Uric acid is a danger signal of increasing risk for osteoarthritis through inflammasome activation

Abstract

Uric acid (UA) is known to activate the NLRP3 (Nacht, leucine-rich repeat and pyrin domain containing protein 3) inflammasome. When activated, the NLRP3 (also known as NALP3) inflammasome leads to the production of IL-18 and IL-1β. In this cohort of subjects with knee osteoarthritis (OA), synovial fluid uric acid was strongly correlated with synovial fluid IL-18 and IL-1β. Synovial fluid uric acid and IL-18 were strongly and positively associated with OA severity as measured by both radiograph and bone scintigraphy, and synovial fluid IL-1β was associated with OA severity but only by radiograph. Furthermore, synovial fluid IL-18 was associated with a 3-y change in OA severity, on the basis of the radiograph. We conclude that synovial fluid uric acid is a marker of knee OA severity. The correlation of synovial fluid uric acid with the two cytokines (IL-18 and IL-1β) known to be produced by uric acid-activated inflammasomes and the association of synovial fluid IL-18 with OA progression, lend strong support to the potential involvement of the innate immune system in OA pathology and OA progression.

Fig. 1.

Blood and synovial fluid uric acid concentrations for paired samples. Mean serum (n = 69) uric acid concentrations were significantly higher than their paired synovial fluid uric acid concentrations for left (n = 67) and right (n = 65) knees (P < 0.0001). Mean synovial fluid uric acid concentrations from left and right knees were not significantly different (P = 0.22) (paired t test). Error bars represent the SD. The numeric values depicted on the bars are mean ± SD (concentration range).

Fig. 2.

Synovial fluid uric acid and cytokine correlations. (A) Bland-Altman analysis showed a significant association of increased uric acid gradient between the blood and synovial fluid with increasing serum uric acid concentration (R² = 0.20, P < 0.0001). (B–D) Strong correlations were found between synovial fluid uric acid, IL-18, and IL1β. Linear regression was used to provide unadjusted r² and general estimating equations (GEEs), with adjustments for age, sex, BMI, and chondrocalcinosis, were used for P values with the following results: (B) IL-18 and UA (r² = 0.41, P < 0.0001); (C) IL-1β and UA (r² = 0.34, P < 0.0001); and (D) IL-18 and IL-1β (r² = 0.69, P < 0.0001).

Fig. 3.

Schematic depicting the interaction of OA and uric acid. According to this model, osteoarthritis leads to the release of nucleating agents for urate crystallization. The development of osteoarthritis also leads to increased cell death and the release of uric acid. Taken together with uric acid diffused into the joint fluid from the blood, these factors could contribute to constitutive subacute inflammation and progression of osteoarthritic joints via inflammasome activation.