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Arthritis Rheum. 2012 Dec;64(12):3972-81. doi: 10.1002/art.34678.

Stress-induced cartilage degradation does not depend on the NLRP3 inflammasome in human osteoarthritis and mouse models.

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University Pierre and Marie Curie Paris VI, Paris, France.



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.

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