Journal Article Glutaminase 1 plays a key role in the cell growth of fibroblast-like synoviocytes in rheumatoid arthritis

Takahashi, Soshi  ,  Saegusa, Jun  ,  Sendo, Sho  ,  Okano, Takaichi  ,  Akashi, Kengo  ,  Irino, Yasuhiro  ,  Morinobu, Akio

19p.76 , 2017-04-11 , BioMed Central
Background: The recent findings of cancer-specific metabolic changes, including increased glucose and glutamine consumption, have provided new therapeutic targets for consideration. Fibroblast-like synoviocytes (FLS) from rheumatoid arthritis (RA) patients exhibit several tumor cell-like characteristics; however, the role of glucose and glutamine metabolism in the aberrant proliferation of these cells is unclear. Here, we evaluated the role of these metabolic pathways in RA-FLS proliferation and in autoimmune arthritis in SKG mice. Methods: The expression of glycolysis-or glutaminolysis-related enzymes was evaluated by real-time polymerase chain reaction (PCR) and Western blotting, and the intracellular metabolites were evaluated by metabolomic analyses. The effects of glucose or glutamine on RA-FLS cell growth were investigated using glucose-or glutamine-free medium. Glutaminase (GLS)1 small interfering RNA (siRNA) and the GLS1 inhibitor compound 968 were used to inhibit GLS1 in RA-FLS, and compound 968 was used to study the effect of GLS1 inhibition in zymosan A-injected SKG mice. Results: GLS1 expression was increased in RA-FLS, and metabolomic analyses revealed that glutamine metabolism was increased in RA-FLS. RA-FLS proliferation was reduced under glutamine-deprived, but not glucose-deprived, conditions. Cell growth of RA-FLS was inhibited by GLS1 siRNA transfection or GLS1 inhibitor treatment. Treating RA-FLS with either interleukin-17 or platelet-derived growth factor resulted in increased GLS1 levels. Compound 968 ameliorated the autoimmune arthritis and decreased the number of Ki-67-positive synovial cells in SKG mice. Conclusions: Our results suggested that glutamine metabolism is involved in the pathogenesis of RA and that GLS1 plays an important role in regulating RA-FLS proliferation, and may be a novel therapeutic target for RA.

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