Background/Purpose: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease characterized by synovial inflammation and hyperplasia. Fibroblast-like synoviocytes (FLS) in RA exhibit a tumor cell-like aggressive phenotype and have a major role in the initiation and perpetuation of joint inflammation. The metabolomic approach enables the elucidation of the current physiological or pathological states of individual cells that result from the interactions between genes and the environment. A systematic characterization of the metabolic pathways in transformed RA FLS is currently lacking. Thus, gas chromatography/time-of-flight-mass spectrometry (GC/TOF-MS) was employed to identify the characteristic metabolic profiling of RA FLS compared to that of osteoarthritis (OA) FLS.

Methods: Metabolite profiling of RA FLS and OA FLS (N = 6, respectively) was performed using GC/TOF-MS in conjunction with univariate and multivariate statistical analyses. We performed metabolite set enrichment analysis (MSEA) to establish which pathways are affected.

Results: A total of 129 metabolites were identified and were classified into sugars and sugar alcohols (20.9% of identified metabolites), amino acids (20.2%), organic acids (19.4%), fatty acids (15.5%), amines (10.9%), phosphates (7.0%), and miscellaneous compounds (6.2%). A principal component analysis based on cellular metabolites showed very clear discrimination between the intracellular metabolite profiles of the two groups (R²X = 53.9% and Q² = 59.5%). The levels of 35 metabolites that belonged to the amines, fatty acids, phosphates, and organic acids class were significantly increased in RA FLS compared to those in OA FLS. Also, the levels of 26 metabolites that belonged to the amino acids, sugars, and sugar alcohols class were significantly decreased in RA FLS compared to those in OA FLS. MSEA demonstrated that the sugar metabolic pathways such as glycolysis, galactose metabolism, gluconeogenesis, and the pentose phosphate pathway; the amino acid metabolism pathways such as tyrosine, phenylalanine, and catecholamine biosynthesis; protein biosynthesis, and the urea cycle were severely disturbed in RA FLS compared to OA FLS.

Conclusion: Our metabolic results suggested that the alteration of sugar metabolism, lipolysis, and amino acid metabolism in RA FLS is related to synovial hyperplasia and inflammation. This is the first metabolomic study to determine metabolic changes characteristic of RA FLS, which will provide valuable information to gain in-depth insights into the pathogenesis of RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gas-chromatographytime-of-flight-mass-spectrometry-based-metabolomic-profiling-in-cultured-fibroblast-like-synoviocytes-from-rheumatoid-arthritis/