title: Interleukin-6 and chondrocyte mineralisation act in tandem to promote experimental osteoarthritis.
abstract: Basic calcium phosphate (BCP) crystal and interleukin 6 (IL-6) have been implicated in osteoarthritis (OA). We hypothesise that these two factors may be linked in a reciprocal amplification loop which leads to OA.
  
  
  
  Primary murine chondrocytes and human cartilage explants were incubated with hydroxyapatite (HA) crystals, a form of BCP, and the modulation of cytokines and matrix-degrading enzymes assayed. The ability of IL-6 to stimulate chondrocyte calcification was assessed in vitro. The mechanisms underlying the effects of HA on chondrocytes were investigated using chemical inhibitors, and the pathways mediating IL-6-induced calcification characterised by quantifying the expression of genes involved in chondrocyte mineralisation. The role of calcification in vivo was studied in the meniscectomy model of murine OA (MNX), and the link between IL-6 and cartilage degradation investigated by histology.
  
  
  
  In chondrocytes, BCP crystals stimulated IL-6 secretion, further amplified in an autocrine loop, through signalling pathways involving Syk and PI3 kinases, Jak2 and Stat3 molecules. Exogenous IL-6 promoted calcium-containing crystal formation and upregulation of genes involved in calcification: the pyrophosphate channel Ank, the calcium channel Annexin5 and the sodium/phosphate cotransporter Pit-1. Treatment of chondrocytes with IL-6 inhibitors significantly inhibited IL-6-induced crystal formation. In meniscectomised mice, increasing deposits of BCP crystals were observed around the joint and correlated with cartilage degradation and IL-6 expression. Finally, BCP crystals induced proteoglycan loss and IL-6 expression in human cartilage explants, which were reduced by an IL-6 inhibitor.
  
  
  
  BCP crystals and IL-6 form a positive feedback loop leading to OA. Targeting calcium-containing crystal formation and/or IL-6 are promising therapeutic strategies in OA.
authors.affiliation: Service of Rheumatology, Department of Musculoskeletal Medicine, CHUV and University of Lausanne, Lausanne, Switzerland.
authors.forename: Sonia
authors.initials: S
authors.lastname: Nasi
authors.affiliation: Service of Rheumatology, Department of Musculoskeletal Medicine, CHUV and University of Lausanne, Lausanne, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: So
authors.affiliation: CIRIMAT, UMR 5085 INPT-UPS-CNRS, Université de Toulouse, ENSIACET, Toulouse, France.
authors.forename: Christèle
authors.initials: C
authors.lastname: Combes
authors.affiliation: AP-HP, service d'Explorations Fonctionnelles, hôpital Tenon, Paris, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Daudon
authors.affiliation: Service of Rheumatology, Department of Musculoskeletal Medicine, CHUV and University of Lausanne, Lausanne, Switzerland.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Busso
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology*; D002113:Calcification, Physiologic; D015220:Calcium Channels / Q000378:metabolism; D002130:Calcium Phosphates / Q000378:metabolism; D019902:Chondrocytes / Q000473:pathology*; D004195:Disease Models, Animal; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D010003:Osteoarthritis / Q000378:metabolism / Q000473:pathology*
chemical_list: D015220:Calcium Channels; D002130:Calcium Phosphates; D015850:Interleukin-6; C020243:calcium phosphate
keywords: Chondrocytes; Cytokines; Osteoarthritis