Drs. Jacques and Berenbaum contributed equally to this work.
Stress-induced cartilage degradation does not depend on the NLRP3 inflammasome in human osteoarthritis and mouse models
Article first published online: 28 NOV 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 12, pages 3972–3981, December 2012
How to Cite
Bougault, C., Gosset, M., Houard, X., Salvat, C., Godmann, L., Pap, T., Jacques, C. and Berenbaum, F. (2012), Stress-induced cartilage degradation does not depend on the NLRP3 inflammasome in human osteoarthritis and mouse models. Arthritis & Rheumatism, 64: 3972–3981. doi: 10.1002/art.34678
- Issue published online: 28 NOV 2012
- Article first published online: 28 NOV 2012
- Accepted manuscript online: 29 AUG 2012 03:07PM EST
- Manuscript Accepted: 14 AUG 2012
- Manuscript Received: 21 DEC 2011
- Agence Nationale de la Recherche. Grant Number: ANR-06-PHYSIO-020-01
- French Society of Rheumatology
- Fondation pour la Recherche Médicale Postdoctoral Fellowship
- Agence Nationale de la Recherche Postdoctoral Fellowships
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.
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.
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.
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.