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Abstract Number: 1451

Glutamine Metabolism Plays a Crucial Role in the Pathogenesis of Rheumatoid Arthritis

Soshi Takahashi1, Jun Saegusa2, Ikuko Naka3, Kosaku Tsuda3, Takaichi Okano4, Kengo Akashi3, Sho Sendo2, Yo Ueda3, Akira Onishi5, Yoshinori Kogata2 and Akio Morinobu2, 1Department of Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan, 2Rheumatology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan, 3Kobe University Graduate School of Medicine, Kobe, Japan, 4Rheumatology and Clinical immunology, Kobe University Graduate School of Medicine, Kobe, Japan, 5Rheumaology and Clinical Immunology, Kobe University Graduate School of Medicine, Kobe, Japan

Meeting: 2016 ACR/ARHP Annual Meeting

Date of first publication: September 28, 2016

Keywords: Animal models, glutamate, metabolomics, pathogenesis and rheumatoid arthritis, rheumatoid arthritis, synovium

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Session Information

Date: Monday, November 14, 2016

Session Title: Rheumatoid Arthritis – Animal Models - Poster II

Session Type: ACR Poster Session B

Session Time: 9:00AM-11:00AM

Background/Purpose: Many signaling pathways activated under inflammatory and hypoxic conditions have profound effects on intracellular metabolism to support cell growth and survival. Cancer cells consume glucose and glutamine at a high rate compared to normal cells. Recent studies have identified cancer-specific metabolic changes that provide new therapeutic targets. The microenvironment in inflamed joints in RA is also characterized by hypoxia and low concentration of nutrients, and fibroblast-like synoviocytes from RA patients (RA-FLS) is known to have several tumor-like characteristics. However, little is known about how glucose or glutamine metabolism are involved in the aberrant proliferation of RA-FLS. We aimed to evaluate the role of these metabolisms in RA-FLS, and discover a metabolic characteristics of RA-FLS.

Methods: The expression of glycolysis- or glutaminolysis-related enzymes was evaluated by real-time PCR and Western blotting. The intracellular metabolites in FLS were analyzed by gas chromatography mass spectrometry (GC/MS) and capillary electrophoresis (CE)-MS. We used glucose- or glutamine-free medium for investigating the effects of glucose or glutamine on cell growth of RA-FLS. siRNA or compound 968 was used to inhibit glutaminase 1 (GLS1). Arthritis was induced in SKG mice by zymosan A injection. SKG mice were treated with compound 968 three days per week. Ki-67-positive cells were analyzed by immunohistochemistry.

Results: GLS1 expression was increased in RA-FLS and metabolome analyses suggested that glutamine metabolism was upregulated in RA-FLS. Cell proliferation of RA-FLS was significantly decreased under the glutamine-derived condition, but not under glucose-derived condition. Cell proliferation of RA-FLS was significantly suppressed by GLS1 inhibition. The levels of GLS1 mRNA was increased by treatment with IL-17 or PDGF in RA-FLS. Administration of GLS1 inhibitor, compound 968, ameliorated autoimmune arthritis in SKG mice. Histologic score of arthritis in compound 968-treated mice were significantly lower than those in control mice. Furthermore, immunohistochemical analysis revealed that compound 968 treatment significantly downregulated the Ki-67-positive synovial cells. The number of Th17 cells and Treg cells in spleens from compound 968-treated and control mice were not changed by compound 968 treatment.

Conclusion: Glutamine metabolism was involved in the pathogenesis of RA. Glutamine deprivation or inhibition of GLS1 inhibited cell proliferation of RA-FLS. Administration of GLS1 inhibitor ameliorated the inflammatory arthritis in SKG mice by suppressing the proliferation of RA-FLS. GLS1 inhibition directly affected the cell cycle progression of RA-FLS and suppresses the aberrant cell proliferation. GLS1 may play an important role in regulating RA-FLS proliferation, and could be a novel therapeutic target in RA. ACR 2016 arthritis score.jpg


Disclosure: S. Takahashi, None; J. Saegusa, None; I. Naka, None; K. Tsuda, None; T. Okano, None; K. Akashi, None; S. Sendo, None; Y. Ueda, None; A. Onishi, None; Y. Kogata, None; A. Morinobu, None.

To cite this abstract in AMA style:

Takahashi S, Saegusa J, Naka I, Tsuda K, Okano T, Akashi K, Sendo S, Ueda Y, Onishi A, Kogata Y, Morinobu A. Glutamine Metabolism Plays a Crucial Role in the Pathogenesis of Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2016; 68 (suppl 10). https://acrabstracts.org/abstract/glutamine-metabolism-plays-a-crucial-role-in-the-pathogenesis-of-rheumatoid-arthritis/. Accessed January 21, 2021.
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