Background and Objectives In seronegative arthritis high levels of the alarmins S100A8 and S100A9 are measured in serum. These alarmins are released by activated macrophages and can mediate cartilage and bone destruction. Additionally, glucocorticoids have been implicated to stimulate S100A8 and S100A9 synthesis. The aim of this study is to identify serum S100A8/A9 complex as a potential biomarker for joint destruction in seronegative arthritis using IL-1Ra-/- mice as an experimental model and whether serum S100A8/A9 levels are associated with serum corticosterone (CORT) levels.
Materials and methods IL-1Ra-/- mice (n = 25, BALB/c background) were macroscopically scored for swelling in the hind paws, at a scale of 0 to 4, at week 15. Serum was collected and levels of IL-1β, IL-4, IL-6, IL-10, IL-17, IFNγ and TNFα were measured by Luminex technology, S100A8/A9 complex levels by ELISA and CORT levels by RIA. Hind paws were isolated and histologically scored for cell influx, cartilage damage (proteoglycan depletion, chondrocyte death, cartilage matrix erosion) and bone erosion, all at a scale of 0 to 8.
Results Cytokine serum levels were very low (<7 pg/ml), except IL-6 levels (55 ± 32 pg/ml), and no correlation between these levels and macroscopic/microscopic parameters were observed. Serum levels of the S100A8/A9 complex were strongly increased (472 ± 296 ng/ml) compared to WT BALB/c mice (190 ± 55 ng/ml) and correlated significantly with macroscopic score (Pearson r = 0.740, P < 0.0001) and with all microscopic parameters (P < 0.0001, Pearson r > 0.672). When mice were stratified according to serum S100A8/A9 level, the high level group (>500 ng/ml, n = 9) showed a significant increased score for all macroscopic and microscopic parameters when compared to the basal level group (<250 ng/ml, n = 7, P < 0.05) and the medium level group (250-500 ng/ml, n = 9, P < 0.01). Mice with full-blown arthritis (macroscopic score > 2.5) had increased levels of CORT (192 ± 99 ng/ml) compared to non-arthritic mice (392 ± 39 ng/ml, P = 0.007).
Conclusions Serum levels of S100A8/A9 complex and CORT are strongly correlated with joint swelling, synovial inflammation, cartilage damage and bone erosion in the IL-1Ra-/- mice. These findings suggest a role for S100A8/A9 as a potential biomarker for joint destruction in patients with IL1β driven seronegative arthritis and it suggest a role for CORT in the increased S100A8/A9 expression.