Background/Purpose: Cellular metabolism has been studied in fibroblast-like synoviocytes (FLS) of rheumatoid arthritis (RA) and osteoarthritis (OA) patients and raises the question whether observed metabolic alterations appear in response to chronic inflammation or whether primary changes in cellular metabolism might underlie disease pathogenesis. Previously, we showed that genes involved in lipid metabolism are significantly lower expressed in synovial tissue from RA-risk individuals that eventually develop RA. Here we investigated whether metabolic changes in FLS are already observed before onset of RA.

Methods: We included individuals with arthralgia who were IgM rheumatoid factor (RF) and/or anti-citrullinated protein antibody (ACPA) positive but without any evidence of arthritis (RA-risk individuals, n=6), RA patients (n=6), OA patients (n=6) and controls without inflammatory disease (n=6). Synovial tissues were collected during orthopedic surgery or individuals underwent mini-arthroscopic synovial tissue sampling of a knee joint. Subsequently, FLS were cultured after synovial tissue digestion. Cellular metabolism was assessed using qPCR, flow cytometry, the XFe96 Seahorse Analyzer and mitochondrial β-oxidation was measured using tritium-labelled oleate.

Results: Real-time analysis of mitochondrial function revealed that basal respiration is significantly lower in FLS from RA-risk individuals and RA patients compared with FLS from controls. When investigating the three main fuel pathways of cellular respiration (glucose, glutamine and fatty acids), basal respiration from all FLS largely depended on fatty acid oxidation, whereas glucose was only highly used by RA FLS. FLS from controls were flexible to switch to another fuel when the other fuel pathways were inhibited, whereas FLS from RA-risk individuals, RA and OA patients were less flexible. When cellular respiration was challenged to maximum capacity, respiration from RA-risk FLS and RA FLS was significantly lower compared with FLS from controls. This was reflected in all three fuel pathways. Based on these data we were able to define the energy profile of our cells. This showed that FLS from controls are relatively more energetic while FLS from RA-risk individuals and RA patients are more quiescent. In addition, mitochondrial β-oxidation was significantly impaired in RA-risk individuals, RA and OA patients compared with FLS from controls. Flow cytometry showed that mitochondrial reactive oxygen species (ROS) production and mitochondrial mass was increased in RA FLS compared with controls.

Conclusion: In this exploratory study, mitochondrial dysfunction and metabolic alterations are already detected in FLS from RA-risk individuals compared with controls, suggesting that these alterations start before clinical manifestation of disease and contribute to disease pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/altered-metabolic-pathways-in-synovial-fibroblasts-of-individuals-at-risk-of-developing-rheumatoid-arthritis/