title: Osteoarthritis-associated basic calcium phosphate crystals induce pro-inflammatory cytokines and damage-associated molecules via activation of Syk and PI3 kinase.
abstract: The pro-inflammatory cytokines, TNFα, IL-1 and IL-18, amplify cartilage destruction associated with osteoarthritis (OA). Current data suggest that basic calcium phosphate (BCP) crystals are potent drivers of inflammatory mediator and matrix metalloprotease expression in the OA joint. It has previously been demonstrated that synovial macrophages play a role in initiating and driving BCP-induced inflammation. However, the molecular mechanisms by which BCP crystals exert their effects remain unclear. Here we demonstrate that exposure of macrophages to BCP crystals leads to activation of Syk and PI3 kinase. Furthermore, we show that production of pro-inflammatory cytokines and phosphorylation of the downstream kinase, ERK, are suppressed following treatment with Syk and PI3 kinase inhibitors. Finally, we demonstrate that treatment of macrophages with BCP crystals induces the production of the damage-associated molecule, S100A8, in a Syk dependent manner. We therefore identify Syk and PI3 kinase as potential novel targets for the treatment of BCP-related pathologies.
authors.affiliation: Immunology Research Centre, School of Biochemistry and Immunology, Trinity College Dublin, Ireland.
authors.forename: Clare C
authors.initials: CC
authors.lastname: Cunningham
authors.forename: Evanna
authors.initials: E
authors.lastname: Mills
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Mielke
authors.forename: Laura K
authors.initials: LK
authors.lastname: O'Farrell
authors.forename: Ed
authors.initials: E
authors.lastname: Lavelle
authors.forename: Andrés
authors.initials: A
authors.lastname: Mori
authors.forename: Geraldine M
authors.initials: GM
authors.lastname: McCarthy
authors.forename: Kingston H G
authors.initials: KH
authors.lastname: Mills
authors.forename: Aisling
authors.initials: A
authors.lastname: Dunne
mesh_terms: D000818:Animals; D002130:Calcium Phosphates / Q000009:adverse effects*; D040501:Calgranulin A / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D020382:Interleukin-18 / Q000378:metabolism; D053582:Interleukin-1alpha / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007596:Joints / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010003:Osteoarthritis / Q000201:enzymology / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D000072377:Syk Kinase
chemical_list: D002130:Calcium Phosphates; D040501:Calgranulin A; D020382:Interleukin-18; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; C086145:S100a8 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases