title: Stress-induced cartilage degradation does not depend on the NLRP3 inflammasome in human osteoarthritis and mouse models.
abstract: OBJECTIVE
  The main feature of osteoarthritis (OA) is degradation and loss of articular cartilage. Interleukin-1β (IL-1β) is thought to have a prominent role in shifting the metabolic balance toward degradation. IL-1β is first synthesized as an inactive precursor that is cleaved to the secreted active form mainly in the "inflammasome," a complex of initiators (including NLRP3), adaptor molecule ASC, and caspase 1. The aim of this study was to clarify the roles of IL-1β and the inflammasome in cartilage breakdown.
  
  
  METHODS
  We assessed IL-1β release by cartilage explants from 18 patients with OA. We also evaluated the lipopolysaccharide (LPS)-, IL-1α-, and tumor necrosis factor α (TNFα)-induced activity of matrix metalloproteinase 3 (MMP-3), MMP-9, and MMP-13 in NLRP3-knockout mice and wild-type mice and the inhibition of caspase 1 with Z-YVAD-FMK and the blockade of IL-1β with IL-1 receptor antagonist (IL-1Ra). Cartilage explants from NLRP3-knockout mice and IL-1R type I (IL-1RI)-knockout mice were subjected to excessive dynamic compression (0.5 Hz, 1 MPa) to trigger degradation, followed by assessment of load-induced glycosaminoglycan (GAG) release and MMP enzymatic activity.
  
  
  RESULTS
  Despite the expression of NLRP3, ASC, and caspase 1, OA cartilage was not able to produce active IL-1β. LPS, IL-1α, and TNFα dose-dependently increased MMP-3, MMP-9, and MMP-13 activity in cultured chondrocytes and in NLRP3(-/-)  chondrocytes, and this effect was not changed by inhibiting caspase 1 or IL-1β. The load-induced increase in GAG release and MMP activity was not affected by knockout of NLRP3 or IL-1RI in cartilage explants.
  
  
  CONCLUSIONS
  OA cartilage may be degraded independently of any inflammasome activity, which may explain, at least in part, the lack of effect of IL-1β inhibitors observed in previous trials.
authors.affiliation: University Pierre and Marie Curie Paris VI, Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Bougault
authors.forename: Marjolaine
authors.initials: M
authors.lastname: Gosset
authors.forename: Xavier
authors.initials: X
authors.lastname: Houard
authors.forename: Colette
authors.initials: C
authors.lastname: Salvat
authors.forename: Lars
authors.initials: L
authors.lastname: Godmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Pap
authors.forename: Claire
authors.initials: C
authors.lastname: Jacques
authors.forename: Francis
authors.initials: F
authors.lastname: Berenbaum
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002358:Cartilage, Articular / Q000503:physiopathology*; D020170:Caspase 1 / Q000378:metabolism; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D006801:Humans; D058847:Inflammasomes / Q000502:physiology*; D053583:Interleukin-1beta / Q000502:physiology; D008070:Lipopolysaccharides / Q000494:pharmacology; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020370:Osteoarthritis, Knee / Q000378:metabolism / Q000503:physiopathology*; D013314:Stress, Mechanical; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D020170:Caspase 1; D020782:Matrix Metalloproteinases