Background/Purpose: The causes of inflammation, pain fluctuations, and disease progression in osteoarthritis (OA) are not well understood. Soluble urate is a “danger signal”, and synovial fluid urate and IL-18, which along with IL-1β is a product of NLRP3 inflammasome activation, are associated with OA severity on imaging (PMID: 21245324) . In a pilot study, we evaluated differences in proteomic profiles of OA synovial fluid stratified by serum urate among people with OA but without gout to examine potential distinct OA phenotypes. We further explored whether the profiles differed by obesity or age as potential confounders in the association between urate and OA.

Methods: We obtained synovial fluid from individuals with knee OA but without a diagnosis of gout (and on no urate-lowering therapy) who had knee aspirations performed as part of standard clinical care (no crystals detected), and who consented to having their synovial fluid used for this pilot research study. The synovial fluid was immediately stored at 4oC, processed within 4 hours of collection, and then stored at -80oC. The samples were prepared with hyaluronidase and analyzed using the 11k SomaScan v5.0 proteomics assay that measures 10,778 proteins. Differentially expressed proteins were identified by t-tests and further evaluated using XLSTAT statistical software. Systems biology analysis used Ingenuity Pathway analysis (IPA) and STRING to define enriched pathophysiological pathways.

Results: We enrolled 30 participants (mean age 67 ± 11.6, 77% female, mean BMI 32.3 ± 6.9), of whom 47% (n=14) had serum urate >6 mg/dL (Elevated Urate Group (EUG). SomaScan analysis identified 186 proteins associated with the EUG that had an absolute fold change of at least 1.3 and p< 0.05. The top 30 proteins accurately discriminated between EUG and lower urate (Fig.1). IPA (Fig.2a) revealed enrichment of inflammatory response, particularly enhanced activity of the myeloid lineage and phagocytosis as key pathophysiological pathways in the EUG. Upstream regulator analysis confirmed that the predicted regulators with highest statistical significance involved enhanced activity of pro-inflammatory cytokines such as IL-1β and TNF and their downstream signaling mediators such as STAT3 and NFKB1. STRING analysis (Fig.2b) defined clusters of interacting proteins linked to inflammation, acute phase response, complement activation, and mRNA processing as key pathways. BMI-and age-associated protein signatures showed only limited overlap with the hyperuricemia-associated protein signature (Fig.3).

Conclusion: The synovial fluid proteome associated with higher urate in patients with OA included differential upregulation of pathways related to inflammation, phagocytosis, and the complement cascade compared with those whose serum urate was lower than 6.0 mg/dL. Furthermore, the protein signature associated with the EUG had minimal overlap with synovial fluid protein signatures associated with obesity or older age. Elevated urate, a biomarker of OA disease severity, may therefore contribute to an inflammatory profile in OA synovial fluid.

Figure 1: Hierarchical Clustering of the Top 30 proteins* that had an absolute fold-change of ≥1.3 and p < 0.05 in differentiating the elevated urate group (>6mg/dL) from lower urate group

Figure 2a: Upstream Regulators identified with Ingenuity Pathways Analysis (IPA) from among the top 30 proteins that had an absolute fold-change of ≥1.3 and p < 0.05 in differentiating the elevated urate group (>6mg/dL) from lower urate group based upon gene expression data. Proteins are listed in ascending order of statistical significance

Figure 2b: Clusters of Protein-Protein Interaction Networks identified with STRING Analysis from among the top 30 proteins that had an absolute fold-change of ≥1.3 and p < 0.05 in differentiating the elevated urate group (>6mg/dL) from lower urate group based upon protein expression data.

Figure 3: Venn Diagram comparing differentially expressed proteins identified with p < 0.05 in the EUG vs. lower urate group, with differentially expressed proteins based upon obesity (BMI>30 vs. not) or Age (>65 vs. younger), demonstrating minimal overlap.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/stratification-for-elevated-urate-identifies-a-pro-inflammatory-synovial-fluid-proteome-in-knee-osteoarthritis-a-pilot-study/