Background/Purpose:  Although obesity, a known risk factor for arthritic diseases, increases mechanical stress on joints, it appears not to be the only factor being responsible for joint damage. Free fatty acid (FFA) levels, which are increased in obese compared to non-obese individuals, may therefore also play a role in different forms of arthritis. In this respect, continuously elevated FFA levels have already been linked to inflammatory cardiovascular and metabolic diseases. To test our hypothesis that FFA play role in arthritic diseases, we investigated the effect of FFA on key effector cells of arthritis.

Methods:  Rheumatoid arthritis (RA) synovial fibroblasts (SF), osteoarthritis (OA) SF, psoriatic arthritis (PsA) SF, human macrovascular (HUVEC) and microvascular (HBdMEC) endothelial cells as well as human primary chondrocytes (HCH) and RA osteoblasts (OB) were stimulated in vitro with different saturated and unsaturated FFA within their physiological range of concentrations. FFA-induced protein secretion was determined by immunoassays. Fatty acid translocase (FAT) was inhibited by   sulfosuccinimidyl oleate sodium (SSO). TLR4 signaling, which can contribute to driving arthritis, was inhibited intracellularly and extracellularly.

Results: 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 in all SF types (e.g. for RASF with lauric acid [100 µM] 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). There was also a high dependency on the cell population. The effects on RASF were not significantly different between saturated and unsaturated FFA of variable lengths as opposed to HCH, in which saturated FFA induced a strong synthesis of IL-6 (up to 11.6-fold increase), while unsaturated FFA only had a weak effect (between 1.2- and 3.9-fold increases). OB increased IL-6 secretion to a similar degree as SF when stimulated with saturated and unsaturated FFA (100 µM). Endothelial cells, HUVEC and HBdMEC, responded only to higher concentrations of FFA (100 µM), lower concentrations of FFA (10 µM) did not induce a significant response in IL-6 secretion. Blocking fatty acid transport into the cell almost completely abrogated the effect of palmitic acid on IL-6 secretion. Both intracellular and extracellular TLR4 signaling inhibition blocked the palmitic acid-induced IL-6 secretion of RASF.

Conclusion:  The data show that FFA not only play a role as high energy source in metabolism but also as contributors to articular inflammation and degradation in arthritis. Therefore, elevated FFA levels (as for example occurring in obesity) may be another element in the multifactorial pathogenesis of arthritic diseases. Additionally, in SF, TLR4 signaling is necessary for FFA-induced gene expression.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pathophysiological-effects-of-free-fatty-acids-on-key-cells-of-arthritis/