title: Hydrogen sulphide decreases IL-1β-induced activation of fibroblast-like synoviocytes from patients with osteoarthritis.
abstract: Balneotherapy employing sulphurous thermal water is still applied to patients suffering from diseases of musculoskeletal system like osteoarthritis (OA) but evidence for its clinical effectiveness is scarce. Since the gasotransmitter hydrogen sulphide (H2 S) seems to affect cells involved in degenerative joint diseases, it was the objective of this study to investigate the effects of exogenous H2 S on fibroblast-like synoviocytes (FLS), which are key players in OA pathogenesis being capable of producing pro-inflammatory cytokines and matrix degrading enzymes. To address this issue primary FLS derived from OA patients were stimulated with IL-1β and treated with the H2 S donor NaHS. Cellular responses were analysed by ELISA, quantitative real-time PCR, phospho-MAPkinase array and Western blotting. Treatment-induced effects on cellular structure and synovial architecture were investigated in three-dimensional extracellular matrix micromasses. NaHS treatment reduced both spontaneous and IL-1β-induced secretion of IL-6, IL-8 and RANTES in different experimental settings. In addition, NaHS treatment reduced the expression of matrix metallo-proteinases MMP-2 and MMP-14. IL-1β induced the phosphorylation of several MAPkinases. NaHS treatment partially reduced IL-1β-induced activation of several MAPK whereas it increased phosphorylation of pro-survival factor Akt1/2. When cultured in spherical micromasses, FLS intentionally established a synovial lining layer-like structure; stimulation with IL-1β altered the architecture of micromasses leading to hyperplasia of the lining layer which was completely inhibited by concomitant exposure to NaHS. These data suggest that H2 S partially antagonizes IL-1β stimulation via selective manipulation of the MAPkinase and the PI3K/Akt pathways which may encourage development of novel drugs for treatment of OA.
authors.affiliation: Division of Rheumatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria; Ludwig Boltzmann Cluster for Rheumatology, Balneology and Rehabilitation, Institute for Rheumatology and Balneology, Vienna-Oberlaa, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Sieghart
authors.forename: Melissa
authors.initials: M
authors.lastname: Liszt
authors.forename: Axel
authors.initials: A
authors.lastname: Wanivenhaus
authors.forename: Hans
authors.initials: H
authors.lastname: Bröll
authors.forename: Hans
authors.initials: H
authors.lastname: Kiener
authors.forename: Burkhard
authors.initials: B
authors.lastname: Klösch
authors.forename: Günter
authors.initials: G
authors.lastname: Steiner
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D006862:Hydrogen Sulfide / Q000494:pharmacology*; D053583:Interleukin-1beta / Q000494:pharmacology*; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010003:Osteoarthritis / Q000201:enzymology / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology; D013583:Synovial Membrane / Q000473:pathology*
chemical_list: C483024:CCL5 protein, human; D018946:Chemokine CCL5; D053583:Interleukin-1beta; D015850:Interleukin-6; D016209:Interleukin-8; D013440:Sulfides; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D020778:Matrix Metalloproteinase 2; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; C025451:sodium bisulfide; D006862:Hydrogen Sulfide
keywords: fibroblast-like synoviocytes; hydrogen sulphide; inflammation; signal transduction