title: Intra-articular basic calcium phosphate and monosodium urate crystals inhibit anti-osteoclastogenic cytokine signalling.
abstract: Basic calcium phosphate (BCP) and monosodium urate (MSU) crystals are particulates with potent pro-inflammatory effects, associated with osteoarthritis (OA) and gout, respectively. Bone erosion, due to increased osteoclastogenesis, is a hallmark of both arthropathies and results in severe joint destruction. The aim of this study was to investigate the effect of these endogenous particulates on anti-osteoclastogenic cytokine signalling.
  
  
  
  Human osteoclast precursors (OcP) were treated with BCP and MSU crystals prior to stimulation with Interleukin (IL-6) or Interferon (IFN-γ) and the effect on Signal Transducer and Activator of Transcription (STAT)-3 and STAT-1 activation in addition to Mitogen Activated Protein Kinase (MAPK) activation was examined by immunoblotting. Crystal-induced suppressor of cytokine signalling (SOCS) protein and SH-2 containing tyrosine phosphatase (SHP) expression was assessed by real-time polymerase chain reaction (PCR) in the presence and absence of MAPK inhibitors.
  
  
  
  Pre-treatment with BCP or MSU crystals for 1 h inhibited IL-6-induced STAT-3 activation in human OcP, while pre-treatment for 3 h inhibited IFN-γ-induced STAT-1 activation. Both crystals activated p38 and extracellular signal-regulated (ERK) MAPKs with BCP crystals also activating c-Jun N-terminal kinase (JNK). Inhibition of p38 counteracted the inhibitory effect of BCP and MSU crystals and restored STAT-3 phosphorylation. In contrast, STAT-1 phosphorylation was not restored by MAPK inhibition. Finally, both crystals potently induced the expression of SOCS-3 in a MAPK dependent manner, while BCP crystals also induced expression of SHP-1 and SHP-2.
  
  
  
  This study provides further insight into the pathogenic effects of endogenous particulates in joint arthropathies and demonstrates how they may contribute to bone erosion via the inhibition of anti-osteoclastogenic cytokine signalling. Potential targets to overcome these effects include p38 MAPK, SOCS-3 and SHP phosphatases.
authors.affiliation: School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland; School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland. Electronic address: cunnincc@tcd.ie.
authors.forename: C C
authors.initials: CC
authors.lastname: Cunningham
authors.affiliation: School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland; School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland. Electronic address: emcorr@tcd.ie.
authors.forename: E M
authors.initials: EM
authors.lastname: Corr
authors.affiliation: Mater Misericordiae University Hospital, Dublin 7, Ireland. Electronic address: g.mccarthy@ucd.ie.
authors.forename: G M
authors.initials: GM
authors.lastname: McCarthy
authors.affiliation: School of Biochemistry & Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland; School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Ireland. Electronic address: aidunne@tcd.ie.
authors.forename: A
authors.initials: A
authors.lastname: Dunne
mesh_terms: D002130:Calcium Phosphates; D006801:Humans; D015850:Interleukin-6; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D015398:Signal Transduction; D014527:Uric Acid
chemical_list: D002130:Calcium Phosphates; D015850:Interleukin-6; D014527:Uric Acid; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases
keywords: Crystal deposition disease; Gout; Osteoarthritis; Osteoclasts