Stress-Induced Cartilage Degradation Does Not Depend on the NLRP3 Inflammasome in Human Osteoarthritis and Mouse Models

Objective. The main feature of osteoarthritis (OA) is degradation and loss of articular cartilage. Interleukin-1 beta (IL-1 beta) is thought to have a prominent role in shifting the metabolic balance toward degradation. IL-1 beta 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-1 beta and the inflammasome in cartilage breakdown. Methods. We assessed IL-1 beta release by cartilage explants from 18 patients with OA. We also evaluated the lipopolysaccharide (LPS)-, IL-1 alpha-, and tumor necrosis factor alpha (TNF alpha)-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-1 beta 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-1 beta. LPS, IL-1 alpha, and TNF alpha 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-1 beta. 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-1 beta inhibitors observed in previous trials.