Background Obesity is a known risk factor for arthritic diseases, especially osteoarthritis (OA). Several observations indicate that this relation is not only due to mechanical stress. Free fatty acid (FFA) levels are increased in obese compared to non-obese individuals and chronically elevated FFA levels have been linked to inflammatory cardiovascular and metabolic diseases.
Objectives We therefore hypothesized that FFA play a role in arthritic diseases including rheumatoid arthritis (RA), osteoarthritis and psoriatic arthritis (PsA). To test this hypothesis, we investigated the effect of FFA on key effector cells of arthritis.
Methods RA synovial fibroblasts (SF), OASF, PsASF, human primary chondrocytes, human osteoblasts, human macrovascular (HUVEC) and microvascular (HBdMEC) endothelial cells were stimulated in vitro with different saturated and unsaturated FFA within their physiological range of concentrations. Immunoassays were used to quantify FFA-induced protein secretion. Sulfosuccinimidyl oleate sodium (SSO) was used to inhibit the fatty acid translocase (FAT), which is responsible for transporting long-chain fatty acids into the cell. In addition, TLR4 signaling, which can contribute to driving arthritis, was inhibited intracellularly and extracellularly.
Results In RASF, FFA dose-dependently enhanced the secretion of the proinflammatory cytokine IL-6, the chemokines IL-8 and MCP-1, as well as the matrix-degrading enzymes MMP-1 and MMP-3 (e.g. for lauric acid [100 µM] with RASF / IL-6: 9.1-fold increase; IL-8: 14.9-fold increase; MCP-1: 2.4-fold increase; pro-MMP1: 5.1-fold increase; MMP-3: 83.6-fold increase). The level of the responses varied between SF populations. At equal concentrations, saturated and unsaturated FFA of variable lengths showed similar effects on RASF. Saturated FFA induced strong secretion of IL-6 in chondrocytes (up to 11.6-fold increase), while unsaturated FFA only had a relatively weak effect on this cell type (between 1.2- and 3.9-fold increases). At 100 µM, both saturated and unsaturated FFA significantly increased IL-6 secretion by osteoblasts to a similar degree as for SF. A low concentration of FFA (10 µM) did not have a significant effect on human endothelial cells, whereas a higher concentration of FFA (100 µM) significantly induced IL-6 secretion in HUVEC and HBdMEC. Pre-incubation of RASF with SSO almost completely abrogated the effect of palmitic acid on IL-8 secretion. However, both intracellular and extracellular TLR4 signaling inhibition blocked the palmitic acid-induced IL-6 secretion of RASF.
Conclusions FFA are not only metabolic substrates but can also directly contribute to articular inflammation and degradation in arthritic diseases. Elevated FFA levels in vivo may therefore be another reason why obesity can be an additional risk factor for arthritis. Moreover, our data show that TLR4 signaling is required for FFA-induced gene expression in SF.
Disclosure of Interest None Declared