In total, 40 patients with long-standing RA fulfilling the American College of Rheumatology revised criteria for RA (24) were included in this study. The RA group comprised of 32 females and 8 males with a mean age of 67.8 years ±10.5 years and 66.9 years ±8.2 years, respectively. C-reactive protein was 47.9 mg/dl ± 186.3 mg/dL for females and 28.7 mg/dL ± 43.2 mg/dL for males and rheumatoid factor was 184.4 iU/mL ± 280.4 iU/mL for females and 31.8 iU/mL ± 37.6 iU/mL for males. IN all, 11 out of 40 patients received glucocorticoids, 7 out of 40 methotrexate, 3 out of 40 biologicals, and 1 out of 40 a JAK inhibitor. All patients underwent elective knee joint replacement surgery, and they were informed about the purpose of the study and gave written consent. Samples from RA synovial tissue were isolated and prepared as described previously22 (for details see also Supplementary methods). G8080) according to manufacturer’s instructions. P6866) for 60 min at 37 °C followed by 30 min at room temperature.

P3584) and respective antagonists/ligands/inhibitors were added for 30 min at room temperature. PoPo3 uptake were evaluated with a TECAN multimode reader over 90 min. RASF were trypsinized, washed and fixed for 20 min with 3.7% formaldehyde (F8775, Sigma Aldrich). Cells were permeabilized with 0.1% Triton X-100 (X100, Sigma) in PBS for 10 min. Then, 0.2 µg/50 µl primary antibody (Proteintech, 19124-1-AP) was added for 2 h. The secondary antibody (Abcam, goat anti-rabbit IgG H&L (Alexa Fluor® 488), ab150077) was incubated for 1 h. Cells were analyzed using a MACS Quant 9 analyzer (Miltenyi Biotec, Bergisch Gladbach, Germany). Statistical analysis was performed with SPSS 25 (IBM, Armonk, USA). The statistic tests used are given in the figure legends. Normal distribution was determined using the Shapiro-Wilk test, equal variance was determined by Levene’s test. In the case of equal variance, the Bonferroni post-hoc test was used, otherwise the Dunnet’s post-hoc test was employed. When data are presented as box plots, the boxes represent the 25th to 75th percentiles, the lines within the boxes represent the median, and the lines outside the boxes represent the 10th and 90th percentiles. When data are presented as line plots, Daily CBD support the line represents the mean. When data are presented as bar charts, the top of the bar represents the mean and error bars depict the standard error of the mean (sem).

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