PMID- 22933232
OWN - NLM
STAT- MEDLINE
DCOM- 20130402
LR  - 20161125
IS  - 1529-0131 (Electronic)
IS  - 0004-3591 (Linking)
VI  - 64
IP  - 12
DP  - 2012 Dec
TI  - Stress-induced cartilage degradation does not depend on the NLRP3 inflammasome in 
      human osteoarthritis and mouse models.
PG  - 3972-81
LID - 10.1002/art.34678 [doi]
AB  - OBJECTIVE: The main feature of osteoarthritis (OA) is degradation and loss of 
      articular cartilage. Interleukin-1beta (IL-1beta) is thought to have a prominent role 
      in shifting the metabolic balance toward degradation. IL-1beta 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-1beta and 
      the inflammasome in cartilage breakdown. METHODS: We assessed IL-1beta release by 
      cartilage explants from 18 patients with OA. We also evaluated the 
      lipopolysaccharide (LPS)-, IL-1alpha-, and tumor necrosis factor alpha (TNFalpha)-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-1beta 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-1beta. LPS, 
      IL-1alpha, and TNFalpha 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-1beta. The load-induced increase in GAG 
      release and MMP activity was not affected by knockout of NLRP3 or IL-1RI in 
      cartilage explants. CONCLUSION: OA cartilage may be degraded independently of any 
      inflammasome activity, which may explain, at least in part, the lack of effect of 
      IL-1beta inhibitors observed in previous trials.
CI  - Copyright (c) 2012 by the American College of Rheumatology.
FAU - Bougault, Carole
AU  - Bougault C
AD  - University Pierre and Marie Curie Paris VI, Paris, France.
FAU - Gosset, Marjolaine
AU  - Gosset M
FAU - Houard, Xavier
AU  - Houard X
FAU - Salvat, Colette
AU  - Salvat C
FAU - Godmann, Lars
AU  - Godmann L
FAU - Pap, Thomas
AU  - Pap T
FAU - Jacques, Claire
AU  - Jacques C
FAU - Berenbaum, Francis
AU  - Berenbaum F
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Arthritis Rheum
JT  - Arthritis and rheumatism
JID - 0370605
RN  - 0 (Carrier Proteins)
RN  - 0 (Inflammasomes)
RN  - 0 (Interleukin-1beta)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (NLRP3 protein, human)
RN  - 0 (Nlrp3 protein, mouse)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 3.4.22.36 (Caspase 1)
RN  - EC 3.4.24.- (Matrix Metalloproteinases)
SB  - IM
MH  - Animals
MH  - Carrier Proteins/genetics/*physiology
MH  - Cartilage, Articular/*physiopathology
MH  - Caspase 1/metabolism
MH  - Cells, Cultured
MH  - Chondrocytes/drug effects/metabolism/pathology
MH  - Disease Models, Animal
MH  - Humans
MH  - Inflammasomes/*physiology
MH  - Interleukin-1beta/physiology
MH  - Lipopolysaccharides/pharmacology
MH  - Matrix Metalloproteinases/metabolism
MH  - Mice
MH  - Mice, Knockout
MH  - NLR Family, Pyrin Domain-Containing 3 Protein
MH  - Osteoarthritis, Knee/metabolism/*physiopathology
MH  - *Stress, Mechanical
MH  - Tumor Necrosis Factor-alpha/pharmacology
EDAT- 2012/08/31 06:00
MHDA- 2013/04/03 06:00
CRDT- 2012/08/31 06:00
PHST- 2011/12/21 00:00 [received]
PHST- 2012/08/14 00:00 [accepted]
PHST- 2012/08/31 06:00 [entrez]
PHST- 2012/08/31 06:00 [pubmed]
PHST- 2013/04/03 06:00 [medline]
AID - 10.1002/art.34678 [doi]
PST - ppublish
SO  - Arthritis Rheum. 2012 Dec;64(12):3972-81. doi: 10.1002/art.34678.