Abstract
Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that mostly affects the synovial joints. It is characterised by chronic inflammation that causes painful swelling and may ultimately lead to tissue damage and pannus development. While many patients can stop the progression of joint degeneration and synovial inflammation with current treatments, relapse prevention usually requires ongoing care. Autoantibodies, such as rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA), can be seen in the peripheral blood of RA patients years before the disease’s clinical manifestations, allowing the identification of individuals who are susceptible of developing RA (RA-risk individuals). These circulating autoantibodies are a sign of systemic autoimmunity, which occurs before inflammation of the synovial tissue. Understanding the early stages of RA, prior to the onset of clinical symptoms and arthritis, may help identify new drug targets and speed the creation of treatments meant to fight off the illness. The study found that synovium from individuals who later developed RA had fewer lipid droplets and showed reduced expression of genes related to fatty acid and lipid metabolism. As overt synovial inflammation is absent in these RA-risk individuals, resident synovial tissue cells are likely contributing to the observed altered synovial gene signature.
Materials and methods
This study compared the metabolic profile of FLS isolated from synovial biopsies from individuals with arthralgia who were autoantibody positive but without any evidence of arthritis (RA-risk individuals, n = 6) with FLS from patients with RA (n = 6), osteoarthritis (OA, n = 6) and seronegative controls (n = 6). After synovial digestion, FLS were cultured in vitro and cellular metabolism was assessed using quantitative PCR, flow cytometry, XFe96 Seahorse Analyzer and tritium-labelled oleate oxidation assays.
Results
Real-time metabolic profiling revealed that basal (p < 0.0001) and maximum mitochondrial respiration (p = 0.0024) were significantly lower in RA FLS compared with control FLS. In all donors, basal respiration was largely dependent on fatty acid oxidation while glucose was only highly used by FLS from RA patients. Moreover, we showed that RA-risk and RA FLS are less metabolically flexible. Strikingly, mitochondrial fatty acid β-oxidation was significantly impaired in RA-risk (p = 0.001) and RA FLS (p < 0.0001) compared with control FLS.
Conclusion
Overall, this study showed several metabolic alterations in FLS even in absence of synovial inflammation, suggesting that these alterations already start before clinical manifestation of disease and may drive disease pathogenesis.
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