THU0039 THE RELATION BETWEEN THE INFLAMMATORY STATUS OF HUMAN END STAGE OSTEOARTHRITIC SYNOVIUM AND LEVELS OF LOW DENSITY LIPOPROTEIN

Abstract

Background High systemic levels of low density lipoprotein (LDL) is a shared metabolic risk factor for osteoarthritis (OA) and cardiovascular disease (CVD), which may point to common biochemical pathways. One of the key events in atherosclerosis is formation and uptake of oxidized LDL (oxLDL) as a consequence of macrophage-mediated inflammation. Studies performed in our lab have previously shown that in mice, high LDL levels enhance synovial activation and ectopic bone formation during development of collagenase-induced OA. Furthermore, injection of oxLDL in naive macrophage depleted joints led to infiltration of myeloid progenitor cells. Although these results strongly indicate towards (ox)LDL-mediated events that enhance OA severity, these processes have not yet been shown to occur in human osteoarthritic synovium. Objectives In the present study, we investigated whether the inflammatory status of OA synovium is associated to systemic and local levels of (ox)LDL. Methods Blood was collected from patients planned to undergo total knee replacement and LDL serum levels were determined (n=16). After surgery, synovial explants from the same patients (2-8 per patient) were collected and incubated at 37°C for 24 hours in presence of LDL (50 µg ApoB/mL), oxLDL (50 µg ApoB/mL) or control medium. Levels of IL-1β, TNF-α, IL-10 and MCP-1 secreted in the conditioned medium were measured using Luminex. Levels of S100A8/A9 were measured using ELISA. Concentrations of secreted factors were normalized for tissue sample weight. Synovial explants were further processed for histological analysis. Immunohistochemical staining of ApoB was performed to assess presence and uptake of (ox)LDL in the synovium. Hematoxylin & eosin-stained sections were used to arbitrarily score cellular infiltration and synovial hyperplasia. Results Around 50% of the patients in our cohort showed synovial activation exemplified by high secretion levels of IL-1β, TNF-α and IL-10. Cellular infiltration and synovial hyperplasia was observed in the majority of synovial tissue samples, their grades did however not correlate with cytokine secretion. Secretion levels of IL-1β positively correlated with serum levels of LDL and total cholesterol and did not correlate with BMI, suggesting a link that runs via systemic metabolic processes rather than increased weight-mediated joint loading. Considering that around 50% of OA patients suffers from synovitis characterized by increased macrophage presence and activity, high LDL in these patients may trigger oxLDL formation and uptake in the synovium. Staining of LDL-associated protein ApoB in histological sections of synovia showed distinct speck-like staining within macrophages and endothelial cells especially, suggesting oxLDL accumulation in these cells. Unexpectedly, presence of high concentrations of LDL or oxLDL during incubation of synovial explants did not significantly affect secretion of IL-1β, TNF-α, IL-10 and MCP-1, whereas presence of LDL but not oxLDL negatively affected secretion of S100A8/A9. Conclusion IL-1β secretion by end stage OA synovium is associated to systemic levels of LDL. Intervention with high concentrations of LDL or oxLDL for 24-hours after synovium extraction did however not alter cytokine secretion, suggesting that LDL and synovitis are linked through more long-term local interactions, or alternatively via systemic inflammatory factors. Disclosure of Interests: None declared