Pini, 20112 Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Corradini
authors.affiliation: Department of Physiatry and Rheumatology, Chief of Centre for Rheumatoid Arthritis, A.O. Institute Gaetano Pini, 20122 Milan, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Viganò
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, School of Medicine, University of Milan, 20129 Milan, Italy.
authors.forename: O
authors.initials: O
authors.lastname: Marelli
authors.affiliation: Department of Medical Biotechnology and Translational Medicine, School of Medicine, University of Milan, 20129 Milan, Italy; NEWRONIKA s.r.l., 20122 Milan, Italy; Fondazione Fernando Santarelli, Systemic Inflammation Lab, 20122 Milan, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Casnici
mesh_terms: D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D013582:Synovial Fluid / Q000166:cytology; D000070918:Synoviocytes / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; C508609:IL10 protein, human; D016753:Interleukin-10